EP4731601A1

EP4731601A1 - Lipid nanoparticles comprising coding rna molecules for use in gene editing and as vaccines and therapeutic agents

Info

Publication number: EP4731601A1
Application number: EP24826611.6A
Authority: EP
Inventors: Muthusamy Jayaraman; Ganapathy Subramanian SANKARAN
Original assignee: Renagade Therapeutics Management Inc
Current assignee: Renagade Therapeutics Management Inc
Priority date: 2023-06-21
Filing date: 2024-06-20
Publication date: 2026-04-29
Also published as: CN121752544A; AU2024312860A1; WO2024263729A1

Abstract

The present disclosure describes improved LNP-based RNA vaccines, nucleobase editing systems, and therapeutics for use in treating and/or immunization against disease. In particular, the disclosure describes improved LNPs, including novel and improved ionizable lipids for making LNPs, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and/or circular mRNAs. The improved LNPs protect linear and/or circular mRNA payloads from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines and/or therapeutic agents.

Description

LIPID NANOPARTICLES COMPRISING CODING RNA MOLECULES FOR USE IN GENE EDITING AND AS VACCINES AND THERAPEUTIC AGENTS CROSS REFERENCE [0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Appl. No.63/509,376 filed June 21, 2023, U.S. Provisional Appl. No.63/509,368 filed June 21, 2023, U.S. Provisional Appl. No.63/509,587 filed June 22, 2023, and U.S. Provisional Appl. No.63/509,638 filed June 22, 2023, the contents of each of which are hereby incorporated by reference herein in their entireties. TECHNICAL FIELD [0002] The present disclosure generally relates to the field of nucleic acid lipid nanoparticle (LNP) compositions and delivery thereof for use as vaccines and/or therapeutics for the treatment of disease. The disclosure further relates to compositions comprising LNPs formulated with coding RNAs, including linear and/or circular mRNAs, for the delivery of encoded vaccine antigens and/or therapeutic proteins for the vaccination against infectious agents and/or treatment of disease, including infectious disease and cancer. SEQUENCE LISTING [0003] The instant application contains a Sequence Listing which has been submitted electronically in xml format and is hereby incorporated by reference in its entirety. The xml copy, created on June 19, 2024, is named RNG038-WO1_REG-020WO.xml and is 44,139 bytes in size. BACKGROUND [0004] There are many challenges associated with the delivery of nucleic acids to affect a desired response in a biological system, such as an immune response or the production of a therapeutically beneficial protein to treat a disease. Nucleic acid-based therapeutics and vaccines have enormous potential but there remains a need for more effective delivery of nucleic acids to appropriate sites within a cell or organism in order to realize this potential. [0005] Nucleic acid-based therapeutics and vaccines are generally composed of DNA or RNA. DNA is known to be relatively stable and easy to handle, however, the use of DNA bears the risk of undesired insertion into a cell’s genome which potentially may produce mutagenic events. As a further concern, the delivery of DNA is associated with unwanted immunogenicity and the production of anti-DNA antibodies. Yet another concern in the use of DNA is the limited expression level of the encoded peptide or protein that is achievable due to the requirement that the administered DNA must first enter the nucleus to undergo transcription prior to translation into a desired protein product (e.g., antigen or therapeutic protein). [0006] In contrast to DNA, the use of RNA is substantially safer because RNA does not involve the risk of being integrated into the genome of a transfected cell, thus eliminating the concern that the introduced genetic material will disrupt the normal functioning of an essential gene or cause a mutation. In addition, RNA-based agents do not require extraneous promoter sequences for effective expression of an encoded protein and are also less immunogenic than DNA-based agents, in part because RNA has a relatively short half-life unlike DNA. In addition, while DNA must enter the nuclease to perform its function, RNA performs its function outside of the nucleus and is therefore more efficient. [0007] Despite the advantages of using RNA-based therapeutics and vaccines, the stability of RNA (e.g., mRNA) is far lower than DNA, especially when it reaches the cytoplasm of a cell and is exposed to RNA-degrading enzymes. In addition, the presence of a hydroxyl group on the second carbon of the sugar moiety in RNA causes steric hindrance that prevents the RNA from forming a more stable double helix structure like in the case of DNA, thus making RNA more prone to hydrolytic degradation than DNA. [0008] To circumvent these challenges, delivery of RNA vaccines (e.g., mRNA vaccines) and therapeutics has recently focused on the use of lipid nanoparticles (LNPs). Indeed, LNPs have emerged as the most promising nonviral delivery vehicle for exogenous mRNA (see e.g., Guan et al., “Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems,” Gene Ther, 24 (2017), pp.133-143). The LNP is a complex nanostructured body that provides protection to payload RNA molecules encapsulated within from the harshly degrading nuclease environment in vivo while facilitating intracellular delivery. LNPs are formed through self-assembly by combining the RNA payload with several lipid components, including an ionizable lipid that plays a central role in delivery efficacy (e.g., Miao et al., “Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation,” Nat. Biotechnol., 27 (2019), pp.1174-1185). Entrapment of RNA is achieved by mixing RNA with lipids at an acidic pH at which the ionizable lipid is positively charged, thus ensuring a charge-driven interaction with the negatively charged RNA molecules (e.g., Mindy et al., “Mechanism of macromolecular structure evolution in self-assembled lipid nanoparticles for siRNA delivery," Langmuir, 20 (2014), pp.4613-4622). The pH is then adjusted to above the pKa of the ionizable lipid, which results in a near-neutral surface charge desirable for clinical administration (see Id.). In addition, the incorporation of a pegylated lipid into the mixture achieves a sterically stabilized core shell nanoparticle useful for clinical applications as vaccines and/or therapeutics. [0009] In spite of the development of LNPs, the delivery of RNA payloads to cells in vivo in a targeted manner that also allows for sufficient levels of protein production (e.g., production of vaccine antigens or therapeutic proteins) remains an important and significant challenge. [0010] Genome editing tools encompass a diverse set of technologies that can make many types of genomic alterations in various contexts. These technologies have evolved over the last couple of decades to provide a range of user-programmable editing tools that include ZFN (zinc finger) nuclease editing systems, meganuclease editing systems, and TALENS (transcription activator-like effector nucleases). The past decade has seen an explosive growth in a new generation of genome editing systems based on components from bacterial immune pathways, including CRISPR (clustered regularly interspaced short palindromic repeats) and the associated CRISPR-associated proteins (e.g., CRISPR-Cas9) (Jinek et al., “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity,” Science, Vol.337 (6096), pp.816-821), meganuclease editors (Boissel et al., “megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering,” Nucleic Acids Research 42: pp.2591-2601) and bacterial retron systems (Schubert et al., “High-throughput functional variant screens via in vivo production of single-stranded DNA,” PNAS, April 27, 2021, Vol.118(18), pp.1-10). In particular, CRISPR-Cas9 has been derivatized in numerous ways to expand upon its guide RNA-based programmable double-strand cutting activity to form systems ranging from finding alternative CRISPR Cas nuclease enzymes having different PAM requirements and cutting properties (e.g., engineered Cas9 proteins and other naturally-occurring Cas9 homologs, including, but not limited to, Cas12a, Cas12f, Cas13a, and Cas13b, and their engineered variants) to base editing (Komor et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage,” Nature, May 19, 2016, 533 (7603); pp.420- 424 [cytosine base editors or CBEs] and Gaudelli et al., “Programmable base editing of A-T to G-C in genomic DNA without DNA cleavage,” Nature, Vol.551, pp.464-471 [adenine base editors or ABEs]) to prime editing (Anzalone et al., “Search-and-replace genome editing without double-strand breaks or donor DNA,” Nature, Dec 2019, 576 (7789): pp.149-157) to twin prime editing (Anzalone et al., “Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing,” Nature Biotechnology, Dec 9, 2021, vol.40, pp.731-740) to epigenetic editing (Kungulovski and Jeltsch, “Epigenome Editing: State of the Art, Concepts, and Perspective,” Trends in Genetics, Vol.32, 206, pp.101-113) to CRISPR-directed integrase editing (Yarnell et al., “Drag- and-drop genome insertion of large sequences without double-stranded DNA cleavage using CRISPR- directed integrases,” Nature Biotechnology, Nov 24, 2022, (“PASTE”)). [0011] While the expansion of genome editing tools has exploded, the development of safe and effective gene editing tool delivery systems has lagged behind. There remain numerous challenges associated with the delivery of gene editing tools—including, but not limited to, CRISPR- Cas9 and alternative Cas nuclease editors, retron editors, base editors, prime editors, twin prime editors, epigenetic editors, and integrase editors—to achieve safe and effective therapeutic application of such tools in cells and patients for treating disease and/or otherwise modifying the nucleotide sequence of a target nucleic acid molecule (e.g., a gene or genome) particularly as it relates to delivery in vivo. That said, the use of lipid nanoparticles (LNPs) has emerged as a leading delivery option for the safe, effective, and targeted delivery of gene editing tools to target tissues and cells. However, there remains a need for improved LNPs, including better performing ionizable lipids, that will enhance the targeted delivery of LNP-based gene editing tools. Preferably, such improved LNPs would protect payloads from degradation and clearance while achieving targeted delivery, be suitable for systemic or local delivery, and provide delivery of RNA cargo, including those relating to a wide variety of gene editing tools, such as those mentioned above. In addition, such improved LNP-based therapeutics should exhibit low toxicity and provide an adequate therapeutic index, such that patient treatment at an effective dose of the LNP minimizes risk to the patient while maximizing therapeutic benefit. [0012] Thus, improved LNPs that enhance the delivery of LNP-based RNA vaccines and therapeutics to cells, tissues, and bodily sites and which are more protective of RNA payloads would advance the art. Preferably, such improved LNPs would protect RNA payloads from degradation and clearance while achieving delivery, be suitable for ex vivo or in vivo delivery , and provide delivery of any target, including RNA in linear and/or circular and/or modified form.. In addition, such improved LNP-based RNA vaccines and therapeutics should exhibit low toxicity and provide an adequate therapeutic index, such that patient treatment at an effective dose of the LNP minimizes risk to the patient while maximizes therapeutic benefit. The present disclosure provides these and related advantages. SUMMARY [0013] Described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA medicines (e.g., vaccines and gene-editing therapeutics). In particular, described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA medicines (e.g., vaccines and gene editing therapeutics) for the delivery of one or more coding and/or non-coding RNA molecules. In various embodiments, the non- coding RNAs may comprise one or more guide RNAs relating to a gene editing system, such as one based on CRISPR-Cas9 or CRISPR-Cas12a, each of which require complexing with a guide RNA that facilitates the localizing the protein-RNA complex to a target sequence having an enzyme- specific PAM site (protospacer adjacent motif – recognized by the CRISPR enzyme) and a target nucleotide sequence (i.e., the protospacer) that is complementary to a portion of the guide RNA (i.e., to the spacer region). In other embodiments, the coding RNA may encode any protein component of LNP-based RNA medicine, such as, but limited to a virus antigen (e.g., a viral envelope spike protein), a therapeutic protein (e.g., a functional version of a defective protein), or one or more gene editing components (e.g., a programmable nuclease or other effector protein, such as a deaminase or reverse transcriptase). Further described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA medicines (e.g., vaccines and/or gene editing therapeutics) for the delivery of one or more RNA molecules, e.g., a coding RNA that codes for one or more therapeutic proteins for the prophylactic and/or therapeutic treatment of one or more diseases or a symptom thereof, or a non-coding RNA, such as, but not limited to a guide RNA for a gene editing system. In various embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a linear mRNA. In other embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a circular mRNA. In still other embodiments, the RNA molecule delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and/or structural modification (e.g., secondary-folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). In various other embodiments, the disclosure provides novel lipid components of the herein disclosed LNPs, including, but not limited to, novel ionizable lipids. [0014] The present disclosure describes improved LNP-based RNA medicines (e.g., vaccines and therapeutics) for use in treating and/or immunization against disease. In particular, the disclosure describes improved LNPs, including better performing ionizable lipids, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and/or circular mRNAs. The improved LNPs protect linear and/or circular mRNA cargos (i.e., the circular and/or linear mRNA molecules encapsulated by the LNPs) from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines and/or therapeutic agents. [0015] In an aspect of the disclosure, provided herein is a compound having a structure of any of Formulae (CT), (CT-A), (CT-A1), (CT-A2), (CT-B), (CT-B’), (CT-C), (CT-D), (CT-D’), (CT- E), (CT-E’), (CT-E’’), (CT-F), (CT-F’), (CT-F’’), (CT-F’’’), (CT-F’’’’), (CT-F’’’’’), (CT-G), (CT- G’), (CT-G’’), (CT-H), (CT-H’), (CT-H’’), (CT-H’’’), (CT-H’’’’), (CT-H’’’’’), (CT-I), (CT-J), (CT- J’), (CT-K), (CT-K’), (CT-K’’), (CT-L), (CT-L’), (CT-L’’), (CT-L’’’), (CT-L’’’’), (CT-L’’’’’), (CT- M), (CT-N), (CT-N’), (CT-O), (CT-O’), (CT-O’’), (CT-P), (CT-P’), (CT-P’’), (CT-P’’’), (CT-P’’’’), (CT-P’’’’’), (CT-Q), (CT-Q1), (CT-R), (CT-R’), (CT-S), (CT-S’), (CT-S’’), (CT-T), (CT-T’), (CT- T’’), (CT-T’’’), (CT-T’’’’), (CT-T’’’’’), (CT-U), (CT-U’), (CT-U’’), (CT-U’’’), (CT-U’’’’), (CT- U’’’’’), (CT-V), (CT-V’), (CT-V’’), (CT-V’’’), (CT-V’’’’), (CT-V’’’’’), or a pharmaceutically acceptable salt thereof, or any lipid in Tables (I), and (IA) or a pharmaceutically salt, solvate, stereoisomer, or enantiomer thereof, see below, collectively referred to as "Lipids of the Disclosure" and each individually referred to as a "Lipid of the Disclosure." [0016] In an aspect of the disclosure, provided herein is a pharmaceutical composition comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0017] In an aspect, provided herein is a pharmaceutical composition comprising: a) at least one lipid nanoparticle comprising at least one compound having a structure of any of Formulae (CT), (CT-A), (CT-A1), (CT-A2), (CT-B), (CT-B’), (CT-C), (CT-D), (CT-D’), (CT-E), (CT-E’), (CT-E’’), (CT-F), (CT-F’), (CT-F’’), (CT-F’’’), (CT-F’’’’), (CT-F’’’’’), (CT-G), (CT-G’), (CT-G’’), (CT-H), (CT-H’), (CT-H’’), (CT-H’’’), (CT-H’’’’), (CT-H’’’’’), (CT-I), (CT-J), (CT-J’), (CT-K), (CT-K’), (CT-K’’), (CT-L), (CT-L’), (CT-L’’), (CT-L’’’), (CT-L’’’’), (CT-L’’’’’), (CT-M), (CT-N), (CT-N’), (CT-O), (CT-O’), (CT-O’’), (CT-P), (CT-P’), (CT-P’’), (CT-P’’’), (CT-P’’’’), (CT-P’’’’’), (CT-Q), (CT-Q1), (CT-R), (CT-R’), (CT-S), (CT-S’), (CT-S’’), (CT-T), (CT-T’), (CT-T’’), (CT-T’’’), (CT- T’’’’), (CT-T’’’’’), (CT-U), (CT-U’), (CT-U’’), (CT-U’’’), (CT-U’’’’), (CT-U’’’’’), (CT-V), (CT-V’), (CT-V’’), (CT-V’’’), (CT-V’’’’), (CT-V’’’’’), or a pharmaceutically acceptable salt thereof, or any lipid in Tables (I), and (IA) or a pharmaceutically salt or solvate, or a pharmaceutically acceptable salt, solvate, stereoisomer, or enantiomer thereof, or any lipid in Tables (I), and (IA), or a salt, solvate, stereoisomer, or enantiomer thereof; and b) at least one nucleobase editing system. [0018] In an aspect, provided herein is a method of delivering a nucleobase editing system to a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition disclosed herein. [0019] In an aspect of the disclosure, provided herein is a lipid nanoparticle (LNP) comprising a compound having a structure of any of Formulae (CT), (CT-A), (CT-A1), (CT-A2), (CT-B), (CT-B’), (CT-C), (CT-D), (CT-D’), (CT-E), (CT-E’), (CT-E’’), (CT-F), (CT-F’), (CT-F’’), (CT-F’’’), (CT-F’’’’), (CT-F’’’’’), (CT-G), (CT-G’), (CT-G’’), (CT-H), (CT-H’), (CT-H’’), (CT- H’’’), (CT-H’’’’), (CT-H’’’’’), (CT-I), (CT-J), (CT-J’), (CT-K), (CT-K’), (CT-K’’), (CT-L), (CT-L’), (CT-L’’), (CT-L’’’), (CT-L’’’’), (CT-L’’’’’), (CT-M), (CT-N), (CT-N’), (CT-O), (CT-O’), (CT-O’’), (CT-P), (CT-P’), (CT-P’’), (CT-P’’’), (CT-P’’’’), (CT-P’’’’’), (CT-Q), (CT-Q1), (CT-R), (CT-R’), (CT-S), (CT-S’), (CT-S’’), (CT-T), (CT-T’), (CT-T’’), (CT-T’’’), (CT-T’’’’), (CT-T’’’’’), (CT-U), (CT-U’), (CT-U’’), (CT-U’’’), (CT-U’’’’), (CT-U’’’’’), (CT-V), (CT-V’), (CT-V’’), (CT-V’’’), (CT- V’’’’), (CT-V’’’’’), or a pharmaceutically acceptable salt thereof, or any lipid in Tables (I), and (IA), or a pharmaceutically acceptable salt, solvate, stereoisomer, or enantiomer thereof, or any lipid in Table (I), and (IA), or a salt, solvate, stereoisomer, or enantiomer thereof. [0020] In another aspect of the disclosure, provided herein is a method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP disclosed herein or a pharmaceutical composition disclosed herein. [0021] In another aspect of the disclosure, provided herein is a method for treating a disease characterized by a deficiency of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP disclosed herein, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein. [0022] In another aspect of the disclosure, provided herein is a method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP disclosed herein and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide. BRIEF DESCRIPTION OF THE DRAWINGS [0023] FIG.1 is a diagram illustrating the LNP-based RNA vaccines and therapeutics disclosed herein which are encapsulated with RNA payloads (e.g., linear and/or circular mRNAs). [0024] FIG.2 is a diagram illustrating an originator polynucleotide construct of the present disclosure which may be linear or circular. DETAILED DESCRIPTION I. Introduction [0025] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA medicines (e.g., vaccines, gene therapies, or gene-editing therapeutics). In various embodiments, the LNP-based RNA medicines comprise an LNP delivery system (as described in detail herein) and an encapsulated cargo/payload (e.g., RNA in the case of RNA medicines). [0026] In various embodiments and as described further herein, the LNP delivery vehicle is a complex nanostructured body that provides protection to an encapsulated RNA payload (i.e., one or more RNA molecules) environmental damage (e.g., an intracellular environment). LNPs are formed through self-assembly of multiple lipid components, including (i) an ionizable lipid (e.g., ALC-0315 as in COMIRNATY® (Pfizer-BioNTech), SM-102 as in SPIKEVAX® (Moderna), or MC3 as in ONPATTRO® (Alnylam), or those ionizable lipids described herein), (ii) a helper lipid (such as, but not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), (iii) a sterol (e.g., cholesterol), and (iv) a PEG-lipid (e.g., PEG-DSPE). [0027] In various embodiments and as described further herein, the RNA payload in the herein described LNP-based medicines may comprise coding and/or non-coding RNA, and/or mixtures thereof. The particular RNA payload constituents will generally reflect the medicine. For example, an LNP-based vaccine or therapeutic may comprise only coding RNA for expressing a vaccine antigen or a therapeutic protein, respectively. However, an LNP-based gene editing medicine may comprise a combination of coding RNA (e.g., encoding a CRISPR nuclease) and non-coding RNAs (e.g., guide RNAs). In various embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a linear mRNA. In other embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a circular mRNA. In still other embodiments, the RNA molecule delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and/or structural modification (e.g., secondary- folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). A. LNP-Based RNA Vaccines [0028] Described herein in certain aspects are improved LNP-based RNA vaccines for use in immunization against disease. In various aspects, the disclosure describes improved LNPs, including better performing ionizable lipids, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and/or circular mRNAs. The improved LNPs protect linear and/or circular mRNA cargos (i.e., the circular and/or linear mRNA molecules encapsulated by the LNPs) from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines. [0029] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA vaccines. In particular, as described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA vaccines for the delivery of an RNA molecule that codes for one or more immunogenic viral antigens for use as vaccine and/or immunogenic compositions. In various embodiments, the RNA molecules delivered by the herein disclosed LNPs can be linear mRNA. In other embodiments, the RNA molecules delivered by the herein disclosed LNPs can be circular mRNA. In still other embodiments, the RNA molecule delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and/or structural modification (e.g., secondary-folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). In various other embodiments, the disclosure provides novel lipid components of the herein disclosed LNPs, including, but not limited to, novel ionizable lipids. B. LNP-Based RNA Therapeutics [0030] Described herein in certain aspects are improved LNP-based RNA therapeutics for use in treating disease or a symptom thereof. In various aspects, the disclosure describes improved LNPs, including better performing ionizable lipids, that enhance the targeted delivery of LNP-based RNA therapeutics based on linear and/or circular mRNAs. The improved LNPs protect linear and/or circular mRNA cargos (i.e., the circular and/or linear mRNA molecules encapsulated by the LNPs) from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced therapeutic agents. [0031] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA therapeutics. In particular, described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA therapeutics for the delivery of an RNA molecule that codes for one or more therapeutic proteins for use treating a disease or a symptom thereof. Further described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA therapeutics for the administration of an RNA molecule that codes for one or more therapeutic proteins for the prophylactic and/or therapeutic treatment of one or more diseases or a symptom thereof. In various embodiments, the RNA molecules delivered by the herein disclosed LNPs can be linear mRNA. In other embodiments, the RNA molecules delivered by the herein disclosed LNPs can be circular mRNA. In still other embodiments, the RNA molecules delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and/or structural modification (e.g., secondary- folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). In various other embodiments, the disclosure provides novel lipid components of the herein disclosed LNPs, including, but not limited to, novel ionizable lipids. C. LNP-Based Gene Editing Therapeutics [0032] Also described herein are LNP compositions comprising gene editing systems for use in treating disease and/or otherwise modifying the sequence and/or expression of target nucleotide sequences. The disclosure provides LNPs capable of delivering a gene editing system to a target organ, tissue, and/or cell. The gene editing systems may be delivered to cells under in vitro or ex vivo conditions and to organs, tissues, or cells under in vivo conditions (e.g., administered to a subject in an effective amount). [0033] The disclosure also provides in various aspects therapeutic or pharmaceutical compositions comprising LNPs comprising gene editing systems or one or more components thereof. The gene editing systems may comprise DNA components, RNA components, protein components, nucleoprotein components, polysaccharide components, or combinations thereof. In other aspects, the disclosure provides nucleic acid molecules (e.g., RNA or DNA) that encode and/or constitute various componentry of the deliverable gene editing systems contemplated herein. In addition, other aspects of the disclosure provide nucleic acid molecules as components of the herein contemplated gene editing systems, such as, but not limited to plasmids or vectors encoding one or more components of a gene editing system, RNAs encoding one or more components of a gene editing system (e.g., mRNAs coding for a nuclease domain of a gene editing system), and non-coding RNAs (e.g., guide RNAs capable of complexing with and targeting a nucleic acid-programmable DNA binding domain to a specific target nucleotide sequence or a retron ncRNAs). [0034] In further embodiments, the nucleic acid components (e.g., RNA) may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and/or structural modification (e.g., secondary-folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). [0035] The disclosure, in other aspects, describes various protein components (which may be encoded by the nucleic acid components described herein) of the various gene editing systems contemplated herein, including, but not limited to, user-programmable DNA binding proteins and various effector proteins, such as nucleases, polymerases, reverse transcriptases, recombinases, integrases, endonucleases, exonucleases, transposases, and deaminases. [0036] The disclosure also describes nucleoprotein components of the gene editing systems contemplated herein, such as, but not limited to nuclease-guide RNA complexes. The disclosure also provides methods of modifying the sequence and/or expression level of a target nucleic acid molecule through the delivery and/or administration of an LNP described herein that comprises a gene editing system or components thereof. Still further, the disclosure provides methods of treating a disease by administering a therapeutically effective amount of an LNP-based gene editing system that results in the modification in the sequence and/or expression level of a target nucleic acid molecule (e.g., a disease-associated gene or regulatory sequence, such as a promoter, transcription factor binding site, or gene enhancer site). [0037] The gene editing systems deliverable by the herein disclosed LNPs can be any type of gene editing system. Without limitation, the gene editing systems contemplated herein can include (A) nucleobase gene editing systems which result in one or more the changes to the sequence of a target nucleic acid molecule (e.g., a gene or gene regulatory sequence) (sequence modifications may include, but are not limited to, an insertion of one or more base pairs, a deletion of one of more base pairs, a substitution or one or more base pairs, a conversion of a base pair to another base pair (e.g., a G:C pair converted to an A:T pair), an inversion, or a translocation), (B) an epigenetic editing system which results in one or more modifications to the epigenome to bring about an effect on gene expression without altering the sequence of a nucleic acid molecule, and (C) gene editing systems that combine the features of nucleobase editing systems and epigenetic editing systems (e.g., combining components from both types of systems to change the sequence and an epigenomic component with one system). [0038] Nucleobase editing systems include a wide array of configurations with various combinations of protein functionalities and/or nucleic acid molecule components, all of which are contemplated herein. In general, nucleobase editing systems comprise at least a (i) DNA binding domain that is user-programmable to target a specific sequence in a nucleic acid molecule and optionally (ii) one or more effector domains that facilitate the modification of the sequence of the nucleic acid molecule. User-programmability may comprise amino acid sequence-programmable DNA binding domains (e.g., TALENS, zinc finger-binding domains, meganucleases (or homing endonucleases)) or nucleic acid sequence-programmable DNA binding domains or proteins (“naspDBP”) (e.g., CRISPR-Cas9, CRISPR-Cas12a, CRISPR-Cas12f, CRISPR-Cas13a, CRISPR- Cas13b, or TnpB). [0039] Similarly, epigenetic editing systems comprise at least a (i) DNA binding domain that targets a specific sequence in a nucleic acid molecule and (ii) one or more effector domains that facilitates the modification of one or more epigenomic features of the nucleic acid molecule. [0040] Gene editing systems may comprise one or more effector domains that provide various functionalities that facilitate changes in nucleotide sequence and/or gene expression, such as, but not limited to, single-strand DNA binding proteins, nucleases, endonucleases, exonucleases, deaminases (e.g., cytidine deaminases or adenosine deaminases), polymerases (e.g., reverse transcriptases), integrases, recombinases, etc., and fusion proteins comprising one or more functional domains linked together. [0041] In addition, gene editing systems that utilize a nucleic acid sequence-programmable DNA binding domain or protein (naspDBP) may also comprise one or more non-coding nucleic acids, such as, one or more guide RNAs which complex with the nucleic acid programmable DNA binding protein (naspDBP) and target the complex to a specific nucleotide sequence. In the case of prime editing, the guide RNA may be a prime editing guide RNA (“pegRNA”) which comprises a specialized RNA template molecule that provides a template or coding sequence for a reverse transcriptase of the prime editing system. In some embodiments, the RNA template molecule may be coupled to a guide RNA as an extension arm at the 5’ or 3’ end of the guide RNA. In other embodiments, the RNA template molecule may be provided in trans as a separate molecule in a manner such that the RNA template molecule may itself become localized and associated with the target sequence and/or the gene editing system at the site of editing. In some embodiments, co- localization of an in trans RNA template molecule may be achieved with an aptamer or other RNA structure which binds to a binding partner that is coupled to, integrated with, or otherwise associated with the editing complex. [0042] In the case of editing systems comprising a nucleic acid sequence-programmable DNA binding protein (naspDBP), such as a CRISPR-Cas9 or CRISPR-Cas12a nuclease, appropriate guides may be designed and synthesized using methods, software, and commercial sources which are well known to those having ordinary skill in the art such that guide RNAs for any given naspDBP may be obtained without undue experimentation. [0043] Reference may be made to the following references providing information and tools for the design, synthesis, modification, and structural configuration of guide RNAs: (1) Mohr SE, Hu Y, Ewen-Campen B, Housden BE, Viswanatha R, Perrimon N. CRISPR guide RNA design for research applications. FEBS J.2016 Sep;283(17):3232-8. doi: 10.1111/febs.13777. Epub 2016 Jun 22. PMID: 27276584; PMCID: PMC5014588; (2) Hoberecht L, Perampalam P, Lun A, Fortin JP. A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies. Nat Commun.2022 Nov 2;13(1):6568. doi: 10.1038/s41467-022-34320-7. PMID: 36323688; PMCID: PMC9630310; (3) Cram D, Kulkarni M, Buchwaldt M, Rajagopalan N, Bhowmik P, Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRISPR/Cas9-mediated genome editing in wheat. BMC Plant Biol.2019 Nov 6;19(1):474. doi: 10.1186/s12870-019-2097-z. PMID: 31694550; PMCID: PMC6836449; (4) Pliatsika V, Rigoutsos I. "Off-Spotter": very fast and exhaustive enumeration of genomic lookalikes for designing CRISPR/Cas guide RNAs. Biol Direct.2015 Jan 29;10:4. doi: 10.1186/s13062-015- 0035-z. PMID: 25630343; PMCID: PMC4326336; (5) Hoof JB, Nødvig CS, Mortensen UH. Genome Editing: CRISPR-Cas9. Methods Mol Biol.2018;1775:119-132. doi: 10.1007/978-1-4939-7804-5_11. PMID: 29876814; (6) Labun K, Krause M, Torres Cleuren Y, Valen E. CRISPR Genome Editing Made Easy Through the CHOPCHOP Website. Curr Protoc.2021 Apr;1(4):e46. doi: 10.1002/cpz1.46. PMID: 33905612; (7) Lee CM, Davis TH, Bao G. Examination of CRISPR/Cas9 design tools and the effect of target site accessibility on Cas9 activity. Exp Physiol.2018 Apr 1;103(4):456-460. doi: 10.1113/EP086043. Epub 2017 Apr 12. PMID: 28303677; PMCID: PMC7266697; (8) Ma S, Lv J, Feng Z, Rong Z, Lin Y. Get ready for the CRISPR/Cas system: A beginner's guide to the engineering and design of guide RNAs. J Gene Med.2021 Nov;23(11):e3377. doi: 10.1002/jgm.3377. Epub 2021 Jul 28. PMID: 34270141; (9) Hiranniramol K, Chen Y, Wang X. CRISPR/Cas9 Guide RNA Design Rules for Predicting Activity. Methods Mol Biol.2020;2115:351- 364. doi: 10.1007/978-1-0716-0290-4_19. PMID: 32006410; (10) Wiles MV, Qin W, Cheng AW, Wang H. CRISPR-Cas9-mediated genome editing and guide RNA design. Mamm Genome.2015 Oct;26(9-10):501-10. doi: 10.1007/s00335-015-9565-z. Epub 2015 May 20. PMID: 25991564; PMCID: PMC4602062; (11) Creutzburg SCA, Wu WY, Mohanraju P, Swartjes T, Alkan F, Gorodkin J, Staals RHJ, van der Oost J. Good guide, bad guide: spacer sequence-dependent cleavage efficiency of Cas12a. Nucleic Acids Res.2020 Apr 6;48(6):3228-3243. doi: 10.1093/nar/gkz1240. PMID: 31989168; PMCID: PMC7102956; (12) Heigwer F, Boutros M. Cloud-Based Design of Short Guide RNA (sgRNA) Libraries for CRISPR Experiments. Methods Mol Biol.2021;2162:3-22. doi: 10.1007/978-1-0716-0687-2_1. PMID: 32926374; (13) Dronina J, Samukaite-Bubniene U, Ramanavicius A. Towards application of CRISPR-Cas12a in the design of modern viral DNA detection tools (Review). J Nanobiotechnology.2022 Jan 21;20(1):41. doi: 10.1186/s12951-022- 01246-7. PMID: 35062978; PMCID: PMC8777428; (14) Krysler AR, Cromwell CR, Tu T, Jovel J, Hubbard BP. Guide RNAs containing universal bases enable Cas9/Cas12a recognition of polymorphic sequences. Nat Commun.2022 Mar 25;13(1):1617. doi: 10.1038/s41467-022-29202-x. PMID: 35338140; PMCID: PMC8956631; (15) Shin HR, Kweon J, Kim Y. Gene Manipulation Using Fusion Guide RNAs for Cas9 and Cas12a. Methods Mol Biol.2021;2162:185-193. doi: 10.1007/978- 1-0716-0687-2_10. PMID: 32926383; (16) Schubert MS, Thommandru B, Woodley J, Turk R, Yan S, Kurgan G, McNeill MS, Rettig GR. Optimized design parameters for CRISPR Cas9 and Cas12a homology-directed repair. Sci Rep.2021 Sep 30;11(1):19482. doi: 10.1038/s41598-021-98965-y. PMID: 34593942; PMCID: PMC8484621; (17) Crone MA, MacDonald JT, Freemont PS, Siciliano V. gDesigner: computational design of synthetic gRNAs for Cas12a-based transcriptional repression in mammalian cells. NPJ Syst Biol Appl.2022 Sep 16;8(1):34. doi: 10.1038/s41540-022-00241-w. PMID: 36114193; PMCID: PMC9481559; (18) Konstantakos V, Nentidis A, Krithara A, Paliouras G. CRISPR-Cas9 gRNA efficiency prediction: an overview of predictive tools and the role of deep learning. Nucleic Acids Res.2022 Apr 22;50(7):3616-3637. doi: 10.1093/nar/gkac192. PMID: 35349718; PMCID: PMC9023298; (19) Wang J, Zhang X, Cheng L, Luo Y. An overview and metanalysis of machine and deep learning-based CRISPR gRNA design tools. RNA Biol.2020 Jan;17(1):13-22. doi: 10.1080/15476286.2019.1669406. Epub 2019 Sep 27. PMID: 31533522; PMCID: PMC6948960; and (20) Cram D, Kulkarni M, Buchwaldt M, Rajagopalan N, Bhowmik P, Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRISPR/Cas9-mediated genome editing in wheat. BMC Plant Biol.2019 Nov 6;19(1):474. doi: 10.1186/s12870-019-2097-z. PMID: 31694550; PMCID: PMC6836449; each of which are incorporated herein by reference in their entireties. [0044] In the case of prime editing, in particular, further reference may be made to the following references providing information and tools for the design, synthesis, modification, and structural configuration of pegRNAs: (1) Hsu JY, Grünewald J, Szalay R, Shih J, Anzalone AV, Lam KC, Shen MW, Petri K, Liu DR, Joung JK, Pinello L. PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nat Commun.2021 Feb 15;12(1):1034. doi: 10.1038/s41467- 021-21337-7. PMID: 33589617; PMCID: PMC7884779; (2) Li Y, Chen J, Tsai SQ, Cheng Y. Easy- Prime: a machine learning-based prime editor design tool. Genome Biol.2021 Aug 19;22(1):235. doi: 10.1186/s13059-021-02458-0. PMID: 34412673; PMCID: PMC8377858; (3) Zhang W, Petri K, Ma J, Lee H, Tsai CL, Joung JK, Yeh JJ. Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions. bioRxiv [Preprint].2023 Aug 15:2023.08.14.553324. doi: 10.1101/2023.08.14.553324. PMID: 37645936; PMCID: PMC10462064; (4) Jin S, Lin Q, Gao Q, Gao C. Optimized prime editing in monocot plants using PlantPegDesigner and engineered plant prime editors (ePPEs). Nat Protoc.2023 Mar;18(3):831-853. doi: 10.1038/s41596-022-00773-9. Epub 2022 Nov 25. PMID: 36434096; (5) Lin Q, Jin S, Zong Y, Yu H, Zhu Z, Liu G, Kou L, Wang Y, Qiu JL, Li J, Gao C. High-efficiency prime editing with optimized, paired pegRNAs in plants. Nat Biotechnol.2021 Aug;39(8):923-927. doi: 10.1038/s41587-021-00868-w. Epub 2021 Mar 25. PMID: 33767395; (6) Standage-Beier K, Tekel SJ, Brafman DA, Wang X. Prime Editing Guide RNA Design Automation Using PINE-CONE. ACS Synth Biol.2021 Feb 19;10(2):422-427. doi: 10.1021/acssynbio.0c00445. Epub 2021 Jan 19. PMID: 33464043; PMCID: PMC7901017; (7) Zhang W, Petri K, Ma J, Lee H, Tsai CL, Joung JK, Yeh JJ. Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions. bioRxiv [Preprint].2023 Aug 15:2023.08.14.553324. doi: 10.1101/2023.08.14.553324. PMID: 37645936; PMCID: PMC10462064; (8) Chow RD, Chen JS, Shen J, Chen S. A web tool for the design of prime-editing guide RNAs. Nat Biomed Eng.2021 Feb;5(2):190-194. doi: 10.1038/s41551-020-00622-8. Epub 2020 Sep 28. PMID: 32989284; PMCID: PMC7882013; each of which are incorporated herein by reference in their entireties. [0045] Reference may also be made to the following commercial vendors which sell guide RNAs for CRISPR editing applications (including base editing and prime editing) and provide various tools and instruction for the ordering, design, synthesis, modification, and structural configuration of guide RNAs: GENSCRIPT, SYNTHEGO, TAKARA BIO, INTEGRATED DNA TECHNOLOGIES, LC SCIENCES, HORIZON DISCOVERY; SIGMA-ALDRICH; ORIGENE, and TWIST BIOSCIENCES, among others. [0046] In addition, guide RNA may be modified with chemical modifications and/or structural modifications for enhancing various properties thereof, including specificity, stability, and limiting off-target activity. One of ordinary skill in the art will be able to modify a guide RNA with any known modification without undue experimentation. Guide modifications are discussed in the following references: (1) Ke Y, Ghalandari B, Huang S, Li S, Huang C, Zhi X, Cui D, Ding X.2'-O- Methyl modified guide RNA promotes the single nucleotide polymorphism (SNP) discrimination ability of CRISPR-Cas12a systems. Chem Sci.2022 Feb 1;13(7):2050-2061. doi: 10.1039/d1sc06832f. PMID: 35308857; PMCID: PMC8848812; (2) Allen D, Rosenberg M, Hendel A. Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells. Front Genome Ed.2021 Jan 28;2:617910. doi: 10.3389/fgeed.2020.617910. PMID: 34713240; PMCID: PMC8525374; (3) Basila M, Kelley ML, Smith AVB. Minimal 2'-O-methyl phosphorothioate linkage modification pattern of synthetic guide RNAs for increased stability and efficient CRISPR-Cas9 gene editing avoiding cellular toxicity. PLoS One.2017 Nov 27;12(11):e0188593. doi: 10.1371/journal.pone.0188593. PMID: 29176845; PMCID: PMC5703482; (4) Sakovina L, Vokhtantsev I, Vorobyeva M, Vorobyev P, Novopashina D. Improving Stability and Specificity of CRISPR/Cas9 System by Selective Modification of Guide RNAs with 2'-fluoro and Locked Nucleic Acid Nucleotides. Int J Mol Sci.2022 Nov 3;23(21):13460. doi: 10.3390/ijms232113460. PMID: 36362256; PMCID: PMC9655745; (5) Shapiro J, Tovin A, Iancu O, Allen D, Hendel A. Chemical Modification of Guide RNAs for Improved CRISPR Activity in CD34+ Human Hematopoietic Stem and Progenitor Cells. Methods Mol Biol.2021;2162:37-48. doi: 10.1007/978-1-0716-0687-2_3. PMID: 32926376; (6) Filippova J, Matveeva A, Zhuravlev E, Stepanov G. Guide RNA modification as a way to improve CRISPR/Cas9-based genome-editing systems. Biochimie.2019 Dec;167:49-60. doi: 10.1016/j.biochi.2019.09.003. Epub 2019 Sep 4. PMID: 31493470; (7) Hendel A, Bak RO, Clark JT, Kennedy AB, Ryan DE, Roy S, Steinfeld I, Lunstad BD, Kaiser RJ, Wilkens AB, Bacchetta R, Tsalenko A, Dellinger D, Bruhn L, Porteus MH. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol.2015 Sep;33(9):985-989. doi: 10.1038/nbt.3290. Epub 2015 Jun 29. PMID: 26121415; PMCID: PMC4729442; (8)_ Ryan DE, Taussig D, Steinfeld I, Phadnis SM, Lunstad BD, Singh M, Vuong X, Okochi KD, McCaffrey R, Olesiak M, Roy S, Yung CW, Curry B, Sampson JR, Bruhn L, Dellinger DJ. Improving CRISPR-Cas specificity with chemical modifications in single-guide RNAs. Nucleic Acids Res.2018 Jan 25;46(2):792-803. doi: 10.1093/nar/gkx1199. Erratum in: Nucleic Acids Res.2022 Mar 21;50(5):2986. PMID: 29216382; PMCID: PMC5778453; (9) Palumbo CM, Gutierrez-Bujari JM, O'Geen H, Segal DJ, Beal PA. Versatile 3' Functionalization of CRISPR Single Guide RNA. Chembiochem.2020 Jun 2;21(11):1633-1640. doi: 10.1002/cbic.201900736. Epub 2020 Mar 5. PMID: 31943634; PMCID: PMC7323579; (10) Mullally G, van Aelst K, Naqvi MM, Diffin FM, Karvelis T, Gasiunas G, Siksnys V, Szczelkun MD.5' modifications to CRISPR-Cas9 gRNA can change the dynamics and size of R-loops and inhibit DNA cleavage. Nucleic Acids Res.2020 Jul 9;48(12):6811-6823. doi: 10.1093/nar/gkaa477. PMID: 32496535; PMCID: PMC7337959; (12) Lu S, Zhang Y, Yin H. Chimeric DNA-RNA Guide RNA Designs. Methods Mol Biol.2021;2162:79-85. doi: 10.1007/978-1-0716-0687-2_6. PMID: 32926379; each of which are incorporated by reference herein in their entireties. [0047] In the specific case of prime editing, pegRNAs may be modified with chemical modifications and/or structural modifications for enhancing various properties thereof, including specificity, stability, and limiting off-target activity. One of ordinary skill in the art will be able to modify a pegRNA for prime editing with any known modification without undue experimentation. pegRNA modifications are discussed in the following references: (1) Nelson JW, Randolph PB, Shen SP, Everette KA, Chen PJ, Anzalone AV, An M, Newby GA, Chen JC, Hsu A, Liu DR. Engineered pegRNAs improve prime editing efficiency. Nat Biotechnol.2022 Mar;40(3):402-410. doi: 10.1038/s41587-021-01039-7. Epub 2021 Oct 4. Erratum in: Nat Biotechnol.2021 Dec 8;: PMID: 34608327; PMCID: PMC8930418; (2) Liu B, Dong X, Cheng H, Zheng C, Chen Z, Rodríguez TC, Liang SQ, Xue W, Sontheimer EJ. A split prime editor with untethered reverse transcriptase and circular RNA template. Nat Biotechnol.2022 Sep;40(9):1388-1393. doi: 10.1038/s41587-022-01255- 9. Epub 2022 Apr 4. PMID: 35379962; each of which are incorporated by reference herein in their entireties. [0048] Other specialized guide RNAs may be included depending upon the requirements and/or nature of the gene editing system and the cognate nucleic acid programmable proteins. For example, TnpB enzymes require a specialized guide RNA referred to as reRNA. Also, guide RNAs have different characteristics (e.g., PAM preferences, the spacer length, and the scaffold portion that binds to the nuclease protein) depending upon the programmable nuclease requirements. [0049] The gene editing systems contemplated here may introduce a wide variety of changes, including (A) a change in the sequence of the target nucleic acid molecule, such as, but not limited to, (i) a nucleobase substitution (e.g., a purine to a pyrimidine), (ii) a deletion of one or more nucleobases, (iii) an insertion of one or more nucleobases, (iv) a combination of a deletion and insertion of one or more nucleobases, (v) an inversion of a nucleobase sequence, a (vi) translocation of a nucleobase sequence, and (vii) a combination or two or more such modifications, and (B) one or more modifications to the epigenome to bring about an effect on gene expression without altering the sequence of a nucleic acid molecule wherein said epigenetic change results in altered gene expression through altered chromatin structure or accessibility. [0050] The LNP compositions and/or gene editing systems described herein may include a variety of coding RNA molecules that code for the various components of gene editors. In various aspects, the coding RNA may be linear mRNA. In other embodiments, the coding RNA may be circular mRNA. In various aspects, the improved LNPs protect linear and/or circular mRNA cargos from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced gene editing platforms and/or therapeutic agents. [0051] In various other aspects, the LNP compositions and/or gene editing systems described herein may also include a repair template, e.g., an homology-directed repair (HDR)-dependent repair template (or HDR template). Such HDR templates are well-known in the art and can include single- strand or double-stranded DNA (e.g., oligos) or RNA. Further information regarding HDR and HDR templates for use in editing systems for various applications, such as gene knock-in, may be found in Fu YW, Dai XY, Wang WT, Yang ZX, Zhao JJ, Zhang JP, Wen W, Zhang F, Oberg KC, Zhang L, Cheng T, Zhang XB. Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing. Nucleic Acids Res.2021 Jan 25;49(2):969-985. doi: 10.1093/nar/gkaa1251. PMID: 33398341; PMCID: PMC7826255; Iyer S, Mir A, Vega-Badillo J, Roscoe BP, Ibraheim R, Zhu LJ, Lee J, Liu P, Luk K, Mintzer E, Guo D, Soares de Brito J, Emerson CP Jr, Zamore PD, Sontheimer EJ, Wolfe SA. Efficient Homology-Directed Repair with Circular Single-Stranded DNA Donors. CRISPR J.2022 Oct;5(5):685-701. doi: 10.1089/crispr.2022.0058. Epub 2022 Sep 7. PMID: 36070530; PMCID: PMC9595650; and Richardson CD, Ray GJ, DeWitt MA, Curie GL, Corn JE. Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol.2016 Mar;34(3):339-44. doi: 10.1038/nbt.3481. Epub 2016 Jan 20. PMID: 26789497, each of which are incorporated herein by reference in their entireties. [0052] Accordingly, the instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP- based gene editing systems as therapeutic compositions. Further described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based gene editing therapeutics for the prophylactic and/or therapeutic treatment of one or more diseases or a symptom thereof. The components capable of being encapsulated by or otherwise incorporated by the LNPs described herein may be referred to as LNP “payloads” and may include all of the biological materials described above, including DNA molecules, RNA molecules (coding and/or non-coding), proteins, and nucleoproteins (e.g., Cas/guide RNA complexes). II. LNP delivery systems [0053] The RNA payloads (e.g., linear and circular mRNAs) described herein may be encapsulated and delivered by lipid nanoparticles (LNPs) and compositions and/or formulations comprising RNA-encapsulated LNPs. [0054] Below describes LNPs that may be used as the RNA payload delivery vehicles contemplated herein, as well as the various ionizable lipids, structural lipids, PEGylated lipids, and phospholipids that may be used to make the herein LNPs for delivery RNA payloads to cells. In addition, below describes additional LNP components that are contemplated, such as targeting moieties and other lipid components. A. Lipid Nanoparticle Compositions [0055] In one aspect, the present disclosure further provides delivery systems for delivery of a therapeutic payload (e.g., the RNA payloads described herein which may encode a polypeptide of interest, e.g., an antigen or a therapeutic protein) disclosed herein. In some embodiments, a delivery system suitable for delivery of the therapeutic payload disclosed herein comprises a lipid nanoparticle (LNP) formulation. [0056] In some embodiments, an LNP of the present disclosure comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a phospholipid. In alternative embodiments, an LNP comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a zwitterionic amino acid lipid. In some embodiments, an LNP further comprises a 5th lipid, besides any of the aforementioned lipid components. In some embodiments, the LNP encapsulates one or more elements of the active agent of the present disclosure. In some embodiments, an LNP further comprises a targeting moiety covalently or non-covalently bound to the outer surface of the LNP. In some embodiments, the targeting moiety is a targeting moiety that binds to, or otherwise facilitates uptake by, cells of a particular organ system. [0057] In some embodiments, an LNP has a diameter of at least about 20nm, 30 nm, 40nm, 50nm, 60nm, 70nm, 80nm, or 90nm. In some embodiments, an LNP has a diameter of less than about 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, or 160nm. In some embodiments, an LNP has a diameter of less than about 120 nm. In some embodiments, an LNP has a diameter of less than about 100nm. In some embodiments, an LNP has a diameter of less than about 90nm. In some embodiments, an LNP has a diameter of less than about 80nm. In some embodiments, an LNP has a diameter of about 60-100nm. In some embodiments, an LNP has a diameter of about 50-120nm. In some embodiments, an LNP has a diameter of about 75-80nm. [0058] In some embodiments, the lipid nanoparticle compositions of the present disclosure are described according to the respective molar ratios of the component lipids in the formulation. As a non-limiting example, the mol-% of the ionizable lipid may be from about 10 mol-% to about 80 mol- %. As a non-limiting example, the mol-% of the ionizable lipid may be from about 20 mol-% to about 70 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 60 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 35 mol-% to about 55 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 40 mol-% to about 50 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 40 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 25 mol-% to about 35 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 10 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 15 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 20 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 25 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 30 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 33 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 35 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 40 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 45 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 55 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 60 mol-%. [0059] In some embodiments, the mol-% of the phospholipid may be from about 1 mol-% to about 50 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 2 mol-% to about 45 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 3 mol- % to about 40 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 4 mol-% to about 35 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 30 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 10 mol-% to about 20 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 20 mol-%. In some embodiments, the mol-% of the phospholipid is from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the phospholipid is from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the phospholipid is from about 35 mol-% to about 45 mol-%. In some embodiments, the mol-% of the phospholipid is about 10 mol-%. In some embodiments, the mol-% of the phospholipid is about 15 mol-%. In some embodiments, the mol-% of the phospholipid is about 20 mol-%. In some embodiments, the mol-% of the phospholipid is about 25 mol-%. In some embodiments, the mol-% of the phospholipid is about 30 mol-%. In some embodiments, the mol-% of the phospholipid is about 35 mol-%. In some embodiments, the mol-% of the phospholipid is about 40 mol-%. In some embodiments, the mol-% of the phospholipid is about 45 mol-%. In some embodiments, the mol-% of the phospholipid is about 55 mol-%. In some embodiments, the mol-% of the phospholipid is about 60 mol-%. [0060] In some embodiments, the mol-% of the phospholipid as described above comprises two or more phospholipids at an individual mol-% that totals to an aforementioned amount. In certain embodiments, the mol-% of the phospholipid is about 20 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 15 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 25 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 30 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 15 mol-% of a first phospholipid and about 20 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 30 mol-% of a first phospholipid and about 10 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 25 mol-% of a first phospholipid and about 10 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 25 mol-% of a first phospholipid and about 20 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 15 mol-% of a first phospholipid and about 20 mol-% of a second phospholipid. [0061] In some embodiments, the mol-% of the structural lipid may be from about 10 mol-% to about 80 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 20 mol-% to about 70 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 40 mol-% to about 50 mol-%. [0062] In some embodiments, the mol-% of the PEG lipid may be from about 0.1 mol-% to about 10 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.2 mol-% to about 5 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.5 mol-% to about 3 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 1 mol-% to about 2 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 1.5 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 2.5 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 3 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 3.5 mol-%. [0063] Where reference is made above to “mol-%” or “mol %”, the amount of the noted LNP component is intended to be the mol% of the specific component as compared to the total lipid component content of the lipid nanoparticle. i. Ionizable lipids [0064] In some embodiments, an LNP disclosed herein comprises an ionizable lipid. In some embodiments, an LNP comprises two or more ionizable lipids. [0065] Described below are a number of exemplary ionizable lipids of the present disclosure. Formula (CT) [0066] In some embodiments, Lipids of the Disclosure have a structure of Formula (CT) (CT), or a pharmaceutically acceptable salt thereof, wherein: , wherein the bond marked with an "*" is attached to X¹; X¹ is optionally substituted C₁-C₆ aliphatic; and R¹ is selected from the group consisting of -OH, -OAc, -NR₂, wherein the bond marked with an "*" is attached to X¹; X¹ is a bond or optionally substituted C₁-C₆ aliphatic; R¹ is selected from the group consisting of -OH, -OAc, -NR₂,

each R is independently -H or C1-C6 aliphatic; X² and X³ are each independently optionally substituted C₁-C₁₂ aliphatic; Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to X² for Y¹ or X³ for Y²; R² is a bond or optionally substituted C₁-C₆ aliphatic; R³ is a bond or optionally substituted C₁-C₆ aliphatic; R⁴ is -CH(OR⁶)(OR⁷), -CH(SR⁶)(SR⁷), -CH(R⁶)(R⁷), or optionally substituted C₁-C₁₄ aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; R⁵ is -CH(OR⁸)(OR⁹), -CH(SR⁸)(SR⁹), -CH(R⁸)(R⁹), -R8, or optionally substituted -C₁-C₆ - aliphatic-R⁸; R⁶ and R⁷ are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R⁸ is optionally substituted C₁-C₁₄ aliphatic, wherein at least one methylene linkage is replaced with an optionally substituted divalent radical of a structure selected from R⁹ is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C₃-C₈ cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl, phenyl, -O-, -NH-, - S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. Formula (CT’) [0067] In some embodiments, Lipids of the Disclosure have a structure of Formula (CT’) or a pharmaceutically acceptable salt thereof, wherein R, X¹, Z, X², X³, Y¹, Y², R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below; i) A is N; Z is a bond, , wherein the bond marked with an "*" is attached to X¹; X¹ is optionally substituted C1-C6 aliphatic; wherein the bond marked with an "*" is attached to X¹; R¹ is selected from the group consisting of -OH, -OAc, -NR2,

R^Z is NR2 or OH; and X⁴ is optionally substituted C₂-C₁₄ alkylenyl or optionally substituted C₂-C₁₄ alkenylenyl. Formula (CT-A) [0068] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-A): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-A1) [0069] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-A1): or a pharmaceutically acceptable salt thereof, wherein , wherei ¹ n the bond marked with an "*" is attached to X ; Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y²; and R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-A2) [0070] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-A2): or a pharmaceutically acceptable salt thereof, wherein Z is , wherein the bond marked with an "*" is attached to X¹; Y¹ and Y² are each ,wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y²; and R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-B) [0071] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-B):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-B’) [0072] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-B’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-C) [0073] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-C): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-D) [0074] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-D): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-D’) [0075] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-D’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-E) [0076] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-E):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-E’) [0077] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-E’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-E’’) [0078] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-E’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-F) [0079] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-F): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-F’) [0080] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-F’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-F’’) [0081] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-F’’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-F’’’) [0082] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-F’’’): (CT-F’’’), or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-F’’’’) [0083] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-F’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-F’’’’’) [0084] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-F’’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, Z, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-G) [0085] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-G): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-G’) [0086] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-G’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-G’’) [0087] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-G’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-H) [0088] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-H): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-H’) [0089] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-H’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-H’’) [0090] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-H’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-H’’’) [0091] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-H’’’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-H’’’’) [0092] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-H’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-H’’’’’) [0093] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-H’’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-I) [0094] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-I): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-J) [0095] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-J): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-J’) [0096] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-J’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-K) [0097] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-K): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-K’) [0098] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-K’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-K’’) [0099] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-K’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-L) [00100] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-L): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-L’) [00101] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-L’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-L’’) [00102] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-L’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-L’’’) [00103] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-L’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-L’’’’) [00104] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-L’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-L’’’’’) [00105] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-L’’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-M) [00106] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-M): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-N) [00107] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-N): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-N’) [00108] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-N’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-O) [00109] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-O): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-O’) [00110] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-O’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-O’’) [00111] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-O’’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, Y¹, Y², X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-P) [00112] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-P): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-P’) [00113] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-P’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-P’’) [00114] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-P’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-P’’’) [00115] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-P’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-P’’’’) [00116] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-P’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-P’’’’’) [00117] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-P’’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-Q) [00118] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-Q): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-Q1) [00119] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-Q1): or a pharmaceutically acceptable salt thereof, wherein Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y²; and R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-R) [00120] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-R): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-R’) [00121] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-R’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-S) [00122] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-S): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-S’) [00123] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-S’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-S’’) [00124] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-S’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, Y¹, Y², R², R³, R⁶, R⁷, R⁸, and R⁹are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-T) [00125] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-T): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-T’) [00126] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-T’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-T’’) [00127] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-T’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-T’’’) [00128] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-T’’’):

or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-T’’’’) [00129] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-T’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-T’’’’’) [00130] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-T’’’’’): or a pharmaceutically acceptable salt thereof, wherein R¹, R, X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-U) [00131] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-U): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-U’) [00132] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-U’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-U’’) [00133] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-U’’):

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-U’’’) [00134] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-U’’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-U’’’’) [00135] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-U’’’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-U’’’’’) [00136] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-U’’’’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, R^Z, R², R³, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-V) [00137] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-V): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-V’) [00138] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-V’):

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-V’’) [00139] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-V’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-V’’’) [00140] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-V’’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-V’’’’) [00141] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-V’’’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. Formula (CT-V’’’’) [00142] In certain embodiments, Lipids of the Disclosure have a structure of Formula (CT), wherein the Lipids of the Disclosure have a structure of Formula (CT-V’’’’): or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, R², R³, X⁴, R^Z, R⁶, R⁷, and R⁸ are as described in Formula (CT) or as otherwise described in any embodiments below. A [00143] As disclosed in Formula (CT), in certain embodiments, A is CH or N. In certain embodiments, A is CH. In certain embodiments, A is N. As disclosed in Formula (CT’), in certain embodiments, A is CR, wherein R is -H or C₁-C₆ aliphatic. Z [00144] As disclosed in Formula (CT), in certain embodiments, Z is wherein the bond marked with an "*" is attached to X¹. In certain embodiments, Z is certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is n certain embodiments, Z is As disclosed in Formula (CT), in certain embodiments wherein A is N, Z is a bond. X¹ [00145] As disclosed in Formula (CT), in certain embodiments wherein A is N, X¹ is optionally substituted C₁-C₆ aliphatic. In certain embodiments wherein A is N, X¹ is unsubstituted C₁-C₆ aliphatic. In certain embodiments, X¹ is optionally substituted C₁-C₆ alkylene. In certain embodiments, X¹ is unsubstituted C₁-C₆ alkylene. In certain embodiments, X¹ is unsubstituted C₂-C₆ alkylene. In certain embodiments, X¹ is optionally substituted methylene. In certain embodiments, R² is optionally substituted C2 alkylene. In certain embodiments, X¹ is optionally substituted C3 alkylene. In certain embodiments, X¹ is optionally substituted C4 alkylene. In certain embodiments, X¹ is optionally substituted C5 alkylene. In certain embodiments, X¹ is optionally substituted C6 alkylene. In certain embodiments, X¹ is –(CH₂)-. In certain embodiments, X¹ is –(CH₂)₂-. In certain embodiments, X¹ is –(CH₂)₃-. In certain embodiments, X¹ is –(CH₂)₄-. In certain embodiments, X¹ is – (CH₂)5-. In certain embodiments, X¹ is –(CH₂)6-. [00146] As disclosed in Formula (CT), in certain embodiments wherein A is CH, X¹ is a bond or optionally substituted C₁-C₆ aliphatic. In certain embodiments, X¹ is a bond. In certain embodiments, X¹ is optionally substituted C₁-C₆ alkylene. In certain embodiments, X¹ is unsubstituted C1-C6 alkylene. In certain embodiments, X¹ is unsubstituted C2-C6 alkylene. In certain embodiments, X¹ is optionally substituted methylene. In certain embodiments, R² is optionally substituted C2 alkylene. In certain embodiments, X¹ is optionally substituted C₃ alkylene. In certain embodiments, X¹ is optionally substituted C₄ alkylene. In certain embodiments, X¹ is optionally substituted C₅ alkylene. In certain embodiments, X¹ is optionally substituted C₆ alkylene. In certain embodiments, X¹ is –(CH₂)-. In certain embodiments, X¹ is –(CH₂)₂-. In certain embodiments, X¹ is –(CH₂)₃-. In certain embodiments, X¹ is –(CH₂)4-. In certain embodiments, X¹ is –(CH₂)5-. In certain embodiments, X¹ is –(CH₂)6-. R¹ [00147] As disclosed in Formula (CT), in certain embodiments R¹ is selected from -OH, -OAc, - [00148] As disclosed in Formula (CT’), in certain embodiments R¹ is selected from -OH, -OAc, -

wherein R^Z is NR2 or OH; and X⁴ is optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl. [00149] In certain embodiments, R¹ is -OH. In certain embodiments, R¹ is -OAc. In certain embodiments, R¹ is -NR₂. In certain embodiments, R¹ is -NH₂. In certain embodiments, R¹ is -NMe₂. In certain embodiments, R¹ is -NEt2. In certain embodiments, R¹ is In certain embodiments, R¹ is In certain embodi ¹ ments, R is In certain embodiments, R¹ is . In certain embodiments, R¹ is In certain ¹ embodiments, R is In certain embodiments, R¹ is In certain embodiments, R¹ is In certain embodiments, R¹ is In certain emb ¹ odiments, R is . In certain embodiments, [00150] In certain embodiments, R¹ is –(CH₂)₄-, X¹ is -OH, A is N and Z is a bond. In certain embodiments, R¹ is –(CH₂)4-, X¹ is -OH, A is N and Z is a bond. X² and X³ [00151] As disclosed in Formula (CT), in certain embodiments, X² and X³ are each independently optionally substituted C1-C12 aliphatic. In certain embodiments, X² and X³ are the same. In certain embodiments, X² and X³ are different. [00152] In certain embodiments, X² is an optionally substituted C₁-C₁₂ alkylene. In certain embodiments, X² is an optionally substituted C1-C12 alkenylene. In certain embodiments, X² is an optionally substituted C1-C10 aliphatic. In certain embodiments, X² is an optionally substituted C1-C10 alkylene. In certain embodiments, X² is an optionally substituted C1-C10 alkenylene. In certain embodiments, X² is an optionally substituted C₁-C₈ aliphatic. In certain embodiments, X² is an optionally substituted C₁-C₈ alkylene. In certain embodiments, X² is an optionally substituted C₁-C₈ alkenylene. In certain embodiments, X² is an optionally substituted C₁-C₆ aliphatic. In certain embodiments, X² is an optionally substituted C₁-C₆ alkylene. In certain embodiments, X² is an optionally substituted C1-C6 alkenylene. In certain embodiments, X² is an optionally substituted C2- C12 aliphatic. In certain embodiments, X² is an optionally substituted C2-C12 alkylene. In certain embodiments, X² is an optionally substituted C2-C12 alkenylene. In certain embodiments, X² is an optionally substituted C₄-C₁₂ aliphatic. In certain embodiments, X² is an optionally substituted C₄-C₁₂ alkylene. In certain embodiments, X² is an optionally substituted C₄-C₁₂ alkenylene. In certain embodiments, X² is an optionally substituted C₄-C₁₀ aliphatic. In certain embodiments, X² is an optionally substituted C4-C10 alkylene. In certain embodiments, X² is an optionally substituted C4-C10 alkenylene. In certain embodiments, X² is an optionally substituted C6-C8 aliphatic. In certain embodiments, X² is an optionally substituted C6-C8 alkylene. In certain embodiments, X² is an optionally substituted C6-C8 alkenylene. In certain embodiments, X² is –(CH₂)-. In certain embodiments, X² is –(CH₂)₂-. In certain embodiments, X² is –(CH₂)₃-. In certain embodiments, X² is – (CH₂)₄-. In certain embodiments, X² is –(CH₂)₅-. In certain embodiments, X² is –(CH₂)₆-. In certain embodiments, X² is –(CH₂)₇-. In certain embodiments, X² is –(CH₂)₈-. In certain embodiments, X² is – (CH₂)9-. In certain embodiments, X² is –(CH₂)10-. [00153] In certain embodiments, X³ is an optionally substituted C₁-C₁₂ alkylene. In certain embodiments, X³ is an optionally substituted C₁-C₁₂ alkenylene. In certain embodiments, X³ is an optionally substituted C1-C10 aliphatic. In certain embodiments, X³ is an optionally substituted C1-C10 alkylene. In certain embodiments, X³ is an optionally substituted C1-C10 alkenylene. In certain embodiments, X³ is an optionally substituted C1-C8 aliphatic. In certain embodiments, X³ is an optionally substituted C1-C8 alkylene. In certain embodiments, X³ is an optionally substituted C1-C8 alkenylene. In certain embodiments, X³ is an optionally substituted C₁-C₆ aliphatic. In certain embodiments, X³ is an optionally substituted C₁-C₆ alkylene. In certain embodiments, X³ is an optionally substituted C1-C6 alkenylene. In certain embodiments, X³ is an optionally substituted C2- C12 aliphatic. In certain embodiments, X³ is an optionally substituted C2-C12 alkylene. In certain embodiments, X³ is an optionally substituted C2-C12 alkenylene. In certain embodiments, X³ is an optionally substituted C₄-C₁₂ aliphatic. In certain embodiments, X³ is an optionally substituted C₄-C₁₂ alkylene. In certain embodiments, X³ is an optionally substituted C₄-C₁₂ alkenylene. In certain embodiments, X³ is an optionally substituted C₄-C₁₀ aliphatic. In certain embodiments, X³ is an optionally substituted C4-C10 alkylene. In certain embodiments, X³ is an optionally substituted C4-C10 alkenylene. In certain embodiments, X³ is an optionally substituted C6-C8 aliphatic. In certain embodiments, X³ is an optionally substituted C6-C8 alkylene. In certain embodiments, X³ is an optionally substituted C6-C8 alkenylene. In certain embodiments, X³ is –(CH₂)-. In certain embodiments, X³ is –(CH₂)₂-. In certain embodiments, X³ is –(CH₂)₃-. In certain embodiments, X³ is – (CH₂)₄-. In certain embodiments, X³ is –(CH₂)₅-. In certain embodiments, X³ is –(CH₂)₆-. In certain embodiments, X³ is –(CH₂)₇-. In certain embodiments, X³ is –(CH₂)₈-. In certain embodiments, X³ is – (CH₂)9-. In certain embodiments, X³ is –(CH₂)10-. _[00154] In certain embodiments, X² and X³ are both optionally substituted C₆-C₈ alkylene. In certain embodiments, X² and X³ are both –(CH₂)₈-. In certain embodiments, X² and X³ are both – (CH₂)₇-. In certain embodiments, X² and X³ are both –(CH₂)₆-. Y¹ and Y² [00155] As disclosed in Formula (CT), in certain embodiments, Y¹ and Y² are each independently , wherein the bond marked with an "*" is attached to X² for Y¹ or X³ for Y². In certain embodiments, Y¹ and Y² are the same. In certain embodiments, Y¹ and Y² are different. [00156] In certain embodiments, Y¹ and Y² are each independently , , , , , . In certain embodiments, Y¹ and Y² are each independently . In certain embodiments, Y¹ is . In certain embodiments, Y¹ is . In certain embodiments, Y¹ is . In certain embodiments, Y¹ is . In certain embodiments, Y¹ is . In certain embodiments, Y¹ is In certain embodiments, Y¹ is In certain embodiments, . In certain embodiments, Y² is . In certain embodiments, Y² is In certain embodiments, Y² is . In certain em ² bodiments, Y is . In certain embodiments, Y² is . I ² n certain embodiments, Y is . In certain embodime ² ² nts, Y is . In certain embodiments, Y is . In certain embodiments, Y¹ and Y² are both . In certain embodiments, Y¹ and Y² are both . R² [00157] As disclosed in Formula (CT), in certain embodiments, R² is a bond or optionally substituted C1-C6 aliphatic. In certain embodiments, R² is a bond. In certain embodiments, R² is optionally substituted C1-C6 aliphatic. In certain embodiments, R² is optionally substituted C1-C6 alkylene. In certain embodiments, R² is optionally substituted methylene. In certain embodiments, R² is optionally substituted C₂ alkylene. In certain embodiments, R² is optionally substituted C₃ alkylene. In certain embodiments, R² is optionally substituted C₄ alkylene. In certain embodiments, R² is optionally substituted C5 alkylene. In certain embodiments, R² is optionally substituted C6 alkylene. In certain embodiments, R² is –(CH₂)-. In certain embodiments, R² is –(CH₂)2-. In certain embodiments, R² is –(CH₂)3-. In certain embodiments, R² is –(CH₂)4-. In certain embodiments, R² is – (CH₂)₅-. In certain embodiments, R² is –(CH₂)₆-. R³ [00158] As disclosed in Formula (CT), in certain embodiments, R³ is a bond or optionally substituted C1-C6 aliphatic. In certain embodiments, R² is a bond. In certain embodiments, R² is optionally substituted C₁-C₆ aliphatic. In certain embodiments, R³ is optionally substituted C₁-C₆ alkylene. In certain embodiments, R³ is optionally substituted methylene. In certain embodiments, R³ is optionally substituted C2 alkylene. In certain embodiments, R³ is optionally substituted C3 alkylene. In certain embodiments, R³ is optionally substituted C4 alkylene. In certain embodiments, R³ is optionally substituted C5 alkylene. In certain embodiments, R³ is optionally substituted C6 alkylene. In certain embodiments, R³ is –(CH₂)-. In certain embodiments, R³ is –(CH₂)₂-. In certain embodiments, R³ is –(CH₂)₃-. In certain embodiments, R³ is –(CH₂)₄-. In certain embodiments, R³ is – (CH₂)₅-. In certain embodiments, R³ is –(CH₂)₆-. [00159] In certain embodiments, R² and R³ are the same. In certain embodiments, R² and R³ are different. R⁴ [00160] As disclosed in Formula (CT), in certain embodiments, R⁴ is -CH(OR⁶)(OR⁷), - CH(SR⁶)(SR⁷), -CH(R⁶)(R⁷), or optionally substituted C₁-C₁₄ aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C₃- C₈ cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. R⁴ is optionally substituted C1-C14 aliphatic. In certain embodiments, R⁴ is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-. In certain embodiments, R⁴ is optionally substituted C₁-C₁₄ aliphatic. In certain embodiments, R⁴ is -CH(OR⁶)(OR⁷). In certain embodiments, R⁴ is -CH(R⁶)(R⁷). In certain embodiments, R⁴ is -CH(SR⁶)(SR⁷). [00161] In certain embodiments, one of the methylene linkages of R⁴ is replaced with an optionally substituted C₃-C₈ cycloalkylenyl, or an optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁴ is replaced with an optionally substituted C3-C8 cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁴ is replaced with an optionally substituted bridged bicyclic or multicyclic C5- C14 cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁴ is replaced with an optionally substituted bridged bicyclic or multicyclic C₅-C₁₂ cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl is selected from: [00162] In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl is a divalent radical of a structure selected from: [00163] In certain embodiments, R⁴ is selected from [00164] In certain embodiments, R⁴ is selected from , [00165] In certain embodiments, R⁴ is selected from , In certain embodiments, R⁴ is R⁵ [00166] As disclosed in Formula (CT), in certain embodiments, R⁵ is -CH(OR⁸)(OR⁹), - CH(SR⁸)(SR⁹), -CH(R⁸)(R⁹), -R⁸, or optionally substituted -C1-C6 aliphatic-R⁸. In certain embodiments, R⁵ is -R⁸ or optionally substituted -C1-C6 aliphatic-R⁸. In certain embodiments, R⁵ is - R⁸. In certain embodiments, R⁵ is optionally substituted C₁-C₁₄ aliphatic. In certain embodiments, R⁵ is -CH(OR⁸)(OR⁹). In certain embodiments, R⁵ is -CH(R⁸)(R⁹). In certain embodiments, R⁵ is - CH(SR⁸)(SR⁹). [00167] In certain embodiments, R⁴ and R⁵ are the same. In certain embodiments, R⁴ and R⁵ are different. R⁶ and R⁷ [00168] As disclosed in Formula (CT), in certain embodiments, R⁶ and R⁷ are each independently optionally substituted C₁-C₁₄ aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C₃-C₈ cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)- , -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. [00169] In certain embodiments, R⁶ and R⁷ are the same. In certain embodiments, R⁶ and R⁷ are different. [00170] In certain embodiments, R⁶ is optionally substituted C1-C14 aliphatic. In certain embodiments, R⁶ is optionally substituted C₁-C₁₄ alkylene. In certain embodiments, R⁶ is optionally substituted C₁-C₁₄ branched alkylene. In certain embodiments, R⁶ is optionally substituted C₁-C₁₄ straight chain alkylene. In certain embodiments, R⁶ is optionally substituted C₁-C₁₄ alkenylene. In certain embodiments, R⁶ is optionally substituted C1-C14 branched alkenylene. In certain embodiments, R⁶ is optionally substituted C₁-C₁₄ straight chain alkenylene. In certain embodiments, R⁶ is optionally substituted C₆-C₁₀ alkylene. In certain embodiments, R⁶ is optionally substituted – (CH₂)5CH3. In certain embodiments, R⁶ is optionally substituted –(CH₂)6CH3. In certain embodiments, R⁶ is optionally substituted –(CH₂)7CH3. In certain embodiments, R⁶ is optionally substituted – (CH₂)8CH3. In certain embodiments, R⁶ is optionally substituted –(CH₂)9CH3. [00171] In certain embodiments, one of the methylene linkages of R⁶ is replaced with an optionally substituted C3-C8 cycloalkylenyl, or an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁶ is replaced with an optionally substituted C₃-C₈ cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁶ is replaced with an optionally substituted bridged bicyclic or multicyclic C₅- C₁₄ cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁶ is replaced with an optionally substituted bridged bicyclic or multicyclic C₅-C₁₂ cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl is selected from: , [00172] In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl is a divalent radical of a structure selected from: [00173] In certain embodiments, R⁷ is optionally substituted C1-C14 aliphatic. In certain embodiments, R⁷ is optionally substituted C1-C14 alkylene. In certain embodiments, R⁷ is optionally substituted C₁-C₁₄ branched alkylene. In certain embodiments, R⁷ is optionally substituted C₁-C₁₄ straight chain alkylene. In certain embodiments, R⁷ is optionally substituted C₁-C₁₄ alkenylene. In certain embodiments, R⁷ is optionally substituted C₁-C₁₄ branched alkenylene. In certain embodiments, R⁷ is optionally substituted C₁-C₁₄ straight chain alkenylene. In certain embodiments, R⁷ is optionally substituted C6-C10 alkylene. In certain embodiments, R⁷ is optionally substituted – (CH₂)₅CH₃. In certain embodiments, R⁷ is optionally substituted –(CH₂)₆CH₃. In certain embodiments, R⁷ is optionally substituted –(CH₂)₇CH₃. In certain embodiments, R⁷ is optionally substituted – (CH₂)8CH3. In certain embodiments, R⁷ is optionally substituted –(CH₂)9CH3. [00174] In certain embodiments, one of the methylene linkages of R⁷ is replaced with an optionally substituted C₃-C₈ cycloalkylenyl, or an optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁷ is replaced with an optionally substituted C3-C8 cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁷ is replaced with an optionally substituted bridged bicyclic or multicyclic C5- C₁₄ cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁷ is replaced with an optionally substituted bridged bicyclic or multicyclic C₅-C₁₂ cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl is selected from: , [00175] In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl is a divalent radical of a structure selected from: In certain embodiments, each R⁶ and R⁷ are selected from , [00176] As disclosed in Formula (CT), in certain embodiments, R⁸ is optionally substituted C₁-C₁₄ aliphatic, wherein at least one methylene linkage is replaced with an optionally substituted divalent radical of a structure selected from In some embodiments, R⁸ is a structure selected from In some embodiments, R⁸ is optionally substituted C₁-C₁₃ alkylene terminated with a monovalent radical of a structure selected from , , , , , , , , , , , embodiments, R⁸ is a structure selected from

In certain embodiments, R⁸ is optionally substituted C1-C13 alkylene terminated with a structure selected from , , , , , , , , a d . [00177] In certain embodiments, R⁸ is a structure selected from [00178] In certain embodiments, R⁸ is optionally substituted C₁-C₁₃ alkylene terminated with a structure selected from [_00179] In certain embodiments, R⁸ is an optionally substituted -CH₂-, -(CH₂)₂-, -(CH₂)₃-, - (CH₂)4-, -(CH₂)5-, or -(CH₂)6-, terminated with a structure selected from , , In certain embodiments, R⁸ is a structure selected from the group consisting of . In certain embodiments, R⁸ is a structure selected from [00180] In certain embodiments, R⁸ is a structure selected from and In certain embodiments, R⁸ is an optionally substituted -CH₂-, -(CH₂)₂-, -(CH₂)₃-, - (CH₂)₄-, -(CH₂)₅-, or -(CH₂)₆-, terminated with a structure selected from and . [00181] In certain embodiments, the optionally substituted divalent radical of the above noted structures is substituted with one or more substituents independently selected from -CH₃, -CH₂CH₃, - (CH₂)2CH3, -CH(CH3)2, and -C(CH3)3. R⁹ [00182] As disclosed in Formula (CT), in certain embodiments, R⁹ is optionally substituted C₁-C₁₄ aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-. [00183] In certain embodiments, R⁸ and R⁹ are the same. In certain embodiments, R⁸ and R⁹ are different. [00184] In certain embodiments, R⁹ is optionally substituted C₁-C₁₄ aliphatic. In certain embodiments, R⁹ is optionally substituted C1-C14 alkylene. In certain embodiments, R⁹ is optionally substituted C1-C14 branched alkylene. In certain embodiments, R⁹ is optionally substituted C1-C14 straight chain alkylene. In certain embodiments, R⁶ is optionally substituted C1-C14 alkenylene. In certain embodiments, R⁹ is optionally substituted C₁-C₁₄ branched alkenylene. In certain embodiments, R⁹ is optionally substituted C₁-C₁₄ straight chain alkenylene. In certain embodiments, R⁹ is optionally substituted C₆-C₁₀ alkylene. In certain embodiments, R⁹ is optionally substituted – (CH₂)₅CH₃. In certain embodiments, R⁹ is optionally substituted –(CH₂)₆CH₃. In certain embodiments, R⁹ is optionally substituted –(CH₂)7CH3. In certain embodiments, R⁹ is optionally substituted – (CH₂)8CH3. In certain embodiments, R⁹ is optionally substituted –(CH₂)9CH3. [00185] In certain embodiments, one of the methylene linkages of R⁹ is replaced with an optionally substituted C3-C8 cycloalkylenyl, or an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁹ is replaced with an optionally substituted C3-C8 cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁹ is replaced with an optionally substituted bridged bicyclic or multicyclic C5- C₁₄ cycloalkylenyl. In certain embodiments, one of the methylene linkages of R⁹ is replaced with an optionally substituted bridged bicyclic or multicyclic C₅-C₁₂ cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C₅-C₁₄ cycloalkylenyl is selected from: , [00186] In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl is a divalent radical of a structure selected from: [00187] In certain embodiments, R⁹ is selected from , [00188] In some embodiments, R⁵ is optionally substituted -C₁-C₆ aliphatic-R⁸ or -R⁸ and R⁹ is absent. [00189] In some embodiments, Lipids of the Present Disclosure are selected from any lipid in Table (I) below or a pharmaceutically acceptable salt thereof: Table (I). Non-Limiting Examples of Ionizable Lipids of the Present Disclosure where n is an integer selected from 0-6. In some embodiments, n is 1. [00190] In some embodiments, Lipids of the Present Disclosure are selected from any lipid in Table (IA) below or a pharmaceutically acceptable salt thereof: Table (IA). Non-Limiting Examples of Ionizable Lipids of the Present Disclosure

[00191] In some embodiments, Lipids of the Disclosure are selected from any lipid in Table (I) and Table (IA) above, any enantiomer thereof, or any mixture of enantiomers thereof, or a pharmaceutically acceptable salt of any of the aforementioned. ii. Structural lipids [00192] In some embodiments, an LNP comprises a structural lipid. In some embodiments, an LNP comprises two or more structural lipids. Structural lipids can be selected from the group consisting of, but are not limited to, cholesterol, fecosterol, fucosterol, beta sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, litocholic acid, tomatine, ursolic acid, alpha-tocopherol, Vitamin D3, Vitamin D2, Calcipotriol, botulin, lupeol, oleanolic acid, beta-sitosterol-acetate and mixtures thereof. In some embodiments, the structural lipid is cholesterol. In some embodiments, the structural lipid is a cholesterol analogue disclosed by Patel, et al., Nat Commun., 11, 983 (2020), which is incorporated herein by reference in its entirety. In some embodiments, the structural lipid includes cholesterol and a corticosteroid (such as prednisolone, dexamethasone, prednisone, and hydrocortisone), or any combinations thereof. In some embodiments, a structural lipid is described in international patent application WO2019152557A1, which is incorporated herein by reference in its entirety. [00193] In some embodiments, a structural lipid is a cholesterol analog. Using a cholesterol analog may enhance endosomal escape as described in Patel et al., Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA, Nature Communications (2020), which is incorporated herein by reference. [00194] In some embodiments, a structural lipid is a phytosterol. Using a phytosterol may enhance endosomal escape as described in Herrera et al., Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery, Biomaterials Science (2020), which is incorporated herein by reference. [00195] In some embodiments, a structural lipid contains plant sterol mimetics for enhanced endosomal release. [00196] In some embodiments, the structural lipid is cholesteryl hemisuccinate (CHEMS). In some embodiments, the structural lipid is 3-(4-((2-(4-morpholinyl)ethyl)amino)-4-oxobutanoate) (Mochol). iii. PEGylated lipids [00197] A PEGylated lipid is a lipid modified with polyethylene glycol. The term “PEGylated lipid” is used interchangeably herein with the shortened term “PEG lipid”. [00198] In some embodiments, an LNP comprises one, two or more PEGylated lipid or PEG- modified lipid. A PEGylated lipid may be selected from the non-limiting group consisting of PEG- modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG- DMPE, PEG-DPPC, or a PEG-DSPE lipid. [00199] In some embodiments, the PEGylated lipid is selected from (R)-2,3- bis(octadecyloxy)propyl-1-(methoxypoly(ethyleneglycol)2000)propylcarbamate, PEG-S-DSG, PEG- S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG- DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEGA, PEG750-C- DMA, PEG400, PEG2k-DMG, PEG2k-C11, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000- DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG Click C12, PEG Click C10, N(Carbonyl-methoxypolyethylenglycol-2000)-l,2-distearoyl-sn-glycero3-phosphoethanolamine, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mDPPE-PEG2000, l,2-distearoyl-sn- glycero-3-phosphoethanolamine-PEG2000, HPEG-2K-LIPD, Folate PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2k, DSPE- PEG2000maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-Peg, DMPE-mPEG2000, DMG-PEGMA, DMG-PEG2000, DMG-PEG, distearoyl-glycerol-polyethyleneglycol, C18PEG750, C18PEG5000, C18PEG3000, C18PEG2000, C16PEG2000, C14PEG2000, C18-PEG5000, C18PEG, C16PEG, C16 mPEG (polyethylene glycol) 2000 Ceramide, C14-PEG-DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3- bis(octadecyloxy)propyl-1-(methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C-DMA, and DSPE-PEG-X. [00200] In some embodiments, the LNP comprises a PEGylated lipid disclosed in one of US 2019/0240354; US 2010/0130588; US 2021/0087135; WO 2021/204179; US 2021/0128488; US 2020/0121809; US 2017/0119904; US 2013/0108685; US 2013/0195920; US 2015/0005363; US 2014/0308304; US 2013/0053572; WO 2019/232095A1; WO 2021/077067; WO 2019/152557; US 2015/0203446; US 2017/0210697; US 2014/0200257; or WO 2019/089828A1, each of which is incorporated by reference herein in their entirety. [00201] In some embodiments, the LNP comprises a PEGylated lipid disclosed and described in PCT Publication WO2024044728A1 filed August 25, 2023, which is incorporated by reference herein, in its entirety. In certain embodiments, the PEGylated lipid is a lipid of any one of formulas PL-I’, PL-I’’, PL-I, PL-Ia, PL-Ib, PL-Iaa, PL-Iab, PL-Iac, PL-Iad, PL-Iae, PL-Iaf, PL-Iag, PL-Iah, PL- Iba, PL-Ibb, PL-Ibc, PL-Ibd, PL-Ibe, PL-Ibf, PL-Ibg, PL-Ibh, PL-Ica, PL-Icb, PL-Icc, PL-Icd, PL-Id PL-Ie, PL-If, PL-Ig, PL-Ih, PL-Ii, PL-Iha, PL-Ihb, PL-Ihc, PL-Ihd, PL-Iia, PL-Iib, PL-Iic, PL-Iid, PL- Ij, PL-Ik, L-Il, PL-Im, PL-In, PL-Io, PL-Ip, PL-Iq, PL-Ioa, PL-Iob, PL-Ioc, PL-Iod, PL-Ioe, PL-Iof, PL-Iog, PL-Ioh, PL-Ipa, PL-Ipb, PL-Ipc, PL-Ipd, PL-Ipe, PL-Ipf, PL-Ipg, PL-Iph, PL-Iqa, PL-Iqb, PL-Iqc, PL-Iqd, PL-Ir, PL-Is, PL-It, PL-Iu, PL-Iv, PL-Iw, PL-Iva, PL-Ivb, PL-Ivc, PL-Ivd, PL-Iwa, PL-Iwb, PL-Iwc, PL-Iwd, PL-Ix, PL-Ixx, PL-Iy, PL-Iyy, PL-Iyyy, PL-Iz, PL-Izz, PL-Izzz, PL-II’, PL- II’’, PL-II, PL-IIc, PL-IId, PL-IIe, PL-IIf, PL-IIg, PL-IIh, PL-IIa, PL-IIb, PL-IIk, PL-IIm or PL-IIn. [00202] In some embodiments, the PEGylated lipid is a compound of formula PL-I’: or a pharmaceutically acceptable salt thereof, wherein: A¹ is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R⁴; X¹ is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-; L¹ is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH₂-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-; L² and L³ are independently a covalent bond or C_1-6 alkylene wherein one methylene unit of the C_1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)₂-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R⁵)=N-, or - C(R⁵)=N-O-; R¹ is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl; R² and R³ are independently a straight or branched C_6-30 alkyl, straight or branched C_6-30 alkenyl, or straight or branched C_6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C_3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of R^x; R⁴ is C1-4 alkyl; R⁵ is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R^x is independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2. [00203] In some embodiments, the PEGylated lipid is a compound of formula PL-II’: or a pharmaceutically acceptable salt thereof, wherein: X¹ is -N(H)-, -N(C_1-6 alkyl)-, -C_1-6 aliphatic-N(H)-, -C_1-6 aliphatic-N(C_1-6 alkyl)-, -O- or -C_1-6 aliphatic-O-; L¹ is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-; L² and L³ are a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)₂-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R⁶)=N-, or -C(R⁶)=N- O-; R¹ is H, C_1-6 alkyl, -(C_1-6 alkyl)-N₃, -(C_1-6 alkyl)-SH, or C_3-8 alkynyl; R² and R³ are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of R^x; R⁶ is C_1-6 alkyl or C_2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R^x is independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4. [00204] In some embodiments, the PEGylated lipid compound is one of those shown in Table (I-X), or a pharmaceutically acceptable salt thereof. Table (I-X). Exemplary PEGylated Compounds

[00205] In some embodiments, the LNP comprises a PEGylated lipid substitute in place of the PEGylated lipid. All embodiments disclosed herein that contemplate a PEGylated lipid should be understood to also apply to PEGylated lipid substitutes. In some embodiments, the LNP comprises a polysarcosine-lipid conjugate, such as those disclosed in US 2022/0001025 A1, which is incorporated by reference herein in its entirety. In some embodiments the LNP comprises a polyoxazoline-lipid conjugate, such as those disclosed in US 2022/0249695 A1, which is incorporated by reference herein in its entirety. iv. Phospholipids [00206] In some embodiments, an LNP of the present disclosure comprises a phospholipid. In some embodiments, an LNP of the present disclosure comprises two or more phospholipids. Phospholipids useful in the compositions and methods may be selected from the non-limiting group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn- glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3- phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2- dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn- glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2- dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3- ((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell- fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), 1,2-Dielaidoyl-sn- phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl- phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn- glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2-dilinoleoyl-sn-glycero-3-phospho-L- serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1- stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3- phospho-L-serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. In some embodiments, an LNP includes DSPC. In certain embodiments, an LNP includes DOPE. In some embodiments, an LNP includes both DSPC and DOPE. [00207] In some embodiments, the LNP comprises a phospholipid selected from 1- pentadecanoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-myristoyl-2-palmitoyl-sn-glycero-3- phosphocholine, 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-myristoyl-sn- glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2- oleoyl-glycero-3-phosphocholine, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-palmitoyl- 2-arachidonoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3- phosphocholine, 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-palmitoyl-sn- glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-linoleoyl- sn-glycero-3-phosphocholine, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2- docosahexaenoyl-sn-glycero-3-phosphocholine, 1-oleoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-oleoyl-2-palmitoyl-sn-glycero-3-phosphocholine, 1-oleoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-acetyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo- inositol-3’,4’-bisphosphate), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol-3’,5’-bisphosphate), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol-4’,5’-bisphosphate), 1,2-dioleoyl-sn-glycero-3- phospho-(1'-myo-inositol-3',4',5'-trisphosphate), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol- 3’-phosphate), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol-4’-phosphate), 1,2-dioleoyl-sn- glycero-3-phospho-(1'-myo-inositol-5'-phosphate), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo- inositol), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine, and 1-(8Z-octadecenoyl)-2-palmitoyl-sn- glycero-3-phosphocholine. [00208] In some embodiments, the LNP comprises a phospholipid selected from DSPS (Distearoylphosphatidylserine), DSPG (1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)), DSPA (1,2-Distearoyl-sn-glycero-3-phosphate), diPhyPC (1,2-diphytanoyl-sn-glycero-3-phosphocholine), diPhy-diether-PC (1,2-di-O-phytanyl-sn-glycero-3-phosphocholine), diPhyPE (1,2-diphytanoyl-sn- glycero-3-phosphoethanolamine), diPhy-diether-PE (1,2-di-O-phytanyl-sn-glycero-3- phosphoethanolamine), diPhyPS (1,2-diphytanoyl-sn-glycero-3-phospho-L-serine), diPhyPG (1,2- diphytanoyl-sn-glycero-3-phospho-(1'-rac-glycerol)), diPhyPA (1,2-diphytanoyl-sn-glycero-3- phosphate), Egg PA (L-α-phosphatidic acid), and Soy PA (L-α-phosphatidic acid). [00209] In some embodiments, the LNP comprises a phospholipid selected from 18:1 (Δ9- Cis) PE (DOPE), 18:0-18:1 PE (SOPE), C16-18:1 PE, 16:0-18:1 PE (POPE), 18:1 BMP (S,R), 18:0- 18:1 PC (SOPC), 16:0-18:1 PC (POPC), 4ME 16:0 Diether PE (4Me), 18:1 (Δ9-Trans) PE (DEPE), 16:1 PE (DPPE), and CL. In certain embodiments, the LNP comprises a phospholipid described or disclosed in Alvarez-Benedicto, et al. (Biomater. Sci., 2022, 10, 549) and Li, et al. (Asian Journal of Pharmaceutical Sciences, 2015, 10, 81-98). [00210] In certain embodiments, the phospholipid is a sphingoid lipid or sphingolipid, such as, but not limited to sphingomyelin. As used herein, the terms “sphingoid lipid” and “sphingolipid” are meant to refer to a class of lipids containing a backbone comprising a sphingoid base. An exemplary sphingoid base is sphingosine. In certain embodiments, the LNP comprises a sphingolipid selected from Egg Sphingomyelin (Egg SM / ESM / (2S,3R,E)-3-hydroxy-2-palmitamidooctadec-4- en-1-yl (2-(trimethylammonio)ethyl) phosphate), Brain or Porcine Sphingomyelin (Brain SM / (2S,3R,E)-3-hydroxy-2-stearamidooctadec-4-en-1-yl (2-(trimethylammonio)ethyl) phosphate), Milk or Bovine Sphingomyelin (Milk SM / (2S,3R,E)-3-hydroxy-2-tricosanamidooctadec-4-en-1-yl (2- (trimethylammonio)ethyl) phosphate), 28:0 SM (N-octacosanoyl-D-erythro- sphingosylphosphorylcholine), 14:0 SM (N-myristoyl-D-erythro-sphingosylphosphorylcholine), 16:1 SM (N-palmitoleoyl-D-erythro-sphingosylphosphorylcholine), 12:0 Dihydro SM (N-lauroyl-D- erythro-sphinganylphosphorylcholine), Lyso SM (Sphingosylphosphorylcholine), Lyso SM (Sphingosylphosphorylcholine), Lyso SM (dihydro) (Sphinganine Phosphorylcholine), 24:1 SM (N- nervonoyl-D-erythro-sphingosylphosphorylcholine), 24:0 SM (N-lignoceroyl-D-erythro- sphingosylphosphorylcholine), 18:1 SM (N-oleoyl-D-erythro-sphingosylphosphorylcholine), 18:0 SM (N-stearoyl-D-erythro-sphingosylphosphorylcholine), 17:0 SM (N-heptadecanoyl-D-erythro- sphingosylphosphorylcholine), 16:0 SM (N-palmitoyl-D-erythro-sphingosylphosphorylcholine), 12:0 SM (N-lauroyl-D-erythro-sphingosylphosphorylcholine), 06:0 SM (N-hexanoyl-D-erythro- sphingosylphosphorylcholine), 02:0 SM (N-acetyl-D-erythro-sphingosylphosphorylcholine), 3-O- methyl Lyso SM (3-O-methyl-spingosylphosphorylcholine), 3-O-methyl-N-methyl Lyso SM (3-O- methyl-N-methyl-spingosylphosphorylcholine), and 3-N-methyl Lyso SM (3-N-methyl- spingosylphosphorylcholine). [00211] In some embodiments, the LNP comprises at least two phospholipids. In certain embodiments, at least a portion of the overall phospholipid content comprises a non- phosphatidylcholine phospholipid, wherein a “non-phosphatidylcholine phospholipid” is a phospholipid that does not comprise a phosphatidylcholine moiety. Exemplary non- phosphatidylcholine phospholipids include, but are not limited to, DOPE, DSPS, and DSPG. In certain embodiments, the LNP comprises at least 5 mol% of a non-phosphatidylcholine phospholipid. In certain embodiments, the LNP comprises at least 6 mol% of a non-phosphatidylcholine phospholipid. In certain embodiments, the LNP comprises at least 10 mol% of a non- phosphatidylcholine phospholipid. [00212] In some embodiments, the LNP comprises a phospholipid comprising at least one constrained tail, such as those described by Gan, et al. (Bioeng Transl Med.2020 Sep; 5(3): e10161.). In certain embodiments, the phospholipid is one selected from: . [00213] In some embodiments, the LNP comprises a phospholipid comprising a ceramide analogue having a triazole linkage, such as those described by Kim et al., Bioorg. Med. Chem. Lett., 17(16), 2007, 4584-4587. [00214] In some embodiments, the LNP comprises a phospholipid disclosed in WO 2023/141470, which is incorporated by reference herein, in its entirety. In certain embodiments, the [00215] In some embodiments, the LNP comprises a phospholipid disclosed in WO 2022/040641, which is incorporated by reference herein, in its entirety. [00216] In some embodiments, a phospholipid tail may be modified in order to promote endosomal escape as described in U.S.2021/0121411, which is incorporated herein by reference. [00217] In some embodiments, the LNP comprises a phospholipid disclosed in one of US 2019/0240354; US 2010/0130588; US 2021/0087135; WO 2021/204179; US 2021/0128488; US 2020/0121809; US 2017/0119904; US 2013/0108685; US 2013/0195920; US 2015/0005363; US 2014/0308304; US 2013/0053572; WO 2019/232095A1; WO 2021/077067; WO 2019/152557; US 2017/0210697; or WO 2019/089828A1, each of which is incorporated by reference herein in their entirety. [00218] In some embodiments, phospholipids disclosed in US 2020/0121809 have the following structure: wherein R1 and R2 are each independently a branched or straight, saturated or unsaturated carbon chain (e.g., alkyl, alkenyl, alkynyl). v. Targeting moieties [00219] In some embodiments, the lipid nanoparticle further comprises a targeting moiety. The targeting moiety may be an antibody or a fragment thereof. The targeting moiety may be capable of binding to a target antigen. In certain embodiments, the lipid nanoparticle comprises more than one targeting moiety. In certain embodiments, the lipid nanoparticle comprises more than one targeting moiety, wherein the targeting moieties target at least two different receptors, and in some embodiments, the at least two different receptors are prevalent on different types of cells or tissues. [00220] In some embodiments, the pharmaceutical composition comprises a targeting moiety that is operably connected to a lipid nanoparticle. In some embodiments, the targeting moiety is capable of binding to a target antigen. In some embodiments, the target antigen is expressed in a target organ. In some embodiments, the target antigen is expressed more in the target organ than it is in the liver. [00221] In some embodiments, the targeting moiety is an antibody as described in WO2016189532A1, which is incorporated herein by reference. For example, in some embodiments, the targeted particles are conjugated to a specific anti-CD38 monoclonal antibody (mAb), which allows specific delivery of the siRNAs encapsulated within the particles at a greater percentage to B- cell lymphocytes malignancies (such as MCL) than to other subtypes of leukocytes. [00222] In some embodiments, the targeting moiety targets a receptor selected from CD20, CCR7, CD3, CD4, CD5, CD8, CD16, CD19, CD20, CD21, CD22, CD25, CD28, CD35, CD40, CD45RA, CD45RO, CD52, CD62L, CD80, CD95, CD127, and CD137. In some embodiments, the targeting moiety targets a receptor selected from CD1, CD2, CD3, CD5, CD7, CD8, CD16, CD25, CD26, CD27, CD28, CD30, CD38, CD39, CD40L, CD44, CD45, CD62L, CD69, CD73, CD80, CD83, CD86, CD95, CD103, CD119, CD126, CD150, CD153, CD154, CD161, CD183, CD223, CD254, CD275, CD45RA, CXCR3, CXCR5, FasL, IL18R1, CTLA-4, 0X40, GITR, LAG3, ICOS, PD-1, leu-12, TCR, TLR1, TLR2, TLR3, TLR4, TLR6, NKG2D, CCR, CCR1, CCR2, CCR4, CCR6, and CCR7. In some embodiments, the targeting moiety targets a receptor selected from CD2, CD3, CD5 and CD7. In some embodiments, the targeting moiety targets a receptor selected from CD2, CD3, CD5, CD7, CD8, CD4, beta 7 integrin, beta 2 integrin, and C1q. In some embodiments, the targeting moiety targets CD117. In some embodiments, the targeting moiety targets CD90. In some embodiments, the targeting moiety targets a receptor selected from a mannose receptor, CD206 and C1q. In some embodiments, the targeting moiety is selected from T-cell receptor motif antibodies, T- cell α chain antibodies, T-cell β chain antibodies, T-cell γ chain antibodies, T-cell δ chain antibodies, CCR7 antibodies, CD3 antibodies, CD4 antibodies, CD5 antibodies, CD7 antibodies, CD8 antibodies, CD11b antibodies, CD11c antibodies, CD16 antibodies, CD19 antibodies, CD20 antibodies, CD21 antibodies, CD22 antibodies, CD25 antibodies, CD28 antibodies, CD34 antibodies, CD35 antibodies, CD40 antibodies, CD45RA antibodies, CD45RO antibodies, CD52 antibodies, CD56 antibodies, CD62L antibodies, CD68 antibodies, CD80 antibodies, CD95 antibodies, CD117 antibodies, CD127 antibodies, CD133 antibodies, CD137 (4-1BB) antibodies, CD163 antibodies, F4/80 antibodies, IL- 4Rα antibodies, Sca-1 antibodies, CTLA-4 antibodies, GITR antibodies GARP antibodies, LAP antibodies, granzyme B antibodies, LFA-1 antibodies, transferrin receptor antibodies, and fragments thereof. In certain embodiments, the targeting moiety is any one described or contemplated in US20230312713A1, US20230203538A1, US20230320995A1, US20160145348, and US20110038941, each of which is incorporated by reference herein in its entirety. [00223] In some embodiments, the targeting moiety is a small molecule. In some embodiments, the small molecule binds to an ectoenzyme on an immune cell, wherein the ectoenzyme is selected from the group consisting of CD38, CD73, adenosine 2a receptor, and adenosine 2b receptor. In some embodiments, the small molecule is mannose, a lectin, acivicin, biotin, or digoxigenin. [00224] In some embodiments, the lipid nanoparticles may be targeted when conjugated/attached/associated with a targeting moiety such as an antibody, or a fragment thereof. vi. Zwitterionic amino lipids [00225] In some embodiments, an LNP comprises a zwitterionic lipid. In some embodiments, an LNP comprising a zwitterionic lipid does not comprise a phospholipid. [00226] Zwitterionic amino lipids have been shown to be able to self-assemble into LNPs without phospholipids to load, stabilize, and release mRNAs intracellularly as described in U.S. Patent Application 20210121411, which is incorporated herein by reference in its entirety. Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR-Cas9 gene editing in spleen, liver and lungs as described in Liu et al., Membrane-destablizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing, Nat Mater. (2021), which is incorporated herein by reference in its entirety. [00227] The zwitterionic lipids may have head groups containing a cationic amine and an anionic carboxylate as described in Walsh et al., Synthesis, Characterization and Evaluation of Ionizable Lysine-Based Lipids for siRNA Delivery, Bioconjug Chem. (2013), which is incorporated herein by reference in its entirety. Ionizable lysine-based lipids containing a lysine head group linked to a long-chain dialkylamine through an amide linkage at the lysine α-amine may reduce immunogenicity as described in Walsh et al., Synthesis, Characterization and Evaluation of Ionizable Lysine-Based Lipids for siRNA Delivery, Bioconjug Chem. (2013). vii. Additional lipid components [00228] In some embodiments, the LNP compositions of the present disclosure further comprise one or more additional lipid components capable of influencing the tropism of the LNP. In some embodiments, the LNP further comprises at least one lipid selected from DDAB, EPC, 14PA, 18BMP, DODAP, DOTAP, and C12-200 (see Cheng, et al. Nat Nanotechnol.2020 April; 15(4): 313– 320.; Dillard, et al. PNAS 2021 Vol.118 No.52.). [00229] In some embodiments, an LNP of the present disclosure further comprises one or more additional ionizable lipids, such as, but not limited to those disclosed in one of US 2023/0053437; US 2019/0240354; US 2010/0130588; US 2021/0087135; WO 2021/204179; US 2021/0128488; US 2020/0121809; US 2017/0119904; US 2013/0108685; US 2013/0195920; US 2015/0005363; US 2014/0308304; US 2013/0053572; WO 2019/232095A1; WO 2021/077067; WO 2019/152557; US 2017/0210697; or WO 2019/089828A1, each of which is incorporated by reference herein in their entirety. In certain embodiments, an LNP of the present disclosure further comprises one or more additional ionizable lipids selected from those disclosed in WO2023044343A1 or WO2023044333A1, both of which are incorporated by reference herein in their entirety. [00230] In some embodiments, the LNP compositions of the present disclosure comprise, or further comprise one or more lipids selected from 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine (18:3 PC), Acylcarnosine (AC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), N-oleoyl-sphingomyelin (SPM) (C18:l), N- lignoceryl SPM (C24:0), N-nervonoylshphingomyelin (C24:l), Cardiolipin (CL), l,2-bis(tricosa- 10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), 1,2-Dipalmitoylglycerol-3-hemisuccinate (DGSucc), short-chain bis-n- heptadecanoyl phosphatidylcholine (DHPC), dihexadecoyl-phosphoethanolamine (DHPE), 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), l,2-dilauroyl-sn-glycero-3-PE (DLPE), dimyristoyl glycerol hemisuccinate (DMGS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzylalcohol (DOBA), 1,2-dioleoylglyceryl-3-hemisuccinate (DOGHEMS), N-[2-(2-{2-[2-(2,3-Bis-octadec-9- enyloxy-propoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-3-(3,4,5-dihydroxy-6-hydroxymethyl-tetrahydro- pyran-2-ylsulfanyl)-propionamide (DOGP4αMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl- phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), histaminedistearoylglycerol (HDSG), 1,2-Dipalmitoylglycerol-hemisuccinate-Nα-Histidinyl- Hemisuccinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12-pentacosadiynamide (h-Pegi- PCDA), 2-[l-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1,2-Dipalmitoylglycerol-O-α-histidinyl-Nα- hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), l,2- Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxamide] (MCC-PE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE), 1-myristoyl-2- hydroxy-sn-glycero-phosphocholine (MHPC), a thiol-reactive maleimide headgroup lipid e.g.1,2- dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophenyl)but-yramid (MPB-PE), Nervonic Acid (NA), sodium cholate (NaChol), l,2-dioleoyl-sn-glycero-3-[phosphoethanolamine-N- dodecanoyl (NC12-DOPE), 1-oleoyl-2-cholesteryl hemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethylene glycol(PEG) (e.g., polyethylene glycol-distearoylphosphatidylethanolamine lipid (PEG-PE)), phosphatidylglycerol (PG), partially hydrogenated soy phosphatidylchloline (PHSPC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lissamine rhodamineB- phosphatidylethanolamine lipid (Rh-PE), purified soy-derived mixture of phospholipids (SIOO), phosphatidylcholine (SM), 18-1-trans-PE,1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), soybean phosphatidylcholine (SPC), sphingomyelins (SPM), alpha,alpha-trehalose-6,6'-dibehenate (TDB), l,2-dielaidoyl-sn-glycero-3-phophoethanolamine (transDOPE), ((23S,5R)-3- (bis(hexadecyloxy)methoxy)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran- 2-yl)methylmethylphosphate, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl- sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3- phosphocholine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 16-O-monomethyl PE, 16-O-dimethyl PE, and dioleylphosphatidylethanolamine. B. Exemplary LNP Compositions [00231] In some embodiments, provided herein are LNPs comprising (a): at least one Lipid of the Disclosure; (b) at least one PEG lipid; (c) at least one structural lipid; and (d) at least one non- ionizable lipid and/or a zwitterionic lipid. In some embodiments, the LNPs further comprise an additional ionizable lipid, besides a compound of any Formula described herein. [00232] In some embodiments, the PEG-lipid is selected from the group consisting of PEG-c- DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE. [00233] In some embodiments, the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha-tocopherol. [00234] In some embodiments, the non-ionizable lipid is a phospholipid selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn- glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3- phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2- dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn- glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2- dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3- ((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell- fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3- phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2-dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho- L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), 1- stearoyl-2-linoleoyl-sn-glycero-3-phospho-L-serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3- phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. [00235] In some embodiments, the non-ionizable lipid is a phospholipid selected from the group consisting of Egg Sphingomyelin (Egg SM / ESM / (2S,3R,E)-3-hydroxy-2- palmitamidooctadec-4-en-1-yl (2-(trimethylammonio)ethyl) phosphate), Brain or Porcine Sphingomyelin (Brain SM / (2S,3R,E)-3-hydroxy-2-stearamidooctadec-4-en-1-yl (2- (trimethylammonio)ethyl) phosphate), Milk or Bovine Sphingomyelin (Milk SM / (2S,3R,E)-3- hydroxy-2-tricosanamidooctadec-4-en-1-yl (2-(trimethylammonio)ethyl) phosphate), 28:0 SM (N- octacosanoyl-D-erythro-sphingosylphosphorylcholine), 14:0 SM (N-myristoyl-D-erythro- sphingosylphosphorylcholine), 16:1 SM (N-palmitoleoyl-D-erythro-sphingosylphosphorylcholine), 12:0 Dihydro SM (N-lauroyl-D-erythro-sphinganylphosphorylcholine), Lyso SM (Sphingosylphosphorylcholine), Lyso SM (Sphingosylphosphorylcholine), Lyso SM (dihydro) (Sphinganine Phosphorylcholine), 24:1 SM (N-nervonoyl-D-erythro-sphingosylphosphorylcholine), 24:0 SM (N-lignoceroyl-D-erythro-sphingosylphosphorylcholine), 18:1 SM (N-oleoyl-D-erythro- sphingosylphosphorylcholine), 18:0 SM (N-stearoyl-D-erythro-sphingosylphosphorylcholine), 17:0 SM (N-heptadecanoyl-D-erythro-sphingosylphosphorylcholine), 16:0 SM (N-palmitoyl-D-erythro- sphingosylphosphorylcholine), 12:0 SM (N-lauroyl-D-erythro-sphingosylphosphorylcholine), 06:0 SM (N-hexanoyl-D-erythro-sphingosylphosphorylcholine), 02:0 SM (N-acetyl-D-erythro- sphingosylphosphorylcholine), 3-O-methyl Lyso SM (3-O-methyl-spingosylphosphorylcholine), 3-O- methyl-N-methyl Lyso SM (3-O-methyl-N-methyl-spingosylphosphorylcholine), and 3-N-methyl Lyso SM (3-N-methyl-spingosylphosphorylcholine). [00236] In some embodiments, (a) the PEG lipid is PEG2k-DMG or PEG2k-DSPE or a mixture thereof; (b) the structural lipid is cholesterol; and (c) the phospholipid, non-ionizable lipid or zwitterionic lipid is a sphingolipid or DSPC or a mixture thereof. [00237] In some embodiments, the lipid component of the nanoparticle comprises: (a) about 0 mol% to about 10 mol% of PEG lipid; (b) about 0 mol% to about 30 mol% structural lipid; (c) about 20 mol% to about 45 mol% phospholipid, non-ionizable lipid or zwitterionic lipid; and (d) about 30 mol% to about 60 mol% of a Lipid of the Disclosure. [00238] In some embodiments, the lipid component of the nanoparticle comprises: (a) about 1 mol% to about 2 mol% of PEG lipid; (b) about 25 mol% to about 40 mol% structural lipid; (c) about 20 mol% to about 45 mol% phospholipid, non-ionizable lipid or zwitterionic lipid; and (d) about 30 mol% to about 60 mol% of a Lipid of the Disclosure. [00239] In some embodiments, the lipid component of the nanoparticle comprises: (a) about 2 mol% of PEG lipid; (b) about 25 mol% structural lipid; (c) about 40 mol% phospholipid, non- ionizable lipid or zwitterionic lipid; and (d) about 33 mol% of a Lipid of the Disclosure. [00240] In some embodiments, the lipid component of the nanoparticle comprises: (a) about 2.5 mol% of PEG lipid; (b) about 39 mol% structural lipid; (c) about 10 mol% phospholipid, non- ionizable lipid or zwitterionic lipid; and (d) about 48.5 mol% of a Lipid of the Disclosure. [00241] In some embodiments, the lipid component of the nanoparticle comprises: (a) about 1.5 mol% of PEG lipid; (b) about 40 mol% structural lipid; (c) about 10 mol% phospholipid, non- ionizable lipid or zwitterionic lipid; and (d) about 48.5 mol% of a Lipid of the Disclosure. [00242] In certain embodiments, the lipid component of the nanoparticle composition comprises about 30 mol % to about 60 mol % ionizable lipid, about 0 mol % to about 30 mol % phospholipid, about 18.5 mol % to about 48.5 mol % structural lipid, and about 0 mol% to about 10 mol% of PEG lipid, provided that the total mol % does not exceed 100%. In certain embodiments, the lipid component of the nanoparticle composition comprises about 20 mol % to about 45 mol % ionizable lipid, about 30 mol % to about 60 mol % phospholipid, about 10 mol % to about 30 mol % structural lipid, and about 0 mol% to about 10 mol% of PEG lipid, provided that the total mol % does not exceed 100%. In some embodiments, the lipid component of the nanoparticle composition comprises about 35 mol % to about 55 mol % ionizable lipid, about 5 mol % to about 25 mol % phospholipid, about 30 mol % to about 40 mol % structural lipid, and about 0 mol % to about 10 mol % of PEG lipid, provided that the total mol % does not exceed 100%. In some embodiments, the lipid component of the nanoparticle composition comprises about 30 mol % to about 40 mol % ionizable lipid, about 35 mol % to about 45 mol % phospholipid, about 20 mol % to about 30 mol % structural lipid, and about 0.5 mol % to about 5 mol % of PEG lipid, provided that the total mol % does not exceed 100%. In certain embodiments, the lipid component of the nanoparticle composition comprises about 25 mol % to about 45 mol % ionizable lipid, about 35 mol % to about 50 mol % phospholipid, about 10 mol % to about 25 mol % structural lipid, and about 1 mol% to about 5 mol% of PEG lipid, provided that the total mol % does not exceed 100%. In a particular embodiment, the lipid component comprises about 50 mol % ionizable lipid, about 10 mol % phospholipid, about 38.5 mol % structural lipid, and about 1.5 mol% of PEG lipid. In another particular embodiment, the lipid component comprises about 40 mol % ionizable lipid, about 20 mol % phospholipid, about 38.5 mol % structural lipid, and about 1.5 mol % of PEG lipid. In another particular embodiment, the lipid component comprises about 48.5 mol % ionizable lipid, about 10 mol % phospholipid, about 40 mol % structural lipid, and about 1.5 mol % of PEG lipid. In another particular embodiment, the lipid component comprises about 48.5 mol % ionizable lipid, about 10 mol % phospholipid, about 39 mol % structural lipid, and about 2.5 mol % of PEG lipid. In another particular embodiment, the lipid component comprises about 33 mol % ionizable lipid, about 40 mol % phospholipid, about 25 mol % structural lipid, and about 2 mol % of PEG lipid. In some embodiments, the phospholipid is DOPE or DSPC. In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is a sphingolipid. In some embodiments, the phospholipid is a sphingomyelin. In other embodiments, the PEG lipid is PEG-DMG (eg. PEG2K-DMG). In other embodiments, the PEG lipid is PEG-DSPE (eg. PEG2K-DSPE). In other embodiments, the PEG lipid is PEG-DMPE (eg. PEG2K-DMPE). In other embodiments, the structural lipid is cholesterol. In other embodiments, the PEG lipid is PEG- DMG and/or the structural lipid is cholesterol. In some embodiments, the PEG lipids is PEG2K- DMG, the structural lipid is cholesterol, and the phospholipid is DSPC. In some embodiments, the PEG lipids is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is sphingomyelin. In some embodiments, the PEG lipids is PEG-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In certain embodiments, the LNP comprises about 33mol% ionizable lipid (eg. at least one ionizable lipid of a Formula described herein), about 40mol% of a sphingolipid, about 25mol% cholesterol and about 2mol% PEG2K-DMG. In some embodiments, the PEG lipids is PEG2K-DSPE, the structural lipid is cholesterol, and the phospholipid is DSPC. In some embodiments, the PEG lipids is PEG2K-DSPE, the structural lipid is cholesterol, and the phospholipid is sphingomyelin. In some embodiments, the PEG lipids is PEG- DSPE, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In some embodiments, the PEG lipids is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is DOPE. In some embodiments, the PEG lipids is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is DOPC. In some embodiments, the PEG lipids is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is DLPC. In some embodiments, the PEG lipids is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is DOPS. In some embodiments, the PEG lipids is PEG-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of a phosphatidylcholine lipid and a sphingolipid. In some embodiments, the PEG lipids is PEG-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of a phosphatidylcholine lipid and phosphatidylserine lipid. In some embodiments, the PEG lipids is PEG-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of a phosphatidylcholine lipid and a phosphoethanolamine lipid. In some embodiments, the PEG lipids is PEG-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of a sphingolipid and phosphatidylserine lipid. In some embodiments, the PEG lipids is PEG-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of a sphingolipid and a phosphoethanolamine lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 20mol% of a sphingolipid, about 20mol% of a non-sphingolipid phospholipid, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 10mol% of a sphingolipid, about 30mol% of a non-sphingolipid phospholipid, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 30mol% of a sphingolipid, about 10mol% of a non- sphingolipid phospholipid, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 20mol% sphingomyelin, about 20mol% of a DSPC, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 10mol% sphingomyelin, about 30mol% of a DSPC, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 30mol% sphingomyelin, about 10mol% of a DSPC, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 25mol% cholesterol, about 2mol% of a PEGylated lipid, and about 40% of a mixture of phosphatidylcholine, phosphatidylserine, phosphoethanolamine, and sphingoid lipids. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 25mol% cholesterol, about 2mol% of a PEGylated lipid, and about 40% of a mixture of phosphatidylcholine, phosphatidylserine, phosphoethanolamine, and sphingoid lipids, wherein each of the phosphatidylcholine, phosphatidylserine, phosphoethanolamine, and sphingoid lipids is present in an amount less than 30 mol% of the total lipid component of the LNP. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 25mol% cholesterol, about 2mol% of a PEGylated lipid, and about 40% of a mixture of phosphatidylcholine, phosphatidylserine, phosphoethanolamine, and sphingoid lipids, wherein each of the phosphatidylcholine, phosphatidylserine, phosphoethanolamine, and sphingoid lipids is present in an amount less than 25 mol% of the total lipid component of the LNP. In certain embodiments, LNP is any one of the aforementioned in this paragraph wherein the PEG lipid is PEG2k-DMG. In certain embodiments, LNP is any one of the aforementioned in this paragraph wherein the PEG lipid is PEG2k-DSPE. [00243] In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % DSPC, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % sphingomyelin, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % DOPE, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % DOPC, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % DLPC, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % DOPS, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 40 mol % phospholipid, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In another particular embodiment, LNP comprises about 33 mol % ionizable lipid, about 20 mol % sphingomyelin, about 20 mol% DSPC, about 25 mol % cholesterol, and about 2 mol % of PEG lipid. In certain embodiments, LNP is any one of the aforementioned in this paragraph wherein the PEG lipid is PEG2k-DMG. In certain embodiments, LNP is any one of the aforementioned in this paragraph wherein the PEG lipid is PEG2k-DSPE. [00244] In certain embodiments, the LNP comprises about 43mol% ionizable lipid, about 15mol% of a sphingolipid, about 15mol% of a non-sphingolipid phospholipid, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 25mol% of a sphingolipid, about 15mol% of a non-sphingolipid phospholipid, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In certain embodiments, the LNP comprises about 33mol% ionizable lipid, about 15mol% of a sphingolipid, about 25mol% of a non-sphingolipid phospholipid, about 25mol% cholesterol and about 2mol% of a PEGylated lipid. In some embodiments, the PEG lipid is PEG2K-DSPE, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In some embodiments, the PEG lipid is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 40mol% cholesterol and about 1.5mol% PEG2K-DSPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 40mol% cholesterol and about 1.5mol% PEG2K-DMG. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39mol% cholesterol and about 2.5mol% PEG2K- DSPE. [00245] In another particular embodiment, the lipid component includes about 48.5 mol % ionizable lipid, about 10 mol % phospholipid, about 38.5 mol % structural lipid, and about 3 mol % of PEG lipid. In another particular embodiment, the lipid component includes about 48.5 mol % ionizable lipid, about 10 mol % phospholipid, about 38 mol % structural lipid, and about 3.5 mol % of PEG lipid. In some embodiments, the PEG lipid is PEG2K-DPPE, the structural lipid is cholesterol, and the phospholipid is a DSPC or a mixture of DSPC and sphingomyelin. In some embodiments, the PEG lipid is PEG2K-DPPE, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 40mol% cholesterol and about 1.5mol% PEG2K-DPPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39.5 mol% cholesterol and about 2 mol% PEG2K-DPPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39mol% cholesterol and about 2.5mol% PEG2K- DPPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 38.5 mol% cholesterol and about 3 mol% PEG2K-DPPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 38 mol% cholesterol and about 3.5mol% PEG2K-DPPE. In some embodiments, the PEG lipid is PEG2K-DMG, the structural lipid is cholesterol, and the phospholipid is a DSPC or a mixture of DSPC and sphingomyelin. In some embodiments, the PEG lipid is PEG2K- DMG, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 40mol% cholesterol and about 1.5mol% PEG2K- DMG. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39.5 mol% cholesterol and about 2 mol% PEG2K-DMG. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39mol% cholesterol and about 2.5mol% PEG2K-DMG. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 38.5 mol% cholesterol and about 3 mol% PEG2K-DMG. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 38 mol% cholesterol and about 3.5mol% PEG2K-DMG. In some embodiments, the PEG lipid is PEG2K-DSPE, the structural lipid is cholesterol, and the phospholipid is a DSPC or a mixture of DSPC and sphingomyelin. In some embodiments, the PEG lipid is PEG2K- DSPE, the structural lipid is cholesterol, and the phospholipid is a mixture of DSPC and sphingomyelin. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 40mol% cholesterol and about 1.5mol% PEG2K- DSPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39.5 mol% cholesterol and about 2 mol% PEG2K-DSPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 39mol% cholesterol and about 2.5mol% PEG2K-DSPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 38.5 mol% cholesterol and about 3 mol% PEG2K-DSPE. In certain embodiments, the LNP comprises about 48.5mol% ionizable lipid, about 10mol% of a phospholipid (such as DSPC), about 38 mol% cholesterol and about 3.5mol% PEG2K-DSPE. [00246] In some embodiments, the LNP further comprises a targeting moiety. In some embodiments, the targeting moiety is an antibody or a fragment thereof. [00247] The amount of active agent in a nanoparticle composition may depend on the size, composition, desired target and/or application, or other properties of the nanoparticle composition as well as on the properties of the active agent. For example, the amount of active agent useful in a nanoparticle composition may depend on the size, sequence, and other characteristics of the active agent. The relative amounts of active agent and other elements (e.g., lipids) in a nanoparticle composition may also vary. In some embodiments, the wt/wt ratio of the lipid component to payload in a nanoparticle composition is from about 5:1 to about 60:1, such as 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, and 60:1. The amount of a payload in a nanoparticle composition may, for example, be measured using absorption spectroscopy (e.g., ultraviolet-visible spectroscopy). [00248] In some embodiments, a nanoparticle composition of the present disclosure is formulated to provide a specific N:P ratio. The N:P ratio of the composition refers to the molar ratio of nitrogen atoms in one or more lipids to the number of phosphate groups in an RNA active agent (e.g., a linear or circular mRNA payload). In general, a lower N:P ratio is preferred. The one or more enzymes, lipids, and amounts thereof is selected to provide an N:P ratio from about 2:1 to about 30:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1. In certain embodiments, the N:P ratio is from about 2:1 to about 8:1. In other embodiments, the N:P ratio is from about 5:1 to about 8:1. For example, the N:P ratio is about 5.0:1, about 5.5:1, about 5.67:1, about 6.0:1, about 6.5:1, or about 7.0:1. [00249] The dose of a pharmaceutical composition provided herein can be measured in units of mg/kg, which refers to mg of total nucleic acid used to formulate the LNPs per kg of body weight of a subject (mg of total mRNA/kg). In some embodiments, the pharmaceutical composition is present in the dosage form at a dose of about 10, 9, 8, 7,6, 5, 4, 3, 2, 1.5, 1.0, 0.5, 0.2, 0.1, 0.05, 0.02, 0.01, .005, 0.002, or 0.001 milligram per kilogram (mg/kg, or mpk) body weight, or of a range between (inclusive) any two of the foregoing values. In some embodiments, the pharmaceutical composition is present in the dosage form at a dose of no more than about 10 milligram per kilogram (mg/kg,or mpk) body weight. In some embodiments, the pharmaceutical composition is present in the dosage form at a dose of no more than about 9 mg/kg, no more than about 8mg/kg , no more than about 7 mg/kg, no more than about 6 mg/kg, no more than about 5 mg/kg, no more than about 4 mg/kg, no more than about 3 mg/kg, no more than about2 mg/kg, no more than about l mg/kg, no more than about 0.5 mg/kg, no more than about 0.2 mg/kg, no more than about 0.1 mg/kg, no more than about 0.05 mg/kg, or no more than about 0.01 mg/kg. [00250] In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about 5 milligram per milliliter (mg/mL). In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of about 5, 4-, 3, 2, 1, 0.5, 0.2, or 0.1 milligram per milliliter(mg/mL), or of a range between (inclusive) any two of the foregoing values. [00251] In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about 5 milligram per milliliter (mg/mL). ln some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about 2 milligram per milliliter (mg/mL). In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about 1 milligram per milliliter (mg/mL). In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about 0.5 milligram per milliliter (mg/mL). In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about 0.1 milligram per milliliter (mg/mL). [00252] In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 microgram per milliliter (µg/mL), or of a range between (inclusive) any two of the foregoing values. In some embodiments, the pharmaceutical composition is present in the dosage form at a concentration of no more than about l0, no more than about 9, no more than about 8, no more than about 7, no more than about 6, no more than about 5, no more than about 4, no more than about 3, no more than about 2, no more than about 1, no more than about 0.5, no more than about 0.2, no more than about 0.1 microgram per milliliter (µg/mL). [00253] The characteristics of a nanoparticle composition may depend on the components thereof. For example, a nanoparticle composition including cholesterol as a structural lipid may have different characteristics than a nanoparticle composition that comprises a different structural lipid. Similarly, the characteristics of a nanoparticle composition may depend on the absolute or relative amounts of its components. For instance, a nanoparticle composition including a higher molar fraction of a phospholipid may have different characteristics than a nanoparticle composition including a lower molar fraction of a phospholipid. Characteristics may also vary depending on the method and conditions of preparation of the nanoparticle composition. Nanoparticle compositions may be characterized by a variety of methods. For example, microscopy (e.g., transmission electron microscopy or scanning electron microscopy) may be used to examine the morphology and size distribution of a nanoparticle composition. Dynamic light scattering or potentiometry (e.g., potentiometric titrations) may be used to measure Zeta potentials. Dynamic light scattering may also be utilized to determine particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) may also be used to measure multiple characteristics of a nanoparticle composition, Such as particle size, polydispersity index, and Zeta potential. [00254] In some embodiments, the mean size of a nanoparticle composition is between 10s of nm and 100s of nm, e.g., measured by dynamic light scattering (DLS). For example, the mean size may be from about 40 nm to about 150 nm, such as about 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm. In some embodiments, the mean size of a nanoparticle composition is from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, from about 50 nm to about 60 nm, from about 60 nm to about 100 nm, from about 60 nm to about 90 nm, from about 60 nm to about 80 nm, from about 60 nm to about 70 nm, from about 70 nm to about 100 nm, from about 70 nm to about 90 nm, from about 70 nm to about 80 nm, from about 80 nm to about 100 nm, from about 80 nm to about 90 nm, or from about 90 nm to about 100 nm. In certain embodiments, the mean size of a nanoparticle composition is from about 70 nm to about 100 nm. In a particular embodiment, the mean size is about 80 nm. In other embodiments, the mean size is about 100 nm. [00255] In some embodiments, the LNPs of the present disclosure can be characterized by their shape. In some embodiments, the LNPs are essentially spherical. In some embodiments, the LNPs are essentially rod-shaped (i.e., cylindrical). In some embodiments, the LNPs are essentially disk shaped. [00256] A nanoparticle composition may be relatively homogenous. A polydispersity index may be used to indicate the homogeneity of a nanoparticle composition, e.g., the particle size distribution of the nanoparticle compositions. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A nanoparticle composition may have a polydispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. [00257] The Zeta potential of a nanoparticle composition may be used to indicate the electrokinetic potential of the composition. For example, the Zeta potential may describe the surface charge of a nanoparticle composition. Nanoparticle compositions with relatively low charges, positive or negative, are generally desirable, as more highly charged species may interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the Zeta potential of a nanoparticle composition is from about -10 mV to about +20 mV, from about -10 mV to about +15 mV, from about -10 mV to about +10 mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about -10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV, from about -5 mV to about 0 mV, from about 0 mV, to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV, to about +15 mV, or from about +5 mV to about +10 mV. [00258] The efficiency of encapsulation of a payload describes the amount of payload that is encapsulated or otherwise associated with a nanoparticle composition after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of payload in a solution containing the nanoparticle composition before and after breaking up the nanoparticle composition with one or more organic solvents or detergents. Fluorescence may be used to measure the amount of free payload in a solution. For the nanoparticle compositions described herein, the encapsulation efficiency of a therapeutic and/or prophylactic may be at least 50%, for example 50%, 55%, 60%.65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency is at least 80%. In certain embodiments, the encapsulation efficiency is at least 90%. [00259] Lipids and their method of preparation are disclosed in, e.g., U.S. Patent Nos. 8,569,256, 5,965,542 and U.S. Patent Publication Nos.2016/0199485, 2016/0009637, 2015/0273068, 2015/0265708, 2015/0203446, 2015/0005363, 2014/0308304, 2014/0200257, 2013/086373, 2013/0338210, 2013/0323269, 2013/0245107, 2013/0195920, 2013/0123338, 2013/0022649, 2013/0017223, 2012/0295832, 2012/0183581, 2012/0172411, 2012/0027803, 2012/0058188, 2011/0311583, 2011/0311582, 2011/0262527, 2011/0216622, 2011/0117125, 2011/0091525, 2011/0076335, 2011/0060032, 2010/0130588, 2007/0042031, 2006/0240093, 2006/0083780, 2006/0008910, 2005/0175682, 2005/017054, 2005/0118253, 2005/0064595, 2004/0142025, 2007/0042031, 1999/009076 and PCT Pub. Nos. WO 99/39741, WO 2017/117528, WO 2017/004143, WO 2017/075531, WO 2015/199952, WO 2014/008334, WO 2013/086373, WO 2013/086322, WO 2013/016058, WO 2013/086373, WO2011/141705, and WO 2001/07548 and Semple et. al, Nature Biotechnology, 2010, 28, 172-176, the full disclosures of which are herein incorporated by reference in their entirety for all purposes. [00260] A nanoparticle composition may comprise any substance useful in pharmaceutical compositions. For example, the nanoparticle composition may comprise one or more pharmaceutically acceptable excipients or accessory ingredients such as, but not limited to, one or more solvents, dispersion media, diluents, dispersion aids, suspension aids, granulating aids, disintegrants, fillers, glidants, liquid vehicles, binders, surface active agents, isotonic agents, thickening or emulsifying agents, buffering agents, lubricating agents, oils, preservatives, and other species. Excipients such as waxes, butters, coloring agents, coating agents, flavorings, and perfuming agents may also be comprised. Pharmaceutically acceptable excipients are well known in the art (see for example Remington’s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro: Lippincott, Williams & Wilkins, Baltimore, Md., 2006). III. LNP payload [00261] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of LNP-based RNA medicines (e.g., vaccines, gene therapies, or gene-editing therapeutics). In various embodiments, the LNP-based RNA medicines comprise an LNP delivery system (as described in detail herein) and an encapsulated cargo/payload (e.g., RNA in the case of RNA medicines). [00262] In the case of RNA medicines, the payload can be one or more RNA molecules, including coding RNA (e.g., linear or circular mRNA) or non-coding RNA (e.g., guide RNA, pegRNA, or retron ncRNA). [00263] In various other embodiments, the payloads can include any type of nucleic acid molecule, including coding RNA molecules (e.g., mRNA), guide RNAs for editing systems (e.g., Cas9 guides, Cas12a guides, base editor guides, and prime editor guides), other non-coding RNAs relating to editing systems (e.g., retron ncRNAs), small RNAs (sRNAs)—which refer to a wide variety of polymeric RNA molecules that are generally less than 200 nucleotides in length with various functionalities, such as RNA interference, and include small-interfering RNA (siRNA), microRNAs (miRNA), piwi-interacting RNA (piRNA), repeat associated small interfering RNA (rasiRNA), small nuclear RNA (snRNA or U-RNA), small nucleolar RNA (snoRNA), small rDNA- derived RNA (srRNA), rRNA fragment (tRF), and Y RNA-derived small RNA, tRNA, rRNA, and self-amplifying RNA (saRNA)—and DNA molecules, such as DNA vectors, DNA plasmids, HDR donors, oligonucleotides, primers, etc., and chimeric molecules comprising both DNA and RNA. The cargo nucleic acid molecules may be single-stranded or double-stranded. Such nucleic acid cargo may comprise exactly one molecule. Such nucleic acid cargo may comprise exactly two molecules. Such nucleic acid cargo may comprise exactly three molecules. Such nucleic acid cargo may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 distinct molecules. Such nucleic acid cargo may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 distinct molecules. Such nucleic acid cargo may comprise between 1-25, or 5-30, or 10-35, or 20-40, or up to 100, or more distinct molecules. [00264] In various other aspects, the LNPs described herein may be used to deliver any payload of interest to a biological target, e.g., to a cell or a bodily tissue. The term “payload” refers to an active substance (i.e., not limited to RNA or DNA), such as a small molecule, polypeptide, peptide, carbohydrate, or nucleic acid molecule, and includes, without limitation, mRNA molecules (including linear and circular mRNA) or non-coding RNA molecules (e.g., guide RNAs, pegRNAs, retron ncRNAs) which are encapsulated within the LNPs described herein. In some embodiments, the LNP cargo may comprise an RNP or ribonucleoprotein, such as a gene editing nuclease protein complexed with a cognate guide RNA. [00265] In various embodiments, the payload is an RNA molecule, which may be linear or circular and may comprise one or more functional nucleotide sequences of interest, which may include, but are not limited to coding and non-coding nucleotide sequences. In various embodiments, the non-coding nucleotide sequences may comprise regulatory elements that influence RNA post- transcriptional processing, nuclear translation control sequences, and sequences which encode one or more biological products of interest, e.g., a therapeutic protein or antigen, among other sequence elements that may impact the functioning of the RNA or its encoded products. As used herein, the term “coding region of interest” or “product coding region” or the like may be used to refer to the encoded one or more biological products of interest. Equivalently, a product coding region may be referred to as a “product expression sequence.” [00266] In various embodiments herein, the specification refers to “originator constructs” (or “originator polynucleotide constructs”) and “benchmark constructs” (or “benchmark polynucleotide constructs”), which are embodiments of payloads comprising nucleic acid molecules, i.e., embodiments of linear and/or circular mRNA payloads, and which may comprise a product coding region that encodes a polypeptide, such as, but not limited to an antigen or a therapeutic protein or to components of a gene editing system (e.g., a programmable nuclease). [00267] FIG.2 shows an example of an originator construct 100, which may be a linear or circular mRNA molecule. The originator construct 100 may include at least one product coding region 10 which is or encodes a polypeptide of interest, such as, but not limited to a vaccine antigen or a therapeutic protein. The originator construct 100 may contain 1 or 2 flanking regions 20. The flanking regions 20 may be located 5' to the product coding region 10 and/or 3' to the product coding region 10. In some instances the originator construct 100 does not contain a flanking region 20. The flanking region 20 of the originator construct 100 may include at least one regulatory region 30. At least one flanking region 20 of the originator polynucleotide construct 100 may include at least one identifier region 40. The identifier region 40 may be, but is not limited to, a barcode, label, signal and/or tag. Additionally, the identifier region 40 may be located within the product coding region 10 or may be located in the product coding region 10 and at least one flanking region 20. [00268] In some embodiments, the originator construct comprises from about 5 to about 10,000 nucleotides in length. As a non-limiting examples, the length of the originator construct may be from 5 to 30, from 5 to 50, from 5 to 100, from 5 to 250, from 5 to 500, from 5 to 1,000, from 5 to 1,500, from 5 to 3,000 from 5 to 5,000, from 5 to 7,000, from 5 to 10,000 from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 3,000 to 5,000, from 3,000 to 7,000, from 3,000 to 10,000, from 5,000 to 7,000, from 5,000 to 10,000, and from 7,000 to 10,000 nucleotides in length. [00269] In some embodiments, the length of the product coding region is greater than about 5 nucleotides in length such as, but not limited to, at least or greater than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000 or more than 10,000 nucleotides in length. [00270] In some embodiments, the flanking region may range independently from 0 to 10,000 nucleotides in length such as, but not limited to, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, and 10,000 nucleotides in length. [00271] In some embodiments, the regulatory region may range independently from 0 to 3,000 nucleotides in length such as, but not limited to, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides in length. [00272] In some embodiments, the originator construct may be circularized. In other embodiments, the originator construct may be concatemerized. [00273] Originator constructs which include at least one identifier 40 or “identifier region” 40 (e.g., barcodes, labels, signals and/or tags) may also be referred to as “benchmark constructs” or “benchmark polynucleotide constructs.” The benchmark construct may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more identifiers which may be the same or different throughout the benchmark polynucleotide construct. [00274] In some embodiments, the identifier region may range independently from 1 to 3,000 nucleotides in length such as, but not limited to, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000. As a non-limiting example the identifier region may be 1-5 residues, 2-5 residues, 3-5 residues, 2-7 residues, 3-7 residues, 1-10 residues, 2-10 residues, 3-10 residues, 5-10 residues, 7-10 residues, 1-15 residues, 2-15 residues, 3-15 residues, 5-15 residues, 7-15 residues, 10-15 residues, 12-15 residues, 1-20 residues, 2- 20 residues, 3-20 residues, 5-20 residues, 7-20 residues, 10-20 residues, 12-20 residues, 15-20 residues, 17-20 residues, 1-25 residues, 2-25 residues, 3-25 residues, 5-25 residues, 7-25 residues, 10- 25 residues, 12-25 residues, 15-25 residues, 17-25 residues, 20-25 residues, 1-30 residues, 2-30 residues, 3-30 residues, 5-30 residues, 7-30 residues, 10-30 residues, 12-30 residues, 15-30 residues, 17-30 residues, 20-30 residues, 25-30 residues, 1-35 residues, 2-35 residues, 3-35 residues, 5-35 residues, 7-35 residues, 10-35 residues, 12-35 residues, 15-35 residues, 17-35 residues, 20-35 residues, 25-35 residues, 30-35 residues, 1-35 residues, 2-35 residues, 3-35 residues, 5-35 residues, 7- 35 residues, 10-35 residues, 12-35 residues, 15-35 residues, 17-35 residues, 20-35 residues, 25-35 residues, 30-35 residues, 1-40 residues, 2-40 residues, 3-40 residues, 5-40 residues, 7-40 residues, 10- 40 residues, 12-40 residues, 15-40 residues, 17-40 residues, 20-40 residues, 25-40 residues, 30-40 residues, 35-40 residues, 1-45 residues, 2-45 residues, 3-45 residues, 5-45 residues, 7-45 residues, 10- 45 residues, 12-45 residues, 15-45 residues, 17-45 residues, 20-45 residues, 25-45 residues, 30-45 residues, 35-45 residues, 40-45 residues, 1-50 residues, 2-50 residues, 3-50 residues, 5-50 residues, 7- 50 residues, 10-50 residues, 12-50 residues, 15-50 residues, 17-50 residues, 20-50 residues, 25-50 residues, 30-50 residues, 35-50 residues, 40-50 residues, or 45-50 nucleotides in length. [00275] In some embodiments, the identifier region in the benchmark construct overlaps with the product coding region. As used herein, "overlap" means that at least one nucleotide of the identifier region extends into the product coding region. In some aspects the identifier region overlaps with the product coding region by 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, 40 nucleotides 41 nucleotides, 42 nucleotides, 43 nucleotides, 44 nucleotides, 45 nucleotides, 46 nucleotides, 47 nucleotides, 48 nucleotides, 49 nucleotides, 50 nucleotides or more than 50 nucleotides. In some aspects the identifier region overlaps with the product coding region by 1-5 nucleotides, 2-5 nucleotides, 3-5 nucleotides, 2- 7 nucleotides, 3-7 nucleotides, 1-10 nucleotides, 2-10 nucleotides, 3-10 nucleotides, 5-10 nucleotides, 7-10 nucleotides, 1-15 nucleotides, 2-15 nucleotides, 3-15 nucleotides, 5-15 nucleotides, 7-15 nucleotides, 10-15 nucleotides, 12-15 nucleotides, 1-20 nucleotides, 2-20 nucleotides, 3-20 nucleotides, 5-20 nucleotides, 7-20 nucleotides, 10-20 nucleotides, 12-20 nucleotides, 15-20 nucleotides, 17-20 nucleotides, 1-25 nucleotides, 2-25 nucleotides, 3-25 nucleotides, 5-25 nucleotides, 7-25 nucleotides, 10-25 nucleotides, 12-25 nucleotides, 15-25 nucleotides, 17-25 nucleotides, 20-25 nucleotides, 1-30 nucleotides, 2-30 nucleotides, 3-30 nucleotides, 5-30 nucleotides, 7-30 nucleotides, 10-30 nucleotides, 12-30 nucleotides, 15-30 nucleotides, 17-30 nucleotides, 20-30 nucleotides, 25-30 nucleotides, 1-35 nucleotides, 2-35 nucleotides, 3-35 nucleotides, 5-35 nucleotides, 7-35 nucleotides, 10-35 nucleotides, 12-35 nucleotides, 15-35 nucleotides, 17-35 nucleotides, 20-35 nucleotides, 25-35 nucleotides, 30-35 nucleotides, 1-35 nucleotides, 2-35 nucleotides, 3-35 nucleotides, 5-35 nucleotides, 7-35 nucleotides, 10-35 nucleotides, 12-35 nucleotides, 15-35 nucleotides, 17-35 nucleotides, 20-35 nucleotides, 25-35 nucleotides, 30-35 nucleotides, 1-40 nucleotides, 2-40 nucleotides, 3-40 nucleotides, 5-40 nucleotides, 7-40 nucleotides, 10-40 nucleotides, 12-40 nucleotides, 15-40 nucleotides, 17-40 nucleotides, 20-40 nucleotides, 25-40 nucleotides, 30-40 nucleotides, 35-40 nucleotides, 1-45 nucleotides, 2-45 nucleotides, 3-45 nucleotides, 5-45 nucleotides, 7-45 nucleotides, 10-45 nucleotides, 12-45 nucleotides, 15-45 nucleotides, 17-45 nucleotides, 20-45 nucleotides, 25-45 nucleotides, 30-45 nucleotides, 35-45 nucleotides, 40-45 nucleotides, 1-50 nucleotides, 2-50 nucleotides, 3-50 nucleotides, 5-50 nucleotides, 7-50 nucleotides, 10-50 nucleotides, 12-50 nucleotides, 15-50 nucleotides, 17-50 nucleotides, 20-50 nucleotides, 25-50 nucleotides, 30-50 nucleotides, 35-50 nucleotides, 40-50 nucleotides, or 45-50 nucleotides. [00276] In some embodiments, the benchmark polynucleotide construct comprises a product coding region and an identifier region. The identifier region may be located 5' to the product coding region, 3' to the product coding region, or the identifier region may overlap with the 5' end or the 3'end of the product coding region. [00277] In some embodiments, the benchmark polynucleotide construct comprises a product coding region and two identifier regions. Each identifier region may independently be located 5' to the product coding region, 3' to the product coding region, or the identifier region may overlap with the 5' end or the 3'end of the product coding region. [00278] As a non-limiting example, the first identifier region is located 5' to the product coding region and the second identifier region is located 3' to the product coding region. As a non- limiting example, the first and second identifier regions are located 5' to the product coding region. As a non-limiting example, the first and second identifier regions are located 3' to the product coding region. [00279] As a non-limiting example, the first identifier region is inverted and is located 5' to the product coding region and the second identifier region is located 3' to the product coding region. As a non-limiting example, the first identifier region is inverted and is located 5' to the product coding region and the second identifier region is inverted and is located 3' to the product coding region. As a non-limiting example, the first identifier region is located 5' to the product coding region and the second identifier region is inverted and is located 3' to the product coding region. As a non-limiting example, the first and second identifier regions are both inverted and are located 5' to the product coding region. As a non-limiting example, the first and second identifier regions are located 5' to the product coding region and the first identifier region is inverted. As a non-limiting example, the first and second identifier regions are located 5' to the product coding region and the second identifier region is inverted. As a non-limiting example, the first and second identifier region are both inverted and located 3' to the product coding region. As a non-limiting example, the first and second identifier regions are located 3' to the product coding region and the first identifier region is inverted. As a non- limiting example, the first and second identifier regions are located 3' to the product coding region and the second identifier region is inverted. [00280] As a non-limiting example, the first identifier region is located 5' to the product coding region and overlaps with the product coding region and the second identifier region is located 3' to the product coding region. As a non-limiting example, the first identifier region is located 5' to the product coding region and the second identifier region is located 3' to the product coding region and overlaps with the product coding region. [00281] As a non-limiting example, the first and second identifier regions are located 5' to the product coding region and the second identifier region overlaps with the product coding region. As a non-limiting example, the first and second identifier regions are located 3' to the product coding region and the first identifier region overlaps with the product coding region. [00282] As a non-limiting example, the first identifier region is inverted, is located 5' to the product coding region and overlaps with the product coding region, and the second identifier region is located 3' to the product coding region. As a non-limiting example, the first identifier region is inverted and is located 5' to the product coding region and the second identifier region is located 3' to the product coding region and overlaps with the product coding region. As a non-limiting example, the first identifier region is inverted, is located 5' to the product coding region, the second identifier region is located 3' to the product coding region, and both of the first and second identifier regions overlap with the product coding region. [00283] As a non-limiting example, the first identifier region is inverted, is located 5' to the product coding region and overlaps with the product coding region, and the second identifier region is inverted and is located 3' to the product coding region. As a non-limiting example, the first identifier region is inverted and is located 5' to the product coding region and the second identifier region is inverted, is located 3' to the product coding region and overlaps with the product coding region. As a non-limiting example, the first identifier region is inverted and is located 5' to the product coding region, and the second identifier region is inverted and is located 3' to the product coding region, and both of the first and second identifier regions overlap with the product coding region. [00284] As a non-limiting example, the first identifier region is located 5' to the product coding region and overlaps with the product coding region, and the second identifier region is inverted and is located 3' to the product coding region. As a non-limiting example, the first identifier region is located 5' to the product coding region and the second identifier region is inverted, is located 3' to the product coding region and overlaps with the product coding region. As a non-limiting example, the first identifier region is located 5' to the product coding region and the second identifier region is inverted and is located 3' to the product coding region, and both of the first and second identifier regions overlap with the product coding region. [00285] As a non-limiting example, the first and second identifier regions are both inverted and are located 5' to the product coding region, and the second identifier region overlaps with the product coding region. As a non-limiting example, the first and second identifier regions are located 5' to the product coding region and the first identifier region is inverted, and the second identifier region overlaps with the product coding region. As a non-limiting example, the first and second identifier regions are located 5' to the product coding region and the second identifier region is inverted and overlaps with the product coding region. As a non-limiting example, the first and second identifier region are both inverted and located 3' to the product coding region, and the first identifier region overlap with the product coding region. As a non-limiting example, the first and second identifier regions are located 3' to the product coding region and the first identifier region is inverted and overlaps with the product coding region. As a non-limiting example, the first and second identifier regions are located 3' to the product coding region and the second identifier region is inverted, and the first product coding region overlap with the product coding region. [00286] In some embodiments, at least one identifier moiety may be associated with the benchmark polynucleotide construct. The benchmark polynucleotide construct may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more identifier moieties associated with the benchmark polynucleotide construct which may be the same moiety or different moieties associated with the benchmark polynucleotide construct. Each identifier moiety may independently be located on the flanking region 5' to the product coding region, on the flanking region 3' to the product coding region, or the location of the identifier moiety may span the 5' end or the 3'end of the product coding region and a flanking region. In some aspects the location of the identifier moiety may include one or more nucleotides of the product coding region such as, but not limited to, 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, 40 nucleotides 41 nucleotides, 42 nucleotides, 43 nucleotides, 44 nucleotides, 45 nucleotides, 46 nucleotides, 47 nucleotides, 48 nucleotides, 49 nucleotides, 50 nucleotides or more than 50 nucleotides. In some aspects the location of the identifier moiety may include one or more nucleotides of the product coding region such as, but not limited to, 1-5 nucleotides, 2-5 nucleotides, 3-5 nucleotides, 2-7 nucleotides, 3-7 nucleotides, 1-10 nucleotides, 2-10 nucleotides, 3-10 nucleotides, 5-10 nucleotides, 7-10 nucleotides, 1-15 nucleotides, 2-15 nucleotides, 3-15 nucleotides, 5-15 nucleotides, 7-15 nucleotides, 10-15 nucleotides, 12-15 nucleotides, 1-20 nucleotides, 2-20 nucleotides, 3-20 nucleotides, 5-20 nucleotides, 7-20 nucleotides, 10-20 nucleotides, 12-20 nucleotides, 15-20 nucleotides, 17-20 nucleotides, 1-25 nucleotides, 2-25 nucleotides, 3-25 nucleotides, 5-25 nucleotides, 7-25 nucleotides, 10-25 nucleotides, 12-25 nucleotides, 15-25 nucleotides, 17-25 nucleotides, 20-25 nucleotides, 1-30 nucleotides, 2-30 nucleotides, 3-30 nucleotides, 5-30 nucleotides, 7-30 nucleotides, 10-30 nucleotides, 12-30 nucleotides, 15-30 nucleotides, 17-30 nucleotides, 20-30 nucleotides, 25-30 nucleotides, 1-35 nucleotides, 2-35 nucleotides, 3-35 nucleotides, 5-35 nucleotides, 7-35 nucleotides, 10-35 nucleotides, 12-35 nucleotides, 15-35 nucleotides, 17-35 nucleotides, 20-35 nucleotides, 25-35 nucleotides, 30-35 nucleotides, 1-35 nucleotides, 2-35 nucleotides, 3-35 nucleotides, 5-35 nucleotides, 7-35 nucleotides, 10-35 nucleotides, 12-35 nucleotides, 15-35 nucleotides, 17-35 nucleotides, 20-35 nucleotides, 25-35 nucleotides, 30-35 nucleotides, 1-40 nucleotides, 2-40 nucleotides, 3-40 nucleotides, 5-40 nucleotides, 7-40 nucleotides, 10-40 nucleotides, 12-40 nucleotides, 15-40 nucleotides, 17-40 nucleotides, 20-40 nucleotides, 25-40 nucleotides, 30-40 nucleotides, 35-40 nucleotides, 1-45 nucleotides, 2-45 nucleotides, 3-45 nucleotides, 5-45 nucleotides, 7-45 nucleotides, 10-45 nucleotides, 12-45 nucleotides, 15-45 nucleotides, 17-45 nucleotides, 20-45 nucleotides, 25-45 nucleotides, 30-45 nucleotides, 35-45 nucleotides, 40-45 nucleotides, 1-50 nucleotides, 2-50 nucleotides, 3-50 nucleotides, 5-50 nucleotides, 7-50 nucleotides, 10-50 nucleotides, 12-50 nucleotides, 15-50 nucleotides, 17-50 nucleotides, 20-50 nucleotides, 25-50 nucleotides, 30-50 nucleotides, 35-50 nucleotides, 40-50 nucleotides, or 45-50 nucleotides. [00287] In some embodiments, one identifier moiety may be associated with the benchmark polynucleotide construct. As a non-limiting example, the identifier moiety may be associated with the benchmark polynucleotide construct on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the identifier moiety may be associated with the benchmark polynucleotide construct on the 5' flanking region. As a non-limiting example, the identifier moiety may be associated with the benchmark polynucleotide construct on the 3' flanking region. As a non-limiting example, the identifier moiety may be associated with the benchmark polynucleotide construct on the 3' end of the benchmark polynucleotide construct. As a non-limiting example, the identifier moiety may be associated with the benchmark polynucleotide construct on the product coding region. As a non-limiting example, the benchmark polynucleotide construct comprises an identifier moiety and the location of the identifier moiety spans the 5' end of the product coding region and the 5' flanking region. As a non-limiting example, the benchmark polynucleotide construct comprises an identifier moiety and the location of the identifier moiety spans the 3' end of the product coding region and the 3' flanking region. [00288] In some embodiments, two identifier moieties are associated with the benchmark polynucleotide construct. As a non-limiting example, the first identifier moiety and the second identifier moiety are located on the 5' flanking region. As a non-limiting example, the first identifier moiety and the second identifier moiety are located on the product coding region. As a non-limiting example, the first identifier moiety and the second identifier moiety are located on the 3' flanking region. As a non-limiting example, the first identifier moiety and the second identifier moiety are located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the first identifier moiety and the second identifier moiety are located on the 3' end of the benchmark polynucleotide construct. [00289] As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the second identifier moiety is located on the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the second identifier moiety is located on the 3' flanking region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the location of the second identifier moiety spans the 5' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the second identifier moiety is located on the 3' end of the benchmark polynucleotide construct. [00290] As a non-limiting example, the first identifier moiety is located on the 5' flanking region and the second identifier moiety is located on the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' flanking region and the second identifier moiety is located on the 3' flanking region. As a non-limiting example, the first identifier moiety is located on the 5' flanking region and the location of the second identifier moiety spans the 5' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' flanking region and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' flanking region and the second identifier moiety is located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the first identifier moiety is located on the 5' flanking region and the second identifier moiety is located on the 3' end of the benchmark polynucleotide construct. [00291] As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the product coding region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the 3' flanking region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the 3' end of the benchmark polynucleotide construct. [00292] As a non-limiting example, the first identifier moiety is located on the product coding region and the second identifier moiety is located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the first identifier moiety is located on the product coding region and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the first identifier moiety is located on the product coding region and the location of the second identifier moiety spans the 5' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the product coding region and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the product coding region and the second identifier moiety is located on the 3' flanking region. As a non-limiting example, the first identifier moiety is located on the product coding region and the second identifier moiety is located on the 3' end of the benchmark polynucleotide construct. [00293] As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the second identifier moiety is located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the location of the second identifier moiety spans the 5' flanking region and the product coding region. As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the second identifier moiety is located on the product coding region. As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the second identifier moiety is located on the 3' flanking region. As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the second identifier moiety is located on the 3'end of the benchmark polynucleotide construct. [00294] As a non-limiting example, the location of the first identifier moiety spans the 3' flanking region and the product coding region and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the product coding region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the 3' flanking region. As a non-limiting example, the location of the first identifier moiety spans the 5' flanking region and the product coding region and the second identifier moiety is located on the 3' end of the benchmark polynucleotide construct. [00295] As a non-limiting example, the first identifier moiety is located on the 3' flanking region and the second identifier moiety is located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the first identifier moiety is located on the 3' flanking region and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the first identifier moiety is located on the 3' flanking region and the location of the second identifier moiety spans the 5' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 3' flanking region and the second identifier moiety is located on the product coding region. As a non-limiting example, the first identifier moiety is located on the 3' flanking region and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 3' flanking region and the second identifier moiety is located on the 3' end of the benchmark polynucleotide construct. [00296] As a non-limiting example, the first identifier moiety is located on the 3' end of the benchmark polynucleotide construct and the second identifier moiety is located on the 5' end of the benchmark polynucleotide construct. As a non-limiting example, the first identifier moiety is located on the 3' end of the benchmark polynucleotide construct and the second identifier moiety is located on the 5' flanking region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the location of the second identifier moiety spans the 5' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 3' end of the benchmark polynucleotide construct and the second identifier moiety is located on the product coding region. As a non-limiting example, the first identifier moiety is located on the 5' end of the benchmark polynucleotide construct and the location of the second identifier moiety spans the 3' flanking region and the product coding region. As a non-limiting example, the first identifier moiety is located on the 3' end of the benchmark polynucleotide construct and the second identifier moiety is located on the 3' flanking region. [00297] In some embodiments, three identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, four identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, five identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, six identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, seven identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, eight identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, nine identifier moieties are associated with the benchmark polynucleotide construct. In some embodiments, ten identifier moieties are associated with the benchmark polynucleotide construct. [00298] In some embodiments, the product coding region encodes a biologically active molecule such as, but not limited to a therapeutic protein or an antigen. As used herein, the term "biologically active" refers to a characteristic of any agent that has activity in a biological system, and particularly in an organism. For instance, an agent that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In some embodiments, the CROI encodes one or more prophylactically- or therapeutically-active proteins, polypeptides, or other factors. As a non-limiting example, the CROI may encode an agent that enhances tumor killing activity such as, but not limited to, TRAIL or tumor necrosis factor (TNF), in a cancer. As another non-limiting example, the CROI may encode an agent suitable for the treatment of conditions such as muscular dystrophy (e.g., CROI encodes Dystrophin), cardiovascular disease (e.g., CROI encodes SERCA2a, GATA4, Tbx5, Mef2C, Hand2, Myocd, etc.), neurodegenerative disease (e.g., CROI encodes NGF, BDNF, GDNF, NT-3, etc.), chronic pain (e.g., CROI encodes GlyRal), an enkephalin, or a glutamate decarboxylase (e.g., CROI encodes GAD65, GAD67, or another isoform), lung disease (e.g., CROI encodes CFTR), hemophilia (e.g., CROI encodes Factor VIII or Factor IX), neoplasia (e.g., CROI encodes PTEN, ATM, ATR, EGFR, ERBB2, ERBB3, ERBB4, Notchl, Notch2, Notch3, Notch4, AKT, AKT2, AKT3, HIF, HI Fla, HIF3a, Met, HRG, Bcl2, PPARalpha, PPAR gamma, WT1 (Wilms Tumor), FGF Receptor Family members (5 members: 1, 2, 3, 4, 5), CDKN2a, APC, RB (retinoblastoma), MEN1, VHL, BRCA1, BRCA2, AR (Androgen Receptor), TSG101, IGF, IGF Receptor, Igfl (4 variants), Igf2 (3 variants), Igfl Receptor, Igf2 Receptor, Bax, Bcl2, caspases family (9 members: 1, 2, 3, 4, 6, 7, 8, 9, 12), Kras, Ape), age-related macular degeneration (e.g., CROI encodes Aber, Ccl2, Cc2, cp (ceruloplasmin), Timp3, cathepsin D, Vldlr), schizophrenia (e.g. Neuregulin (Nrgl), Erb4 (receptor for Neuregulin), Complexin-l (Cplxl), Tphl Tryptophan hydroxylase, Tph2 Tryptophan hydroxylase 2, Neurexin 1, GSK3, GSK3a, GSK3b, 5-HIT (Slc6a4), COMT, DRD (Drdla), SLC6A3, DAOA, DTNBPI, Dao (Daol)), trinucleotide repeat disorders (e.g., HTT (Huntington's Dx), SBMA/SMAXI/AR (Kennedy's Dx), FXN/X25 (Friedrich's Ataxia), ATX3 (Machado-Joseph's Dx), ATXNI and ATXN2 (spinocerebellar ataxias), DMPK (myotonic dystrophy), Atrophin-1 and Atnl(DRPLA Dx), CBP (Creb-BP-global instability), VLDLR (Alzheimer's), Atxn7, Atxn10), fragile X syndrome (e.g., CROI encodes FMR2, FXRI, FXR2, mGLUR5), secretase related disorders (e.g., CROI encodes APH-1 (alpha and beta), Presenilin (Psenl), nicastrin (Ncstn), PEN-2), ALS (e.g., CROI encodes SOD1, ALS2, STEX, FUS, TARD BP, VEGF (VEGF-a, VEGF-b, VEGF- c)), autism (e.g., CROI encodes Mecp2, BZRAP1, MDGA2, Sema5A, Neurexin 1), Alzheimer's disease (e.g., CROI encodes El, CHIP, UCH, UBB, Tau, LRP, PICALM, Clusterin, PS1, SORL1, CR1, Vldlr, Ubal, Uba3, CHIP28 (Aqpl, Aquaporin 1), Uchll, Uchl3, APP), inflammation (e.g., CROI encodes IL-10, IL-1 (IL-Ia, IL-Ib), IL-13, IL-17 (IL-17a (CTLA8), IL-17b, IL-17c, IL-17d, IL-171), 11-23, Cx3crl, ptpn22, TNFa, NOD2/CARD15 for IBD, IL-6, IL-12 (IL-12a, IL-12b), CTLA4, Cx3cll), Parkinson's Disease (e.g., x-Synuclein, DJ-1, LRRK2, Parkin, PINK1), blood and coagulation disorders, such as, e.g., anemia, bare lymphocyte syndrome, bleeding disorders, hemophagocytic lymphohistiocytosis disorders, hemophilia A, hemophilia B, hemorrhagic disorders, leukocyte deficiencies and disorders, sickle cell anemia, and thalassemia (e.g., CROI encodes CRAN1, CDA1, RPS19, DBA, PKLR, PK1, NT5C3, UMPH1, PSNI, RHAG, RH50A, NRAMP2, SPTB, ALAS2, ANH1, ASB, ABCB7, ABC7, ASAT, TAPBP, TPSN, TAP2, ABCB3, PSF2, RING11, MHC2TA, C2TA, RFX5, RFXAP, RFX5, TBXA2R, P2RX1, P2X1, HF1, CFH, HUS, MCFD2, FANCA, FAC A, FA1, FA, FA A, FAAP95, FAAP90, FLJ34064, FANCB, FANCC, FACC, BRCA2, FANCDI, FANCD2, FANCD, FACD, FAD, FANCE, FACE, FANCF, XRCC9, FANCG, BR1PI, BACH1, FANCJ, PHF9, FANCL, FANCM, KIAA1596, PRF1, HPLH2, UNC13D, MUNC13-4, HPLH3, HLH3, FHL3, F8, FSC, PI, ATT, F5, ITGB2, CD18, LCAMB, LAD, EIF2B1, EIF2BA, EIF2B2, EIF2B3, EIF2B5, LVWM, CACH, CLE, EIF2B4, HBB, HBA2, HBB, HBD, LCRB, HBA1), B-cell non-Hodgkin lymphoma or leukemia (e.g., CROI encodes BCL7A, BCL7, ALI, TCL5, SCL, TAL2, FLT3, NBS1, NBS, ZNFN1AI, 1KI, LYF1, HOXD4, HOX4B, BCR, CML, PHL, ALL, ARNT, KRAS2, RASK2, GMPS, AFIO, ARHGEF12, LARG, KIAA0382, CALM, CLTH, CEBPA, CEBP, CHIC2, BTL, FLT3, KIT, PBT, LPP, NPMI, NUP214, D9S46E, CAN, CAIN, RUNXI, CBFA2, AML1, WHSC1LI, NSD3, FLT3, AF1Q, NPMI, NUMA1, ZNF145, PLZF, PML, MYL, STAT5B, AF1Q, CALM, CLTH, ARL11, ARLTS1, P2RX7, P2X7, BCR, CML, PHL, ALL, GRAF, NF1, VRNF, WSS, NFNS, PTPNII, PTP2C, SHP2, NS1, BCL2, CCND1, PRAD1, BCL1, TCRA, GATA1, GF1, ERYF1, NFE1, ABLI, NQO1, DIA4, NMOR1, NUP214, D9S46E, CAN, CAIN), inflammation and immune related diseases and disorders (e.g., CROI encodes KIR3DL1, NKAT3, NKB1, AMB11, K1R3DS1, IFNG, CXCL12, TNFRSF6, APT1, FAS, CD95, ALPS1A, IL2RG, SCIDX1, SCIDX, IMD4, CCL5, SCYA5, D17S136E, TCP228, IL10, CSIF, CMKBR2, CCR2, CMKBR5, CCCKR5 (CCR5), CD3E, CD3G, AICDA, AID, HIGM2, TNFRSF5, CD40, UNG, DGU, HIGM4, TNFSFS, CD40LG, HIGM1, IGM, FOXP3, IPEX, AIID, XPID, PIDX, TNFRSF14B, TACI), inflammation (e.g., CROI encodes IL-10, IL-1 (IL-IA, IL-IB), IL-13, IL-17 (IL- 17a (CTLA8), IL-17b, IL-17c, IL-17d, IL-171), 11-23, Cx3crl, ptpn22, TNFa, NOD2/CARD15 for IBD, IL-6, IL-12 (IL-12a, IL-12b), CTLA4, Cx3cII), JAK3, JAKL, DCLREIC, ARTEMIS, SCIDA, RAG1, RAG2, ADA, PTPRC, CD45, LCA, IL7R, CD3D, T3D, IL2RG, SCIDXI, SCIDX, IMD4), metabolic, liver, kidney and protein diseases and disorders (e.g., CROI encodes TTR, PALB, APOA1, APP, AAA, CVAP, ADI, GSN, FGA, LYZ, TTR, PALB, KRT18, KRT8, CIRH1A, NAIC, TEX292, KIAA1988, CFTR, ABCC7, CF, MRP7, SLC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM, TCF1, HNF1A, MODY3, SCOD1, SCOl, CTNNB1, PDGFRL, PDGRL, PRLTS, AX1NI, AXIN, CTNNB1, TP53, P53, LFS1, IGF2R, MPRI, MET, CASP8, MCH5, UMOD, HNFJ, FJHN, MCKD2, ADMCKD2, PAH, PKU1, QDPR, DHPR, PTS, FCYT, PKHD1, ARPKD, PKD1, PKD2, PKD4, PKDTS, PRKCSH, G19P1, PCLD, SEC63), muscular/skeletal diseases and disorders (e.g., CROI encodes DMD, BMD, MYF6, LMNA, LMN1, EMD2, FPLD, CMDIA, HGPS, LGMDIB, LMNA, LMNI, EMD2, FPLD, CMDIA, FSHMD1A, FSHD1A, FKRP, MDC1C, LGMD2I, LAMA2, LAMM, LARGE, KIAA0609, MDC1D, FCMD, TTID, MYOT, CAPN3, CANP3, DYSF, LGMD2B, SGCG, LGMD2C, DMDA1, SCG3, SGCA, ADL, DAG2, LGMD2D, DMDA2, SGCB, LGMD2E, SGCD, SGD, LGMD2F, CMD1L, TCAP, LGMD2G, CMD1N, TRIM32, HT2A, LGMD2H, FKRP, MDCIC, LGMD21, TTN, CMD1G, TMD, LGMD2J, POMT1, CAV3, LGMD1C, SEPN1, SELN, RSMD1, PLEC1, PLTN, EBS1, LRP5, BMNDl, LRP7, LR3, OPPG, VBCH2, CLCN7, CLC7, OPTA2, OSTMI, GL, TCIRG1, TIRC7, OC116, OPTB1, VAPB, VAPC, ALS8, SMN1, SMA1, SMA2, SMA3, SMA4, BSCL2, SPG17, GARS, SMAD1, CMT2D, HEXB, IGHMBP2, SMUBP2, CATF1, SMARD1), neurological and neuronal diseases and disorders (e.g., CROI encodes SOD1, ALS2, STEX, FUS, TARDBP, VEGF (VEGF-a, VEGF-b, VEGF-c), APP, AAA, CVAP, ADI, APOE, AD2, PSEN2, AD4, STM2, APBB2, FE65LI, NOS3, PLAU, URK, ACE, DCPI, ACEI, MPO, PAC1PI, PAXIPIL, PTIP, A2M, BLMH, BMH, PSEN1, AD3, Mecp2, BZRAP1, MDGA2, Sema5A, Neurexin 1, GLOl, MECP2, RTT, PPMX, MRX16, MRX79, NLGN3, NLGN4, KIAA1260, AUTSX2, FMR2, FXR1, FXR2, mGLUR5, HD, IT15, PRNP, PRIP, JPH3, JP3, HDL2, TBP, SCA17, NR4A2, NURR1, NOT, TINUR, SNCAIP, TBP, SCA17, SNCA, NACP, PARK1, PARK4, DJI, PARK7, LRRK2, PARK8, PINK1, PARK6, UCHL1, PARK5, SNCA, NACP, PARKl, PARK4, PRKN, PARK2, PDJ, DBH, NDUFV2, MECP2, RTT, PPMX, MRX16, MRX79, CDKL5, STK9, MECP2, RTT, PPMX, MRX16,MRX79, x- Synuclein, DJ-1, Neuregulin-l (Nrgl), Erb4 (receptor for Neuregulin), Complexin-l (Cplxl), Tphl Tryptophan hydroxylase, Tph2, Tryptophan hydroxylase 2, Neurexin 1, GSK3, GSK3a, GSK3b, 5- HTT (Slc6a4), CONT, DRD (Drdla), SLC6A , DAOA, DTNBP1, Dao (Daol), APH-l(alpha and beta), Presenilin (Psenl), Nicastrin, (Ncstn), PEN-2, Nosl, Parpl, Natl, Nat2, HTT, SBMA/SMAX1/AR, FXN/X25, ATX3, TXN, ATXN2, DMPK, Atrophin-1, Atnl, CBP, VLDLR, Atxn7, and AtxnlO), and ocular diseases and disorders (e.g., Aber, Ccl2, Cc2, cp (ceruloplasmin), Timp3, cathepsin-D, Vldlr, Ccr2, CRYAA, CRYA1, CRYBB2, CRYB2, PITX3, BFSP2, CP49, CP47, CRYAA, CRYAI, PAX6, AN2, MGDA, CRYBA1, CRYB1, CRYGC, CRYG3, CCL, LIM2, MP19, CRYGD, CRYG4, BFSP2, CP49, CP47, HSF4, CTM, HSF4, CTM, MIP, AQPO, CRYAB, CRYA2, CTPP2, CRYBB1, CRYGD, CRYG4, CRYBB2, CRYB2, CRYGC, CRYG3, CCL, CRYAA, CRYAI, GJA8, CX50, CAE1, GJA3, CX46, CZP3, CAE3, CCM1, CAM, KRIT1, APOA1, TGFBI, CSD2, CDGG1, CSD, BIGH3, CDG2, TACSTD2, TROP2, M1SI, VSX1, RINX, PPCD, PPD, KTCN, COL8A2, FECD, PPCD2, PIP5K3, CFD, KERA, CNA2, MYOC, TIGR, GLCIA, JO AG, GPOA, OPTN, GLC1E, FIP2, HYPL, NRP, CYP1BI, GLC3A, OPA1, NTG, NPG, CYP1BI, GLC3A, CRB1, RP12, CRX, CORD2, CRD, RPGRIPI, LCA6, CORD9, RPE65, RP20, AIPL1, LCA4, GUCY2D, GUC2D, LCA1, CORD6, RDH12, LCA3, ELOVL4, ADMD, STGD2, STGD3, RDS, RP7, PRPH2, PRPH, AVMD, AOFMD, and VMD2). [00299] In some embodiments, the product coding region of the RNA payloads described herein encodes a factor that can affect the differentiation of a cell. As a non-limiting example, the expression of one or more of Oct4, Klf4, Sox2, c-Myc, L-Myc, dominant-negative p53, Nanog, Glisl, Lin28, TFIID, mir-302/367, or other miRNAs can cause the cell to become an induced pluripotent stem (iPS) cell. [00300] In some embodiments, the product coding region of the RNA payloads described herein encodes a factor for transdifferentiating cells. Non-limiting examples of factors include: one or more of GATA4, Tbx5, Mef2C, Myocd, Hand2, SRF, Mespl, SMARCD3 for cardiomyocytes; Ascii, Nurrl, LmxlA, Bm2, Mytll, NeuroDl, FoxA2 for neural cells; and Hnf4a, Foxal, Foxa2 or Foxa3 for hepatic cells. [00301] Additional product coding regions of the RNA payloads described herein are described elsewhere. A. Nucleic acid payloads [00302] In various embodiments, the LNP compositions described herein can be used to deliver a nucleic acid or polynucleotide payload, e.g., a DNA HDR donor, a linear or circular mRNA, or a chimeric DNA/RNA guide. [00303] In some embodiments, a LNP is capable of delivering a polynucleotide to a target cell, tissue, or organ. A polynucleotide, in its broadest sense of the term, includes any compound and/or substance that is or can be incorporated into an oligonucleotide chain. Exemplary polynucleotides for use in accordance with the present disclosure include, but are not limited to, one or more of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) including messenger mRNA (mRNA), hybrids thereof, RNAi-inducing agents, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, RNAs that induce triple helix formation, aptamers, vectors, etc. RNAs useful in the compositions and methods described herein can be selected from the group consisting of but are not limited to, shortimers, antagomirs, antisense, ribozymes, short interfering RNA (siRNA), asymmetrical interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), short hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), and mixtures thereof. In some embodiments, a polynucleotide is mRNA. In some embodiments, a polynucleotide is circular RNA. In some embodiments, a polynucleotide encodes a protein, e.g., a vaccine antigen, a therapeutic protein, or a nucleobase editing enzyme. A polynucleotide may encode any polypeptide of interest, including any naturally or non-naturally occurring or otherwise modified polypeptide. A polypeptide may be of any size and may have any secondary structure or activity. In some embodiments, a polypeptide encoded by an mRNA may have a therapeutic effect when expressed in a cell. [00304] In other embodiments, a polynucleotide is an siRNA. An siRNA may be capable of selectively knocking down or down regulating expression of a gene of interest. For example, an siRNA could be selected to silence a gene associated with a particular disease, disorder, or condition upon administration to a subject in need thereof of a nanoparticle composition including the siRNA. An siRNA may comprise a sequence that is complementary to an mRNA sequence that encodes a gene or protein of interest. In some embodiments, the siRNA may be an immunomodulatory siRNA. [00305] In some embodiments, a polynucleotide is an shRNA or a vector or plasmid encoding the same. An shRNA may be produced inside a target cell upon delivery of an appropriate construct to the nucleus. Constructs and mechanisms relating to shRNA are well known in the relevant arts. [00306] A polynucleotide may include a first region of linked nucleosides encoding a polypeptide of interest (e.g., a coding region), a first flanking region located at the 5'-terminus of the first region (e.g., a 5'-UTR), a second flanking region located at the 3'-terminus of the first region (e.g., a 3'-UTR), at least one 5'-cap region, and a 3'-stabilizing region. In some embodiments, a polynucleotide further includes a poly-A region or a Kozak sequence (e.g., in the 5'-UTR). In some cases, polynucleotides may contain one or more intronic nucleotide sequences capable of being excised from the polynucleotide. In some embodiments, a polynucleotide (e.g., an mRNA) may include a 5'cap structure, a chain terminating nucleotide, a stem loop, a polyA sequence, and/or a polyadenylation signal. [00307] In various embodiments, the nucleic acid payloads may contain one or more modifications. Such modifications include various chemical and/or structural modifications. For example, in the case of RNA, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and/or structural modification (e.g., secondary- folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). To date, hundreds of different RNA modifications have been characterized. Among them, several RNA modifications, including N⁶-methyladenosine (m⁶A), N⁶,2'-O-dimethyladenosine (m⁶Am), 8-oxo-7,8- dihydroguanosine (8-oxoG), pseudouridine (Ψ), 5-methylcytidine (m⁵C), and N⁴-acetylcytidine (ac⁴C), have been shown to regulate mRNA stability, consequently affecting diverse cellular and biological processes. Any known modification to RNA or DNA is contemplated herein. [00308] In some embodiments, a nucleic acid may include one or more alternative components (e.g., an alternative nucleoside). For example, the 3'-stabilizing region may contain an alternative nucleoside such as an L-nucleoside, an inverted thymidine, or a 2'-O-methyl nucleoside and/or the coding region, 5'-UTR, 3'-UTR, or cap region may include an alternative nucleoside such as a 5-substituted uridine (e.g., 5-methoxyu ridine), a 1-substituted pseudouridine (e.g., 1-methyl pseudouridine or 1-ethyl-pseudouridine), and/or a 5-substituted cytidine (e.g., 5-methyl-cytidine). In some embodiments, a polynucleotide contains only naturally occurring nucleosides. Nucleic acid modifications are well known in the art and are further discussed in the following references: (1) Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-Targeted Therapeutics. Cell Metab.2018 Apr 3;27(4):714-739. doi: 10.1016/j.cmet.2018.03.004. Erratum in: Cell Metab.2019 Feb 5;29(2):501. PMID: 29617640; (2) JP, Wen W, Zhang F, Oberg KC, Zhang L, Cheng T, Zhang XB. Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing. Nucleic Acids Res.2021 Jan 25;49(2):969-985. doi: 10.1093/nar/gkaa1251. PMID: 33398341; PMCID: PMC7826255; (3) Pradeep SP, Malik S, Slack FJ, Bahal R. Unlocking the potential of chemically modified peptide nucleic acids for RNA-based therapeutics. RNA.2023 Apr;29(4):434-445. doi: 10.1261/rna.079498.122. Epub 2023 Jan 18. PMID: 36653113; PMCID: PMC10019372; (4) Haruehanroengra P, Zheng YY, Zhou Y, Huang Y, Sheng J. RNA modifications and cancer. RNA Biol.2020 Nov;17(11):1560-1575. doi: 10.1080/15476286.2020.1722449. Epub 2020 Feb 7. PMID: 31994439; PMCID: PMC7567502; (5) Heidenreich O, Pieken W, Eckstein F. Chemically modified RNA: approaches and applications. FASEB J.1993 Jan;7(1):90-6. doi: 10.1096/fasebj.7.1.7678566. PMID: 7678566; (6) Zhang HY, Du Q, Wahlestedt C, Liang Z. RNA Interference with chemically modified siRNA. Curr Top Med Chem.2006;6(9):893-900. doi: 10.2174/156802606777303676. PMID: 16787282; (7) Jin G, Xu M, Zou M, Duan S. The Processing, Gene Regulation, Biological Functions, and Clinical Relevance of N4-Acetylcytidine on RNA: A Systematic Review. Mol Ther Nucleic Acids.2020 Jun 5;20:13-24. doi: 10.1016/j.omtn.2020.01.037. Epub 2020 Feb 8. PMID: 32171170; PMCID: PMC7068197; (8) Gao M, Zhang Q, Feng XH, Liu J. Synthetic modified messenger RNA for therapeutic applications. Acta Biomater.2021 Sep 1;131:1- 15. doi: 10.1016/j.actbio.2021.06.020. Epub 2021 Jun 13. PMID: 34133982; PMCID: PMC8198544; (9) Filippova JA, Semenov DV, Juravlev ES, Komissarov AB, Richter VA, Stepanov GA. Modern Approaches for Identification of Modified Nucleotides in RNA. Biochemistry (Mosc).2017 Nov;82(11):1217-1233. doi: 10.1134/S0006297917110013. PMID: 29223150; (10) Röthlisberger P, Berk C, Hall J. RNA Chemistry for RNA Biology. Chimia (Aarau).2019 May 29;73(6):368-373. doi: 10.2533/chimia.2019.368. PMID: 31118118; and (11) Elkhalifa D, Rayan M, Negmeldin AT, Elhissi A, Khalil A. Chemically modified mRNA beyond COVID-19: Potential preventive and therapeutic applications for targeting chronic diseases. Biomed Pharmacother.2022 Jan;145:112385. doi: 10.1016/j.biopha.2021.112385. Epub 2021 Oct 28. PMID: 34915673; PMCID: PMC8552589; (12) Boo SH, Kim YK. The emerging role of RNA modifications in the regulation of mRNA stability. Exp Mol Med.2020 Mar;52(3):400-408. doi: 10.1038/s12276-020-0407-z. Epub 2020 Mar 24. PMID: 32210357; PMCID: PMC7156397; (13) Varshney D, Spiegel J, Zyner K, Tannahill D, Balasubramanian S. The regulation and functions of DNA and RNA G-quadruplexes. Nat Rev Mol Cell Biol.2020 Aug;21(8):459-474. doi: 10.1038/s41580-020-0236-x. Epub 2020 Apr 20. PMID: 32313204; PMCID: PMC7115845; each of which are incorporated herein by reference in their entireties. [00309] In some cases, a polynucleotide is greater than 30 nucleotides in length. In another embodiment, the poly nucleotide molecule is greater than 35 nucleotides in length. In another embodiment, the length is at least 40 nucleotides. In another embodiment, the length is at least 45 nucleotides. In another embodiment, the length is at least 55 nucleotides. In another embodiment, the length is at least 50 nucleotides. In another embodiment, the length is at least 60 nucleotides. In another embodiment, the length is at least 80 nucleotides. In another embodiment, the length is at least 90 nucleotides. In another embodiment, the length is at least 100 nucleotides. In another embodiment, the length is at least 120 nucleotides. In another embodiment, the length is at least 140 nucleotides. In another embodiment, the length is at least 160 nucleotides. In another embodiment, the length is at least 180 nucleotides. In another embodiment, the length is at least 200 nucleotides. In another embodiment, the length is at least 250 nucleotides. In another embodiment, the length is at least 300 nucleotides. In another embodiment, the length is at least 350 nucleotides. In another embodiment, the length is at least 400 nucleotides. In another embodiment, the length is at least 450 nucleotides. In another embodiment, the length is at least 500 nucleotides. In another embodiment, the length is at least 600 nucleotides. In another embodiment, the length is at least 700 nucleotides. In another embodiment, the length is at least 800 nucleotides. In another embodiment, the length is at least 900 nucleotides. In another embodiment, the length is at least 1000 nucleotides. In another embodiment, the length is at least 1100 nucleotides. In another embodiment, the length is at least 1200 nucleotides. In another embodiment, the length is at least 1300 nucleotides. In another embodiment, the length is at least 1400 nucleotides. In another embodiment, the length is at least 1500 nucleotides. In another embodiment, the length is at least 1600 nucleotides. In another embodiment, the length is at least 1800 nucleotides. In another embodiment, the length is at least 2000 nucleotides. In another embodiment, the length is at least 2500 nucleotides. In another embodiment, the length is at least 3000 nucleotides. In another embodiment, the length is at least 4000 nucleotides. In another embodiment, the length is at least 5000 nucleotides, or greater than 5000 nucleotides. [00310] In some embodiments, a polynucleotide molecule, formula, composition or method associated therewith comprises one or more polynucleotides comprising features as described in WO2002/098443, WO2003/051401, WO2008/052770, WO2009/127230, WO2006/122828, WO2008/083949, WO2010/088927, WO2010/037539, WO2004/004743, WO2005/016376, WO2006/024518, WO2007/095,976, WO2008/014979, WO2008/077592, WO2009/030481, WO2009/095226, WO2011/069586, WO2011/026641, WO2011/144358, WO2012/019780, WO2012/013326, WO2012/089338, WO2012/113513, WO2012/116811, WO2012/116810, WO2013/113502, WO2013/113501, WO2013/113736, WO2013/143698, WO2013/143699, WO2013/143700, WO2013/120626, WO2013/120627, WO2013/120628, WO2013/120629, WO2013/174409, WO2014/127917, WO2015/024669, WO2015/024668, WO2015/024667, WO2015/024665, WO2015/024666, WO2015/024664, WO2015/101415, WO2015/101414, WO2015/024667, WO2015/062738, WO2015/101416, all of which are incorporated by reference herein. [00311] In some embodiments, a polynucleotide comprises one or more microRNA binding sites. In some embodiments, a microRNA binding site is recognized by a microRNA in a non-target organ. In some embodiments, a microRNA binding site is recognized by a microRNA in the liver. In some embodiments, a microRNA binding site is recognized by a microRNA in hepatic cells. B. Linear mRNA payloads [00312] In various embodiments, the LNP-based RNA vaccines, RNA therapeutics and pharmaceutical compositions thereof described herein can be used to deliver an RNA payload that is a linear mRNA molecule. [00313] In various embodiments, the LNP-based pharmaceutical compositions described herein, e.g., LNP-based gene editing systems, may include one or more linear mRNA molecules or linear mRNA payloads. In various embodiments, the mRNA payloads may encode one or more components of the herein described gene editing systems. For example, an mRNA payload may encode an amino acid sequence-programmable DNA binding domain (e.g., TALENS and zinc finger- binding domains) or a nucleic acid sequence-programmable DNA binding domain (e.g., CRISPR Cas9, CRISPR Cas12a, CRISPR Cas12f, CRISPR Cas13a, CRISPR Cas13b, or TnpB). [00314] mRNA payloads may also encode, depending upon the nature of the gene editing system, one or more effector domains that provide various functionalities that facilitate changes in nucleotide sequence and/or gene expression, such as, but not limited to, single-strand DNA binding proteins, nucleases, endonucleases, exonucleases, deaminases (e.g., cytidine deaminases or adenosine deaminases), polymerases (e.g., reverse transcriptases), integrases, recombinases, etc., and fusion proteins comprising one or more functional domains linked together. [00315] Ribonucleic acid (RNA) is a molecule that is made up of nucleotides, which are ribose sugars attached to nitrogenous bases and phosphate groups. The nitrogenous bases include adenine (A), guanine (G), uracil (U), and cytosine (C). Generally, RNA mostly exists in the single- stranded form but can also exists double-stranded in certain circumstances. The length, form and structure of RNA is diverse depending on the purpose of the RNA. For example, the length of an RNA can vary from a short sequence (e.g., siRNA) to a long sequences (e.g., lncRNA), can be linear (e.g., mRNA) or circular (e.g., oRNA), and can either be a coding (e.g., mRNA) or a non-coding (e.g., lncRNA) sequence. [00316] In various embodiments, the LNP-based RNA vaccines, RNA therapeutics, gene editing systems and pharmaceutical compositions thereof described herein can be used to deliver a mRNA payload that is a linear mRNA molecule. In embodiments, the mRNA payload may comprise one or more nucleotide sequences that encode a product of interest, such as, but not limited to a vaccine antigen, a component of a gene editing system (e.g., an endonuclease, a prime editor, etc.) and/or a therapeutic protein. [00317] In some embodiments, the RNA payload may be a linear mRNA. As used herein, the term "messenger RNA" (mRNA) refers to any polynucleotide which encodes a protein of interest and which is capable of being translated to produce the encoded protein of interest in vitro, in vivo, in situ or ex vivo. [00318] Generally, a mRNA molecule comprises at least a coding region, a 5' untranslated region (UTR), a 3' UTR, a 5' cap and a poly-A tail. In some aspects, one or more structural and/or chemical modifications or alterations may be included in the RNA which can reduce the innate immune response of a cell in which the mRNA is introduced. As used herein, a "structural" feature or modification is one in which two or more linked nucleotides are inserted, deleted, duplicated, inverted or randomized in a nucleic acid without significant chemical modification to the nucleotides themselves. Because chemical bonds will necessarily be broken and reformed to affect a structural modification, structural modifications are of a chemical nature and hence are chemical modifications. However, structural modifications will result in a different sequence of nucleotides. For example, the polynucleotide "ATCG" may be chemically modified to "AT-5meC-G". [00319] Generally, a coding region of interest in an mRNA used herein may encode a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide. In another embodiment, the mRNA may encode a peptide of 2-30 amino acids, e.g.5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids. The mRNA may encode a peptide of at least 10, 11, 12, 13, 14, 15, 17, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids, or a peptide that is no longer than 10, 11, 12, 13, 14, 15, 17, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids. [00320] Generally, the length of the region of the mRNA encoding a product of interest is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides). [00321] In some embodiments, the mRNA has a total length that spans from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1 ,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1 ,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000 nucleotides). [00322] In some embodiments, the region or regions flanking the region encoding the product of interest may range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, and 900 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1,000 nucleotides). [00323] In some embodiments, the mRNA comprises a tailing sequence which can range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, or 500 nucleotides). Where the tailing region is a polyA tail, the length may be determined in units of or as a function of polyA Binding Protein binding. In this embodiment, the polyA tail is long enough to bind at least 4 monomers of PolyA Binding Protein. PolyA Binding Protein monomers bind to stretches of approximately 38 nucleotides. As such, it has been observed that polyA tails of about 80 nucleotides and 160 nucleotides are functional. [00324] In some embodiments, the mRNA comprises a capping sequence which comprises a single cap or a series of nucleotides forming the cap. The capping sequence may be from 1 to 10, e.g. 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length. In some embodiments, the caping sequence is absent. [00325] In some embodiments, the mRNA comprises a region comprising a start codon. The region comprising the start codon may range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length. [00326] In some embodiments, the mRNA comprises a region comprising a stop codon. The region comprising the stop codon may range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length. [00327] In some embodiments, the mRNA comprises a region comprising a restriction sequence. The region comprising the restriction sequence may range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length. Untranslated Regions (UTRs) [00328] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems and pharmaceutical compositions thereof described herein, may comprise at least one untranslated region (UTR) which flanks the region encoding the product of interest and/or is incorporated within the mRNA molecule. UTRs are transcribed by not translated. The mRNA payloads can include 5’ UTR sequences and 3’ UTR sequences, as well as internal UTRs. [00329] The RNA payloads of the present disclosure may comprise one or more regions or parts which act or function as an untranslated region. Where nucleic acids are designed to encode at least one polypeptide of interest, the nucleic acid may comprise one or more of these untranslated regions (UTRs). Wild-type untranslated regions of a nucleic acid are transcribed but not translated. In mRNA, the 5′ UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3′ UTR starts immediately following the stop codon and continues until the transcriptional termination signal. There is growing body of evidence about the regulatory roles played by the UTRs in terms of stability of the nucleic acid molecule and translation. The regulatory features of a UTR can be incorporated into the RNA payload molecules (e.g., linear and circular mRNA molecules) of the present disclosure to, among other things, enhance the stability of the molecule. The specific features can also be incorporated to ensure controlled down-regulation of the transcript in case they are misdirected to undesired organs sites. A variety of 5′UTR and 3′UTR sequences are known and available in the art. [00330] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise at least one UTR that may be selected from any UTR sequence listed in Tables 19 or 20 of U.S. Patent No.10,709,779, which is incorporated herein by reference. 5' UTR regions [00331] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise at least one 5′ UTR. [00332] In an embodiment, the 5’ UTR comprises a sequence provided in Table (II) or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a 5’ UTR sequence provided in Table (II), or a variant or a fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, or six nucleotides of the 5’ UTR sequence provided in Table (II)). In an embodiment, the 5’ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28. [00333] Table (II) – Exemplary nucleotide sequences of 5’ UTRs

[00334] A 5′ UTR is region of an mRNA that is directly upstream (5′) from the start codon (the first codon of an mRNA transcript translated by a ribosome). A 5′ UTR does not encode a protein (is non-coding). Natural 5′UTRs have features that play roles in translation initiation. They harbor signatures like Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A/G)CCAUGG, where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’.5′UTR also have been known to form secondary structures which are involved in elongation factor binding. 5’ UTR sequences are also known to be important for ribosome recruitment to the mRNA and have been reported to play a role in translation (Hinnebusch A, et al., (2016) Science, 352:6292: 1413-6). In addition, 5’ UTR sequences may confer increased half-life, increased expression and/or increased activity of a polypeptide encoded by the RNA payload described herein. [00335] In various embodiments, the RNA payload constructs contemplated herein may include 5’UTRs that are found in nature and those that are not. For example, the 5’UTRs can be synthetic and/or can be altered in sequence with respect to a naturally occurring 5’UTR. Such altered 5’UTRs can include one or more modifications relative to a naturally occurring 5’UTR, such as, for example, an insertion, deletion, or an altered sequence, or the substitution of one or more nucleotide analogs in place of a naturally occurring nucleotide. [00336] The 5' UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3 'UTR starts immediately following the stop codon and continues until the transcriptional termination signal. While not wishing to be bound by theory, the UTRs may have a regulatory role in terms of translation and stability of the nucleic acid. [00337] Natural 5' UTRs usually include features which have a role in translation initiation as they tend to include Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A/G)CCAUGG, where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another 'G'.5'UTR also have been known to form secondary structures which are involved in elongation factor binding. [00338] In some embodiments of the disclosure, a 5′ UTR is a heterologous UTR, i.e., is a UTR found in nature associated with a different mRNA. In another embodiment, a 5′ UTR is a synthetic UTR, i.e., does not occur in nature. Synthetic UTRs include UTRs that have been mutated to improve their properties, e.g., which increase gene expression as well as those which are completely synthetic. Exemplary 5′ UTRs include Xenopus or human derived alpha-globin or beta-globin (e.g., US8,278,063 and US9,012,219), human cytochrome b-245 polypeptide, and hydroxysteroid (17b) dehydrogenase, and Tobacco etch virus. CMV immediate-early 1 (IE1) gene (see US20140206753 and WO2013/185069), the sequence GGGAUCCUACC (SEQ ID NO: 29) (WO2014144196) may also be used. In another embodiment, 5′ UTR of a TOP gene is a 5′ UTR of a TOP gene lacking the 5′ TOP motif (the oligopyrimidine tract) (e.g., WO/2015101414, WO2015101415, WO/2015/062738, WO2015024667, WO2015024667; 5′ UTR element derived from ribosomal protein Large 32 (L32) gene (WO/2015101414, WO2015101415, WO/2015/062738)), 5′ UTR element derived from the 5′UTR of an hydroxysteroid (17-β) dehydrogenase 4 gene (HSD17B4) (WO2015024667), or a 5′ UTR element derived from the 5′ UTR of ATP5A1 (WO2015024667) can be used. In one embodiment, an internal ribosome entry site (IRES) is used as a substitute for a 5′ UTR. [00339] In some embodiments, a 5′ UTR of the present disclosure comprises SEQ ID NO: 30 (GGGAAAUAAG AGAGAAAAGA AGAGUAAGAA GAAAUAUAAG AGCCACC). 3' UTR regions [00340] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise at least one 3′ UTR.3′ UTRs may be heterologous or synthetic. [00341] A 3′ UTR is region of an mRNA that is directly downstream (3′) from the stop codon (the codon of an mRNA transcript that signals a termination of translation). A 3′ UTR does not encode a protein (is non-coding). Natural or wild type 3′ UTRs are known to have stretches of adenosines and uridines embedded in them. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Based on their sequence features and functional properties, the AU rich elements (AREs) can be separated into three classes (Chen et al, 1995): Class I AREs contain several dispersed copies of an AUUUA motif within U-rich regions. C-Myc and MyoD contain class I AREs. Class II AREs possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers. Molecules containing this type of AREs include GM-CSF and TNF-α. Class III ARES are less well defined. These U rich regions do not contain an AUUUA motif. c-Jun and Myogenin are two well-studied examples of this class. Most proteins binding to the AREs are known to destabilize the messenger, whereas members of the ELAV family, most notably HuR, have been documented to increase the stability of mRNA. HuR binds to AREs of all the three classes. Engineering the HuR specific binding sites into the 3′ UTR of nucleic acid molecules will lead to HuR binding and thus, stabilization of the message in vivo. [00342] 3' UTRs are known to have stretches of adenosines and uridines embedded in them. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Based on their sequence features and functional properties, the AU rich elements (AREs) can be separated into three classes (Chen et al., 1995): Class I AREs contain several dispersed copies of an AUUUA motif within U-rich regions. C-Myc and MyoD contain class I AREs. Class II AREs possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers. Molecules containing this type of AREs include GM- CSF and TNF-a. Class III ARES are less well defined. These U rich regions do not contain an AUUUA motif. c-Jun and Myogenin are two well-studied examples of this class. Most proteins binding to the AREs are known to destabilize the messenger, whereas members of the ELAV family, most notably HuR, have been documented to increase the stability of mRNA. HuR binds to AREs of all the three classes. Engineering the HuR specific binding sites into the 3' UTR of nucleic acid molecules will lead to HuR binding and thus, stabilization of the message in vivo. [00343] Introduction, removal or modification of 3' UTR AU rich elements (AREs) can be used to modulate the stability of the mRNA payloads described herein. For example, one or more copies of an ARE can be introduced to make mRNA less stable and thereby curtail translation and decrease production of the resultant protein. Alternatively, AREs can be identified and removed or mutated to increase the intracellular stability and thus increase translation and production of the resultant protein. [00344] In some embodiments, the introduction of features often expressed in genes of target organs the stability and protein production of the mRNA can be enhanced in a specific organ and/or tissue. As a non-limiting example, the feature can be a UTR. As another example, the feature can be introns or portions of introns sequences. [00345] Those of ordinary skill in the art will understand that 5′ UTRs that are heterologous or synthetic may be used with any desired 3′ UTR sequence. For example, a heterologous 5′ UTR may be used with a synthetic 3′ UTR with a heterologous 3′ UTR. [00346] Non-UTR sequences may also be used as regions or subregions within an RNA payload construct. For example, introns or portions of introns sequences may be incorporated into regions of nucleic acid of the disclosure. Incorporation of intronic sequences may increase protein production as well as nucleic acid levels. [00347] Combinations of features may be included in flanking regions and may be contained within other features. For example, the polypeptide coding region of interest in an mRNA payload may be flanked by a 5′ UTR which may contain a strong Kozak translational initiation signal and/or a 3′ UTR which may include an oligo(dT) sequence for templated addition of a poly-A tail.5′ UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different genes such as the 5′ UTRs described in US Patent Application Publication No.20100293625 and PCT/US2014/069155, herein incorporated by reference in its entirety [00348] It should be understood that any UTR from any gene may be incorporated into the regions of an RNA payload molecule (e.g., a linear mRNA). Furthermore, multiple wild-type UTRs of any known gene may be utilized. It is also within the scope of the present disclosure to provide artificial UTRs which are not variants of wild type regions. These UTRs or portions thereof may be placed in the same orientation as in the transcript from which they were selected or may be altered in orientation or location. Hence a 5′ or 3′ UTR may be inverted, shortened, lengthened, made with one or more other 5′ UTRs or 3′ UTRs. As used herein, the term “altered” as it relates to a UTR sequence, means that the UTR has been changed in some way in relation to a reference sequence. For example, a 3′ UTR or 5′ UTR may be altered relative to a wild-type or native UTR by the change in orientation or location as taught above or may be altered by the inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. Any of these changes producing an “altered” UTR (whether 3′ or 5′) comprise a variant UTR. [00349] In some embodiments, a double, triple or quadruple UTR such as a 5′ UTR or 3′ UTR may be used. As used herein, a “double” UTR is one in which two copies of the same UTR are encoded either in series or substantially in series. For example, a double beta-globin 3′ UTR may be used as described in US Patent publication 20100129877, the contents of which are incorporated herein by reference in its entirety. [00350] It is also within the scope of the present disclosure to have patterned UTRs. As used herein “patterned UTRs” are those UTRs which reflect a repeating or alternating pattern, such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than 3 times. In these patterns, each letter, A, B, or C represent a different UTR at the nucleotide level. [00351] In some embodiments, flanking regions are selected from a family of transcripts whose proteins share a common function, structure, feature or property. For example, polypeptides of interest may belong to a family of proteins which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of these genes may be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. As used herein, a “family of proteins” is used in the broadest sense to refer to a group of two or more polypeptides of interest which share at least one function, structure, feature, localization, origin, or expression pattern. [00352] The untranslated region may also include translation enhancer elements (TEE). As a non-limiting example, the TEE may include those described in US Application No.20090226470, herein incorporated by reference in its entirety, and those known in the art. 5' Capping [00353] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise a 5’ cap structure. [00354] The 5' cap structure of an mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5' proximal introns removal during mRNA splicing. [00355] Endogenous mRNA molecules may be 5'-end capped generating a 5'-ppp-5'- triphosphate linkage between a terminal guanosine cap residue and the 5'-terminal transcribed sense nucleotide of the mRNA molecule. This 5'-guanylate cap may then be methylated to generate an N7- methyl-guanylate residue. The ribose sugars of the terminal and/or anteterminal transcribed nucleotides of the 5' end of the mRNA may optionally also be 2'-0-methylated.5'-decapping through hydrolysis and cleavage of the guanylate cap structure may target a nucleic acid molecule, such as an mRNA molecule, for degradation. [00356] Modifications to mRNA may generate a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5'-ppp-5' phosphorodiester linkages, modified nucleotides may be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, MA) may be used with a-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5'-ppp-5' cap. [00357] Additional modified guanosine nucleotides may be used such as a-methyl- phosphonate and seleno-phosphate nucleotides. [00358] Additional modifications include, but are not limited to, 2'-0-methylation of the ribose sugars of 5 '-terminal and/or 5'-anteterminal nucleotides of the mRNA (as mentioned above) on the 2'- hydroxyl group of the sugar ring. Multiple distinct 5 '-cap structures can be used to generate the 5 '- cap of a nucleic acid molecule, such as an mRNA molecule. [00359] Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e. endogenous, wild-type or physiological) 5'-caps in their chemical structure, while retaining cap function. Cap analogs may be chemically (i.e. non-enzymatically) or enzymatically synthesized and/or linked to a nucleic acid molecule. [00360] For example, the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5 '-5 '-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3'-0-methyl group (i.e., N7,3'-0-dimethyl-guanosine-5'-triphosphate-5 '-guanosine (m⁷G-3'mppp-G; which may equivalently be designated 3' O-Me-m7G(5')ppp(5')G). The 3'-0 atom of the other, unmodified, guanine becomes linked to the 5'-terminal nucleotide of the capped nucleic acid molecule (e.g. an mRNA). The N7- and 3'-0-methlyated guanine provides the terminal moiety of the capped nucleic acid molecule (e.g. mRNA). [00361] Another exemplary cap is mCAP, which is similar to ARCA but has a 2'-0-methyl group on guanosine (i.e., N7,2'-0-dimethyl-guanosine-5'-triphosphate-5'-guanosine, m⁷Gm-ppp-G). [00362] While cap analogs allow for the concomitant capping of a nucleic acid molecule in an in vitro transcription reaction, up to 20% of transcripts can remain uncapped. This, as well as the structural differences of a cap analog from an endogenous 5 '-cap structures of nucleic acids produced by the endogenous, cellular transcription machinery, may lead to reduced translational competency and reduced cellular stability. [00363] mRNA may also be capped post-transcriptionally, using enzymes, in order to generate more authentic 5'-cap structures. As used herein, the phrase "more authentic" refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a "more authentic" feature is better representative of an endogenous, wild-type, natural or physiological cellular function and/or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects. Non-limiting examples of more authentic 5 'cap structures are those which, among other things, have enhanced binding of cap binding proteins, increased half-life, reduced susceptibility to 5' endonucleases and/or reduced 5'decapping, as compared to synthetic 5 'cap structures known in the art (or to a wild-type, natural or physiological 5 'cap structure). For example, recombinant Vaccinia Virus Capping Enzyme and recombinant 2'-0- methyltransferase enzyme can create a canonical 5 '-5 '-triphosphate linkage between the 5 '-terminal nucleotide of an mRNA and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5 '-terminal nucleotide of the mRNA contains a 2'-0-methyl. Such a structure is termed the Capl structure. This cap results in a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5 'cap analog structures known in the art. Cap structures include, but are not limited to, 7mG(5^*)ppp(5^*)N,pN2p (cap 0), 7mG(5^*)ppp(5^*)NlmpNp (cap 1), and 7mG(5^*)-ppp(5')NlmpN2mp (cap 2). [00364] In some embodiments, the 5' terminal caps may include endogenous caps or cap analogs. [00365] In some embodiments, a 5' terminal cap may comprise a guanine analog. Useful guanine analogs include, but are not limited to, inosine, Nl-methyl-guanosine, 2'fluoro-guanosine, 7- deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. IRES Sequences [00366] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise one or more IRES sequences. [00367] In some embodiments, the mRNA may contain an internal ribosome entry site (IRES). First identified as a feature Picorna virus RNA, IRES plays an important role in initiating protein synthesis in absence of the 5' cap structure. An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA. An mRNA that contains more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes. Non-limiting examples of IRES sequences that can be used include without limitation, those from picornaviruses (e.g. FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and-mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV). [00368] In some embodiments, the IRES is from Taura syndrome virus, Triatoma virus, Theiler's encephalomyelitis virus, Simian Virus 40, Solenopsis invicta virus 1, Rhopalosiphum padi virus, Reticuloendotheliosis virus, Human poliovirus 1, Plautia stali intestine virus, Kashmir bee virus, Human rhinovirus 2, Homalodisca coagulata virus-1, Human Immunodeficiency Virus type 1, Homalodisca coagulata virus-1, Himetobi P virus, Hepatitis C virus, Hepatitis A virus, Hepatitis GB virus, Foot and mouth disease virus, Human enterovirus 71, Equine rhinitis virus, Ectropis obliqua picorna-like virus, Encephalomyocarditis virus, Drosophila C Virus, Human coxsackievirus B3, Crucifer tobamovirus, Cricket paralysis virus, Bovine viral diarrhea virus 1, Black Queen Cell Virus, Aphid lethal paralysis virus, Avian encephalomyelitis virus, Acute bee paralysis virus, Hibiscus chlorotic ringspot virus, Classical swine fever virus, Human FGF2, Human SFTPA1, Human AML1/RUNX1, Drosophila antennapedia, Human AQP4, Human AT1R, Human BAG-1, Human BCL2, Human BiP, Human c-IAP1, Human c-myc, Human eIF4G, Mouse NDST4L, Human LEF1, Mouse HIF1 alpha, Human n.myc, Mouse Gtx, Human p27kip1, Human PDGF2/c-sis, Human p53, Human Pim-1, Mouse Rbm3, Drosophila reaper, Canine Scamper, Drosophila Ubx, Human UNR, Mouse UtrA, Human VEGF-A, Human XIAP, Drosophila hairless, S. cerevisiae TFIID, S. cerevisiae YAP1, tobacco etch virus, turnip crinkle virus, EMCV-A, EMCV-B, EMCV-Bf, EMCV- Cf, EMCV pEC9, Picobirnavirus, HCV QC64, Human Cosavirus E/D, Human Cosavirus F, Human Cosavirus JMY, Rhinovirus NAT001, HRV14, HRV89, HRVC-02, HRV-A21, Salivirus A SH1, Salivirus FHB, Salivirus NG-J1, Human Parechovirus 1, Crohivirus B, Yc-3, Rosavirus M-7, Shanbavirus A, Pasivirus A, Pasivirus A 2, Echovirus E14, Human Parechovirus 5, Aichi Virus, Hepatitis A Virus HA16, Phopivirus, CVA10, Enterovirus C, Enterovirus D, Enterovirus J, Human Pegivirus 2, GBV-C GT110, GBV-C K1737, GBV-C Iowa, Pegivirus A 1220, Pasivirus A 3, Sapelovirus, Rosavirus B, Bakunsa Virus, Tremovirus A, Swine Pasivirus 1, PLV-CHN, Pasivirus A, Sicinivirus, Hepacivirus K, Hepacivirus A, BVDV1, Border Disease Virus, BVDV2, CSFV-PK15C, SF573 Dicistrovirus, Hubei Picorna-like Virus, CRPV, Salivirus A BNS, Salivirus A BN2, Salivirus A 02394, Salivirus A GUT, Salivirus A CH, Salivirus A SZ1, Salivirus FHB, CVB3, CVB1, Echovirus 7, CVBS, EVA71, CVA3, CVA12, EV24 or an aptamer to eIF4G. Poly-A tails and 3’ stabilizing region [00369] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise a poly-A tail. [00370] During RNA processing, a long chain of adenine nucleotides (poly-A tail) may be added to a polynucleotide such as an mRNA molecules in order to increase stability. Immediately after transcription, the 3' end of the transcript may be cleaved to free a 3' hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the free 3' hydroxyl end. The process, called polyadenylation, adds a poly-A tail of a certain length. [00371] In some embodiments, the length of a poly-A tail is greater than 30 nucleotides in length. In another embodiment, the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides) and no more than about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, or 3000 nucleotides in length. In some embodiments, the mRNA includes a poly-A tail from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1 ,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, and from 2,500 to 3,000). [00372] In some embodiments, the poly-A tail is designed relative to the length of the overall mRNA. This design may be based on the length of the region coding for a target of interest, the length of a particular feature or region (such as a flanking region), or based on the length of the ultimate product expressed from the mRNA. [00373] In this context the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the mRNA or feature thereof. The poly-A tail may also be designed as a fraction of mRNA to which it belongs. In this context, the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct or the total length of the construct minus the poly-A tail. Further, engineered binding sites and conjugation of mRNA for poly-A binding protein may enhance expression. [00374] Additionally, multiple distinct mRNA may be linked together to the PABP (Poly-A binding protein) through the 3'-end using modified nucleotides at the 3 '-terminus of the poly-A tail. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12hr, 24hr, 48hr, 72 hr and day 7 post-transfection. [00375] In some embodiments, the mRNA are designed to include a polyA-G Quartet. The G- quartet is a cyclic hydrogen bonded array of four guanine nucleotides that can be formed by G-rich sequences in both DNA and RNA. In this embodiment, the G-quartet is incorporated at the end of the poly-A tail. Stop Codons [00376] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise one or more translation stop codons. Translational stop codons, UAA, UAG, and UGA, are an important component of the genetic code and signal the termination of translation of an mRNA. During protein synthesis, stop codons interact with protein release factors and this interaction can modulate ribosomal activity thus having an impact translation (Tate WP, et al., (2018) Biochem Soc Trans, 46(6):1615-162). [00377] A stop element as used herein, refers to a nucleic acid sequence comprising a stop codon. The stop codon can be selected from TGA, TAA and TAG in the case of DNA, or from UGA, UAA and UAG in the case of RNA. In an embodiment, a stop element comprises two consecutive stop codons. In an embodiment, a stop element comprises three consecutive stop codons. In an embodiment, a stop element comprises four consecutive stop codons. In an embodiment, a stop element comprises five consecutive stop codons. [00378] In some embodiments, the mRNA may include one stop codon. In some embodiments, the mRNA may include two stop codons. In some embodiments, the mRNA may include three stop codons. In some embodiments, the mRNA may include at least one stop codon. In some embodiments, the mRNA may include at least two stop codons. In some embodiments, the mRNA may include at least three stop codons. As non-limiting examples, the stop codon may be selected from TGA, TAA and TAG. [00379] In other embodiments, the stop codon may be selected from one or more of the following stop elements of Table (III): Table (III): Additional stop elements [00380] In some embodiments, the mRNA includes the stop codon TGA and one additional stop codon. In a further embodiment the addition stop codon may be TAA. MicroRNA binding sites and other regulatory elements [00381] In various embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein, may comprise one or more regulatory elements, including, but not limited to microRNA (miRNA) binding sites, structured mRNA sequences and/or motifs, artificial binding sites to bind to endogenous nucleic acid binding molecules, and combinations thereof. Chemically unmodified nucleotides [00382] In some embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein are not chemically modified and comprises the standard ribonucleotides consisting of adenosine, guanosine, cytosine and uridine. In some embodiments, nucleotides and nucleosides of the present disclosure comprise standard nucleoside residues such as those present in transcribed RNA (e.g. A, G, C, or U). In some embodiments, nucleotides and nucleosides of the present disclosure comprise standard deoxyribonucleosides such as those present in DNA (e.g. dA, dG, dC, or dT). Chemically modified nucleotides [00383] In some embodiments, the mRNA payloads of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions thereof described herein comprise, in some embodiments, comprises at least one chemical modification. [00384] The terms “chemical modification” and “chemically modified” refer to modification with respect to adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribonucleosides or deoxyribnucleosides in at least one of their position, pattern, percent or population. Generally, these terms do not refer to the ribonucleotide modifications in naturally occurring 5′- terminal mRNA cap moieties. With respect to a polypeptide, the term “modification” refers to a modification relative to the canonical set 20 amino acids. Polypeptides, as provided herein, are also considered “modified” of they contain amino acid substitutions, insertions or a combination of substitutions and insertions. [00385] Polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides), in some embodiments, comprise various (more than one) different modifications. In some embodiments, a particular region of a polynucleotide contains one, two or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified RNA polynucleotide (e.g., a modified mRNA polynucleotide), introduced to a cell or organism, exhibits reduced degradation in the cell or organism, respectively, relative to an unmodified polynucleotide. In some embodiments, a modified RNA polynucleotide (e.g., a modified mRNA polynucleotide), introduced into a cell or organism, may exhibit reduced immunogenicity in the cell or organism, respectively (e.g., a reduced innate response). [00386] Modifications of polynucleotides include, without limitation, those described herein. Polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) may comprise modifications that are naturally-occurring, non-naturally-occurring or the polynucleotide may comprise a combination of naturally-occurring and non-naturally-occurring modifications. Polynucleotides may include any useful modification, for example, of a sugar, a nucleobase, or an internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage or to the phosphodiester backbone). [00387] Polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides), in some embodiments, comprise non-natural modified nucleotides that are introduced during synthesis or post-synthesis of the polynucleotides to achieve desired functions or properties. The modifications may be present on an internucleotide linkages, purine or pyrimidine bases, or sugars. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a polynucleotide may be chemically modified. [00388] The present disclosure provides for modified nucleosides and nucleotides of a polynucleotide (e.g., RNA polynucleotides, such as mRNA polynucleotides). A “nucleoside” refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). A “nucleotide” refers to a nucleoside, including a phosphate group. Modified nucleotides may by synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides. Polynucleotides may comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages may be standard phosphodiester linkages, in which case the polynucleotides would comprise regions of nucleotides. [00389] Modified nucleotide base pairing encompasses not only the standard adenosine- thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non-standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures. One example of such non-standard base pairing is the base pairing between the modified nucleotide inosine and adenine, cytosine or uracil. Any combination of base/sugar or linker may be incorporated into polynucleotides of the present disclosure. [00390] In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) include a combination of at least two (e.g., 2, 3, 4 or more) of the aforementioned modified nucleobases. [00391] In some embodiments, modified nucleobases in polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) are selected from the group consisting of pseudouridine (ψ), N1-methylpseudouridine (m¹ψ), N1-ethylpseudouridine, 2-thiouridine, 4′- thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl- pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio- pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl- pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine and 2′- O-methyl uridine. In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) include a combination of at least two (e.g., 2, 3, 4 or more) of the aforementioned modified nucleobases. [00392] In some embodiments, modified nucleobases in polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) are selected from the group consisting of 1-methyl- pseudouridine (m¹ψ), 5-methoxy-uridine (mo⁵U), 5-methyl-cytidine (m⁵C), pseudouridine (ψ), α-thio- guanosine and α-thio-adenosine. In some embodiments, polynucleotides includes a combination of at least two (e.g., 2, 3, 4 or more) of the aforementioned modified nucleobases. [00393] In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise pseudouridine (ψ) and 5-methyl-cytidine (m⁵C). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 1-methyl- pseudouridine (m¹ψ). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 1-methyl-pseudouridine (m¹ψ) and 5-methyl-cytidine (m⁵C). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 2-thiouridine (s²U). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 2-thiouridine and 5-methyl-cytidine (m⁵C). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise methoxy-uridine (mo⁵U). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 5-methoxy-uridine (mo⁵U) and 5-methyl-cytidine (m⁵C). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 2′-O-methyl uridine. In some embodiments polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise 2′-O-methyl uridine and 5-methyl-cytidine (m⁵C). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise N6-methyl-adenosine (m⁶A). In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprise N6-methyl-adenosine (m⁶A) and 5-methyl-cytidine (mC). [00394] In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) are uniformly modified (e.g., fully modified, modified throughout the entire sequence) for a particular modification. For example, a polynucleotide can be uniformly modified with 5-methyl-cytidine (m⁵C), meaning that all cytosine residues in the mRNA sequence are replaced with 5-methyl-cytidine (m⁵C). Similarly, a polynucleotide can be uniformly modified for any type of nucleoside residue present in the sequence by replacement with a modified residue such as those set forth above. [00395] Exemplary nucleobases and nucleosides having a modified cytosine include N4- acetyl-cytidine (ac4C), 5-methyl-cytidine (m5C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5- hydroxymethyl-cytidine (hm5C), 1-methyl-pseudoisocytidine, 2-thio-cytidine (s2C), and 2-thio-5- methyl-cytidine. [00396] In some embodiments, a modified nucleobase is a modified uridine. Exemplary nucleobases and In some embodiments, a modified nucleobase is a modified cytosine. nucleosides having a modified uridine include 5-cyano uridine, and 4′-thio uridine. [00397] The polynucleotides of the present disclosure may be partially or fully modified along the entire length of the molecule. For example, one or more or all or a given type of nucleotide (e.g., purine or pyrimidine, or any one or more or all of A, G, U, C) may be uniformly modified in a polynucleotide of the disclosure, or in a given predetermined sequence region thereof (e.g., in the mRNA including or excluding the polyA tail). In some embodiments, all nucleotides X in a polynucleotide of the present disclosure (or in a given sequence region thereof) are modified nucleotides, wherein X may any one of nucleotides A, G, U, C, or any one of the combinations A+G, A+U, A+C, G+U, G+C, U+C, A+G+U, A+G+C, G+U+C or A+G+C. [00398] The polynucleotide may contain from about 1% to about 100% modified nucleotides (either in relation to overall nucleotide content, or in relation to one or more types of nucleotide, i.e., any one or more of A, G, U or C) or any intervening percentage (e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 20% to 95%, from 20% to 100%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 50% to 95%, from 50% to 100%, from 70% to 80%, from 70% to 90%, from 70% to 95%, from 70% to 100%, from 80% to 90%, from 80% to 95%, from 80% to 100%, from 90% to 95%, from 90% to 100%, and from 95% to 100%). It will be understood that any remaining percentage is accounted for by the presence of unmodified A, G, U, or C. [00399] The polynucleotides may contain at a minimum 1% and at maximum 100% modified nucleotides, or any intervening percentage, such as at least 5% modified nucleotides, at least 10% modified nucleotides, at least 25% modified nucleotides, at least 50% modified nucleotides, at least 80% modified nucleotides, or at least 90% modified nucleotides. For example, the polynucleotides may contain a modified pyrimidine such as a modified uracil or cytosine. In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90% or 100% of the uracil in the polynucleotide is replaced with a modified uracil (e.g., a 5-substituted uracil). The modified uracil can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures). In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90% or 100% of the cytosine in the polynucleotide is replaced with a modified cytosine (e.g., a 5-substituted cytosine). The modified cytosine can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures). C. Circular mRNA payloads [00400] In various embodiments, the LNP-based RNA vaccines, RNA therapeutics and pharmaceutical compositions thereof described herein can be used to deliver an RNA payload that is a circular mRNA molecule or “oRNA.” The circular mRNA molecule may encode a CROI, such as a vaccine antigen, cancer antigen, or therapeutic protein as described in this specification. [00401] In various embodiments, the LNP-based pharmaceutical compositions described herein, e.g., LNP-based gene editing systems, may include one or more circular mRNA molecules or “oRNAs.” In various embodiments, the circular mRNA payloads may encode one or more components of the herein described gene editing systems or other therapeutic protein of interest. For example, a circular mRNA payload may encode an amino acid sequence-programmable DNA binding domain (e.g., TALENS and zinc finger-binding domains) or a nucleic acid sequence-programmable DNA binding domain (e.g., CRISPR Cas9, CRISPR Cas12a, CRISPR Cas12f, CRISPR Cas13a, CRISPR Cas13b, or TnpB). [00402] The circular mRNA payloads may also encode, depending upon the nature of the gene editing system, one or more effector domains that provide various functionalities that facilitate changes in nucleotide sequence and/or gene expression, such as, but not limited to, single-strand DNA binding proteins, nucleases, endonucleases, exonucleases, deaminases (e.g., cytidine deaminases or adenosine deaminases), polymerases (e.g., reverse transcriptases), integrases, recombinases, etc., and fusion proteins comprising one or more functional domains linked together. [00403] In some embodiments, the RNA payload is a circular RNA (oRNA). As used herein, the terms “oRNA” or “circular RNA” are used interchangeably and can refer to a RNA that forms a circular structure through covalent or non-covalent bonds. [00404] Circular RNA described herein are polyribonucleotides that form a continuous structure through covalent or non-covalent bonds. Due to the circular structure, oRNAs have improved stability, increased half-life, reduced immunogenicity, and/or improved functionality (e.g., of a function described herein) compared to a corresponding linear RNA. [00405] In some embodiments, an oRNA binds a target. In some embodiments, an oRNA binds a substrate. In some embodiments, an oRNA binds a target and binds a substrate of the target. In some embodiments, an oRNA binds a target and mediates modulation of a substrate of the target. In some embodiments, an oRNA brings together a target and its substrate to mediate modification of the substrate, e.g., post-translational modification. In some embodiments, an oRNA brings together a target and its substrate to mediate a cellular process (e.g., alters protein degradation or signal transduction) involving the substrate. In some embodiments, a target is a target protein and a substrate is a substrate protein. [00406] In some embodiments, an oRNA comprises a conjugation moiety for binding to chemical compound. The conjugation moiety can be a modified polyribonucleotide. The chemical compound can be conjugated to the oRNA by the conjugation moiety. In some embodiments, the chemical compound binds to a target and mediates modulation of a substrate of the target. In some embodiments, an oRNA binds a substrate of a target and a chemical compound conjugated to the oRNA by the conjugation moiety binds the target to bring together the target and its substrate to mediate modification of the substrate, e.g., post-translational modification. In some embodiments, an oRNA binds a substrate of a target and a chemical compound conjugated to the oRNA by the conjugation moiety binds the target to bring together the target and its substrate to mediate modification of the substrate to mediate a cellular process (e.g., alters protein degradation or signal transduction) involving the substrate. In some embodiments, a target is a target protein and a substrate is a substrate protein. [00407] In some embodiments, the oRNA may be non-immunogenic in a mammal (e.g., a human, non-human primate, rabbit, rat, and mouse). [00408] In some embodiments, the oRNA may be capable of replicating or replicates in a cell from an aquaculture animal (e.g., fish, crabs, shrimp, oysters etc.), a mammalian cell, a cell from a pet or zoo animal (e.g., cats, dogs, lizards, birds, lions, tigers and bears etc.), a cell from a farm or working animal (e.g., horses, cows, pigs, chickens etc.), a human cell, cultured cells, primary cells or cell lines, stem cells, progenitor cells, differentiated cells, germ cells, cancer cells (e.g., tumorigenic, metastatic), non-tumorigenic cells (e.g., normal cells), fetal cells, embryonic cells, adult cells, mitotic cells, non-mitotic cells, or any combination thereof. [00409] In one aspect, provided herein is a pharmaceutical composition comprising: a circular RNA comprising, in the following order, a 3’ group I intron fragment, an Internal Ribosome Entry Site (IRES), an expression sequence encoding a polypeptide (e.g., a vaccine antigen, therapeutic protein, such as a chimeric antigen receptor (CAR) or T cell receptor (TCR) complex protein or a nucleobase editing system or component thereof), and a 5’ group I intron fragment, and a transfer vehicle comprising at least one of (i) an ionizable lipid, (ii) a structural lipid, and (iii) a PEG-modified lipid, wherein the transfer vehicle is capable of delivering the circular RNA polynucleotide to a cell (e.g., a human cell, such as an immune cell present in a human subject), such that the polypeptide is translated in the cell. [00410] In some embodiments, the pharmaceutical composition is formulated for intravenous administration to the human subject in need thereof. In some embodiments, the 3’ group I intron fragment and 5’ group I intron fragment are Anabaena group I intron fragments. [00411] In certain embodiments, the 3’ intron fragment and 5’ intron fragment are defined by the L9a-5 permutation site in the intact intron. In certain embodiments, the 3’ intron fragment and 5’ intron fragment are defined by the L8-2 permutation site in the intact intron. [00412] In some embodiments, the IRES is from Taura syndrome virus, Tiiatoma virus, Theiler's encephalomyelitis virus, Simian Virus 40, Solenopsis invicta virus 1, Rhopalosiphum padi virus, Reticuloendotheliosis virus, Human poliovirus 1, Plautia stall intestine virus, Kashmir bee virus, Human rhinovirus 2, Homalodisca coagulata virus- 1, Human Immunodeficiency Virus type 1, Homalodisca coagulata virus- 1, Himetobi P virus, Hepatitis C virus, Hepatitis A virus, Hepatitis GB virus , Foot and mouth disease virus, Human enterovirus 71, Equine rhinitis virus, Ectropis obliqua picoma-like virus, Encephalomyocarditis virus, Drosophila C Virus, Human coxsackievirus B3, Crucifer tobamovirus, Cricket paralysis virus, Bovine viral diarrhea virus 1, Black Queen Cell Virus, Aphid lethal paralysis virus, Avian encephalomyelitis virus, Acute bee paralysis virus, Hibiscus chlorotic ringspot virus, Classical swine fever virus, Human FGF2, Human SFTPA1, Human AML1/RUNX1, Drosophila antennapedia, Human AQP4, Human AT1R, Human BAG-1, Human BCL2, Human BiP, Human c-IAPl, Human c-myc, Human eIF4G, Mouse NDST4L, Human LEF1, Mouse HIFl alpha, Human n.myc, Mouse Gtx, Human p27kipl, Human PDGF2/c-sis, Human p53, Human Pim-1, Mouse Rbm3, Drosophila reaper, Canine Scamper, Drosophila Ubx, Human UNR, Mouse UtrA, Human VEGF-A, Human XIAP, Drosophila hairless, S. cerevisiae TFIID, S. cerevisiae YAP1, tobacco etch virus, turnip crinkle virus, EMCV-A, EMCV-B, EMCV-Bf, EMCV-Cf, EMCV pEC9, Picobirnavirus, HCV QC64, Human Cosavirus E/D, Human Cosavirus F, Human Cosavirus JMY, Rhinovirus NAT001, HRV14, HRV89, HRVC-02, HRV-A21, Salivirus A SHI, Salivirus FHB, Salivirus NG-J1, Human Parechovirus 1, Crohivirus B, Yc-3, Rosavirus M-7, Shanbavirus A, Pasivirus A, Pasivirus A 2, Echovirus E14, Human Parechovirus 5, Aichi Virus, Hepatitis A Virus HA 16, Phopivirus, CVA10, Enterovirus C, Enterovirus D, Enterovirus J, Human Pegivirus 2, GBV-C GT110, GBV-C K1737, GBV-C Iowa, Pegivirus A 1220, Pasivirus A 3, Sapelovirus, Rosavirus B, Bakunsa Virus, Tremovirus A, Swine Pasivirus 1, PLV-CHN, Pasivirus A, Sicinivirus, Hepacivirus K, Hepacivirus A, BVDV1, Border Disease Virus, BVDV2, CSFV- PK15C, SF573 Dicistravirus, Hubei Picoma-like Virus, CRPV, Salivirus A BN5, Salivirus A BN2, Salivirus A 02394, Salivirus A GUT, Salivirus A CH, Salivirus A SZ1, Salivirus FHB, CVB3, CVB1, Echovirus 7, CVB5, EVA71, CVA3, CVA12, EV24 or an aptamer to eIF4G. [00413] In some embodiments, the IRES comprises a CVB3 IRES or a fragment or variant thereof. In some embodiments, the pharmaceutical composition comprises a first internal spacer between the 3’ group I intron fragment and the IRES, and a second internal spacer between the expression sequence and the 5’ group I intron fragment. In certain embodiments, the first and second internal spacers each have a length of about 10 to about 60 nucleotides. [00414] In some embodiments, the circular mRNA comprises a nucleotide sequence encoding a polypeptide of interest, such as a vaccine antigen, nucleobase editing system, or therapeutic protein (e.g., a CAR or TCR complex protein). [00415] In embodiments where the therapeutic protein encoded by the herein RNA payload (e.g., circular or linear mRNA) is a CAR or TCR complex protein, the CAR or TCR complex protein comprises an antigen binding domain specific for an antigen selected from the group: CD 19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule- 1, CD33, epidermal growth factor receptor variant III (EGFRvIII), disialoganglioside GD2, disaloganglioside GD3, TNF receptor family member, B cell maturation antigen (BCMA), Tn antigen ((Tn Ag) or (GalNAca-Ser/Thr)), prostate- specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms- Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD 117), Interleukin- 13 receptor subunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL-l lRa), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, HER2, HER3, Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gplOO), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type- A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (0AcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1/CD248), tumor endothelial marker 7 -related (TEM7R), claudin 6 (CLDN6), claudin 18.2 (CLDN18.2), thyroid stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, and CD179a. [00416] In further embodiments where the therapeutic protein encoded by the herein RNA payload (e.g., circular or linear mRNA) is a CAR or TCR complex protein, the CAR or TCR complex protein comprises a CAR comprising an antigen binding domain specific for CD19. In some embodiments, the CAR or TCR complex protein comprises a CAR comprising a costimulatory domain selected from the group CD28, 4-1BB, 0X40, CD27, CD30, ICOS, GITR, CD40, CD2, SLAM, and combinations thereof. In some embodiments, the CAR or TCR complex protein comprises a CAR comprising a CD3zeta signaling domain. In some embodiments, the CAR or TCR complex protein comprises a CAR comprising a CH2CH3, CD28, and/or CD8 spacer domain. In some embodiments, the CAR or TCR complex protein comprises a CAR comprising a CD28 or CD8 transmembrane domain. [00417] In some embodiments, the CAR or TCR complex protein comprises a CAR comprising: an antigen binding domain, a spacer domain, a transmembrane domain, a costimulatory domain, and an intracellular T cell signaling domain. [00418] In some embodiments, the CAR or TCR complex protein comprises a multispecific CAR comprising antigen binding domains for at least two different antigens. In some embodiments, the CAR or TCR complex protein comprises a TCR complex protein selected from the group TCRalpha, TCRbeta, TCRgamma, and TCRdelta. [00419] In some embodiments, the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing system, and pharmaceutical compositions described herein further comprise a targeting moiety. In certain embodiments, the targeting moiety mediates receptor-mediated endocytosis or direct fusion of the delivery vehicle (LNPs) into selected cells of a selected cell population or tissue in the absence of cell isolation or purification. In certain embodiments, the targeting moiety is capable of binding to a protein selected from the group CD3, CD4, CD8, CDS, CD7, PD-1, 4-1BB, CD28, Clq, and CD2. In certain embodiments, the targeting moiety comprises an antibody specific for a macrophage, dendritic cell, NK cell, NKT, or T cell antigen. In certain embodiments, the targeting moiety comprises a scFv, nanobody, peptide, minibody, polynucleotide aptamer, heavy chain variable region, light chain variable region or fragment thereof. [00420] In some embodiments, the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing system, and pharmaceutical compositions described herein are administered in an amount effective to treat a disease in the human subject (e.g., wherein the disease can be cancer, muscle disorder, or CNS disorder, etc.). In some embodiments, the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing system, and pharmaceutical compositions have an enhanced safety profile when compared to a pharmaceutical composition comprising T cells or vectors comprising exogenous DNA encoding the same polypeptide, e.g., a CAR complex protein. [00421] In some embodiments, the LNP-based RNA vaccines and pharmaceutical compositions thereof are administered in an amount effective to mount an immunogenic response in a human subject for the vaccination against an infectious agent and/or cancer. In some embodiments, the LNP-based RNA vaccines and pharmaceutical compositions have an enhanced safety profile when compared to state of the art vaccine compositions. [00422] In some embodiments, the LNP-based nucleobase editing systems and pharmaceutical compositions thereof are administered in an amount effective to induce a desire precise edit in a genome. In some embodiments, the LNP-based nucleobase editing systems and pharmaceutical compositions have an enhanced safety profile when compared to state of the art gene editing delivery compositions. [00423] In another aspect, the present disclosure provides a circular RNA comprising, in the following order, a 3’ group I intron fragment, an Internal Ribosome Entry Site (IRES), an expression sequence encoding a polypeptide (e.g., a vaccine antigen, nucleobase editing system or component thereof, therapeutic protein, such as a chimeric antigen receptor (CAR) or T cell receptor (TCR) complex protein), and a 5’ group I intron fragment. [00424] In some embodiments, the 3’ group I intron fragment and 5’ group I intron fragment are Anabaena group I intron fragments. In certain embodiments, the 3’ intron fragment and 5’ intron fragment are defined by the L9a-5 permutation site in the intact intron. In certain embodiments, the 3’ intron fragment and 5’ intron fragment are defined by the L8-2 permutation site in the intact intron. In certain embodiments, the IRES comprises a CVB3 IRES or a fragment or variant thereof. [00425] In some embodiments, the circular RNA comprises a first internal spacer between the 3’ group I intron fragment and the IRES, and a second internal spacer between the expression sequence and the 5’ group I intron fragment. [00426] In certain embodiments, the first and second internal spacers each have a length of about 10 to about 60 nucleotides. [00427] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein consists of natural nucleotides. In some embodiments, the circular RNA further comprises a second expression sequence encoding a therapeutic protein. In some embodiments, the therapeutic protein comprises a checkpoint inhibitor. In certain embodiments, the therapeutic protein comprises a cytokine. [00428] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing system, and pharmaceutical compositions described herein consists of natural nucleotides. [00429] In some embodiments, the circular RNA payload LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises a nucleotide sequence that is codon optimized, either partially or fully. In some embodiments, the circular RNA is optimized to lack at least one microRNA binding site present in an equivalent pre-optimized polynucleotide. In some embodiments, the circular RNA is optimized to lack at least one endonuclease susceptible site present in an equivalent pre-optimized polynucleotide. In some embodiments, the circular RNA is optimized to lack at least one RNA-editing susceptible site present in an equivalent pre-optimized polynucleotide. [00430] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing system, and pharmaceutical compositions described herein has an in vivo functional half- life in humans greater than that of an equivalent linear RNA having the same expression sequence. In some embodiments, the circular RNA has a length of about 100 nucleotides to about 10 kilobases. In some embodiments, the circular RNA has a functional half-life of at least about 20 hours. In some embodiments, the circular RNA has a duration of therapeutic effect in a human cell of at least about 20 hours. In some embodiments, the circular RNA has a duration of therapeutic effect in a human cell greater than or equal to that of an equivalent linear RNA comprising the same expression sequence. In some embodiments, the circular RNA has a functional half-life in a human cell greater than or equal to that of an equivalent linear RNA comprising the same expression sequence. [00431] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, nucleobase editing systems, RNA therapeutics and pharmaceutical compositions described herein has a half-life of at least that of a linear counterpart. In some embodiments, the oRNA has a half-life that is increased over that of a linear counterpart. In some embodiments, the half-life is increased by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or greater. In some embodiments, the oRNA has a half-life or persistence in a cell for at least about 1 hour to about 30 days, or at least about 2 hours, 6 hours, 12 hours, 18 hours, 24 hours (1 day), 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 60 days, or longer or any time therebetween. In some embodiments, the oRNA has a half-life or persistence in a cell for no more than about 10 mins to about 7 days, or no more than about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 24 hours (1 day), 36 hours (1.5 days), 48 hours (2 days),60 hours (2.5 days), 72 hours (3 days), 4 days, 5 days, 6 days, or 7 days. [00432] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, nucleobase editing systems, RNA therapeutics and pharmaceutical compositions described herein has a half-life or persistence in a cell while the cell is dividing. In some embodiments, the oRNA has a half-life or persistence in a cell post division. [00433] In certain embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein has a half-life or persistence in a dividing cell for greater than about 10 minutes to about 30 days, or at least about 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 24 hours (1 day), 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 60 days, or longer or any time therebetween. [00434] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein modulates a cellular function, e.g., transiently or long term. In certain embodiments, the cellular function is stably altered, such as a modulation that persists for at least about 1 hour to about 30 days, or at least about 2 hours, 6 hours, 12 hours, 18 hours, 24 hours (1 day), 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 60 days, or longer. In certain embodiments, the cellular function is transiently altered, e.g., such as a modulation that persists for no more than about 30 mins to about 7 days, or no more than about 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours (1 day), 36 hours (1.5 days), 48 hours (2 days), 60 hours (2.5 days), 72 hours(3 days), 4 days, 5 days, 6 days, or 7 days. [00435] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein is at least about 20 nucleotides, at least about 30 nucleotides, at least about 40 nucleotides, at least about 50 nucleotides, at least about 75 nucleotides, at least about 100 nucleotides, at least about 200 nucleotides, at least about 300 nucleotides, at least about 400 nucleotides, at least about 500 nucleotides, at least about 1,000 nucleotides, at least about 2,000 nucleotides, at least about 5,000 nucleotides, at least about 6,000 nucleotides, at least about 7,000 nucleotides, at least about 8,000 nucleotides, at least about 9,000 nucleotides, at least about 10,000 nucleotides, at least about 12,000 nucleotides, at least about 14,000 nucleotides, at least about 15,000 nucleotides, at least about 16,000 nucleotides, at least about 17,000 nucleotides, at least about 18,000 nucleotides, at least about 19,000 nucleotides, or at least about 20,000 nucleotides. In some embodiments, the oRNA may be of a sufficient size to accommodate a binding site for a ribosome. [00436] In some embodiments, the maximum size of the circular RNA payload of the LNP- based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein may be limited by the ability of packaging and delivering the RNA to a target. In some embodiments, the size of the oRNA is a length sufficient to encode polypeptides, and thus, lengths of at least 20,000 nucleotides, at least 15,000 nucleotides, at least 10,000 nucleotides, at least 7,500 nucleotides, or at least 5,000 nucleotides, at least 4,000 nucleotides, at least 3,000 nucleotides, at least 2,000 nucleotides, at least 1,000 nucleotides, at least 500 nucleotides, at least 400 nucleotides, at least 300 nucleotides, at least 200 nucleotides, at least 100 nucleotides may be useful. [00437] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises one or more elements described elsewhere herein. In some embodiments, the elements may be separated from one another by a spacer sequence or linker. In some embodiments, the elements may be separated from one another by 1 nucleotide, 2 nucleotides, about 5 nucleotides, about 10 nucleotides, about 15 nucleotides, about 20 nucleotides, about 30 nucleotides, about 40 nucleotides, about 50 nucleotides, about 60 nucleotides, about 80 nucleotides, about 100 nucleotides, about 150 nucleotides, about 200 nucleotides, about 250 nucleotides, about 300 nucleotides, about 400 nucleotides, about 500 nucleotides, about 600 nucleotides, about 700 nucleotides, about 800 nucleotides, about 900 nucleotides, about 1000 nucleotides, up to about 1 kb, at least about 1000 nucleotides. [00438] In some embodiments, one or more elements are contiguous with one another, e.g., lacking a spacer element. [00439] In some embodiments, one or more elements is conformationally flexible. In some embodiments, the conformational flexibility is due to the sequence being substantially free of a secondary structure. [00440] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises a secondary or tertiary structure that accommodates a binding site for a ribosome, translation, or rolling circle translation. [00441] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises particular sequence characteristics. For example, the oRNA may comprise a particular nucleotide composition. In some such embodiments, the oRNA may include one or more purine rich regions (adenine or guanosine). In some such embodiments, the oRNA may include one or more purine rich regions (adenine or guanosine).In some embodiments, the oRNA may include one or more AU rich regions or elements (AREs). In some embodiments, the oRNA may include one or more adenine rich regions. [00442] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises one or more modifications described elsewhere herein. [00443] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises one or more expression sequences and is configured for persistent expression in a cell of a subject in vivo. In some embodiments, the oRNA is configured such that expression of the one or more expression sequences in the cell at a later time point is equal to or higher than an earlier time point. In such embodiments, the expression of the one or more expression sequences can be either maintained at a relatively stable level or can increase over time. The expression of the expression sequences can be relatively stable for an extended period of time. For instance, in some cases, the expression of the one or more expression sequences in the cell over a time period of at least 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 23 or more days does not decrease by 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, in some cases, the expression of the one or more expression sequences in the cell is maintained at a level that does not vary by more than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% for at least 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 23 or more days. Regulatory Elements [00444] In some embodiments, the circular RNA payload of the LNP-based RNA vaccines, RNA therapeutics, nucleobase editing systems, and pharmaceutical compositions described herein comprises one or more regulatory elements. As used herein, a "regulatory element" is a sequence that modifies expression of an expression sequence, e.g., a nucleotide sequence encoding an antigen, nucleobase editing system, or a therapeutic protein, i.e., a coding region of interest (CROI). The regulatory element may include a sequence that is located adjacent to a coding region of interest encoded on the circular RNA payload. The regulatory element may be operatively linked to a nucleotide sequence of the circular RNA that encodes a coding region of interest (e.g., an antigen, nucleobase editing system, or therapeutic polypeptide). [00445] In some embodiments, a regulatory element may increase an amount of expression of a coding region of interest encoded on the circular RNA payload as compared to an amount expressed when no regulatory element exists. [00446] In some embodiments, a regulatory element may comprise a sequence to selectively initiates or activates translation of a coding sequence of interest encoded on the circular RNA payload. [00447] In some embodiments, a regulatory element may comprise a sequence to initiate degradation of the oRNA or the payload or cargo. Non-limiting examples of the sequence to initiate degradation includes, but is not limited to, riboswitch aptazyme and miRNA binding sites. [00448] In some embodiments, a regulatory element can modulate translation of a coding region of interest encoded on the oRNA. The modulation can create an increase (enhancer) or decrease (suppressor) in the expression of the coding region of interest. The regulatory element may be located adjacent to the CROI (e.g., on one side or both sides of the CROI). Translation Initiation Sequence [00449] In some embodiments, a translation initiation sequence functions as a regulatory element. In some embodiments, the translation initiation sequence comprises an AUG/ATG codon. In some embodiments, a translation initiation sequence comprises any eukaryotic start codon such as, but not limited to, AUG/ATG, CUG/CTG, GUG/GTG, UUG/TTG, ACG, AUC/ATC, AUU, AAG, AUA/ATA, or AGG. In some embodiments, a translation initiation sequence comprises a Kozak sequence. In some embodiments, translation begins at an alternative translation initiation sequence, e.g., translation initiation sequence other than AUG/ATG codon, under selective conditions, e.g., stress induced conditions. As a non-limiting example, the translation of the circular polyribonucleotide may begin at alternative translation initiation sequence, such as ACG. As another non-limiting example, the circular polyribonucleotide translation may begin at alternative translation initiation sequence, CUG/CTG. As another non-limiting example, the translation may begin at alternative translation initiation sequence, GUG/GTG. As yet another non-limiting example, the translation may begin at a repeat-associated non-AUG (RAN) sequence, such as an alternative translation initiation sequence that includes short stretches of repetitive RNA e.g. CGG, GGGGCC, CAG, or CTG. [00450] In some embodiments, the oRNA encodes a polypeptide or peptide and may comprise a translation initiation sequence. The translation initiation sequence may comprise, but is not limited to a start codon, a non-coding start codon, a Kozak sequence or a Shine-Dalgarno sequence. The translation initiation sequence may be located adjacent to the payload or cargo (e.g., on one side or both sides of the coding region of interest). [00451] In some embodiments, the translation initiation sequence provides conformational flexibility to the oRNA. In some embodiments, the translation initiation sequence is within a substantially single stranded region of the oRNA. [00452] The oRNA may include more than 1 start codon such as, but not limited to, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or more than 15 start codons. Translation may initiate on the first start codon or may initiate downstream of the first start codon. [00453] In some embodiments, the oRNA may initiate at a codon which is not the first start codon, e.g., AUG. Translation of the circular polyribonucleotide may initiate at an alternative translation initiation sequence, such as, but not limited to, ACG, AGG, AAG, CUG/CTG, GUG/GTG, AUA/ATA, AUU/ATT, UUG/TTG. In some embodiments, translation begins at an alternative translation initiation sequence under selective conditions, e.g., stress induced conditions. As a non- limiting example, the translation of the oRNA may begin at alternative translation initiation sequence, such as ACG. As another non-limiting example, the oRNA translation may begin at alternative translation initiation sequence, CUG/CTG. As yet another non-limiting example, the oRNA translation may begin at alternative translation initiation sequence, GTG/GUG. As yet another non- limiting example, the oRNA may begin translation at a repeat-associated non-AUG (RAN) sequence, such as an alternative translation initiation sequence that includes short stretches of repetitive RNA e.g. CGG, GGGGCC, CAG, CTG. IRES Sequences [00454] In some embodiments, the oRNA described herein comprises an internal ribosome entry site (IRES) element capable of engaging an eukaryotic ribosome. In some embodiments, the IRES element is at least about 5 nucleotides, at least about 8 nucleotides, at least about 9 nucleotides, at least about 10 nucleotides, at least about 15 nucleotides, at least about 20 nucleotides, at least about 25 nucleotides, at least about 30 nucleotides, at least about 40 nucleotides, at least about 50 nucleotides, at least about 100 nucleotides, at least about 200 nucleotides, at least about 250 nucleotides, at least about 350 nucleotides, or at least about 500 nucleotides. In one embodiment, the IRES element is derived from the DNA of an organism including, but not limited to, a virus, a mammal, and a Drosophila. Such viral DNA may be derived from, but is not limited to, picornavirus complementary DNA (cDNA), with encephalomyocarditis virus (EMCV) cDNA and poliovirus cDNA. In one embodiment, Drosophila DNA from which an IRES element is derived includes, but is not limited to, an Antennapedia gene from Drosophila melanogaster. [00455] In some embodiments, the IRES element is at least partially derived from a virus, for instance, it can be derived from a viral IRES element, such as ABPV_IGRpred, AEV, ALPV_IGRpred, BQCV_IGRpred, BVDV1_1-385, BVDV1_29-391, CrPV_5NCR, CrPV_IGR, crTMV_IREScp, crTMV_IRESmp75, crTMV_IRESmp228, crTMV_IREScp, crTMV_IREScp, CSFV, CVB3, DCV_IGR, EMCV-R, EoPV_5NTR, ERAV 245-961, ERBV 162-920, EV71_1-748, FeLV-Notch2, FMDV_type_C, GBV-A, GBV-B, GBV-C, gypsy_env, gypsyD5, gypsyD2, HAV_HM175, HCV_type_1a, HiPV_IGRpred, HIV-1, HoCV1_IGRpred, HRV-2, IAPV_IGRpred, idefix, KBV_IGRpred, LINE-1_ORF1_-101_to_-1, LINE-1_ORF1-302_to_-202, LINE-1_ORF2- 138_to_-86, LINE-1_ORF1_-44to_-1, PSIV_IGR, PV_type1_Mahoney,PV_type3_Leon, REV-A, RhPV_5NCR, RhPV_IGR, SINV1_IGRpred, SV40_661-830, TMEV, TMV_UI_IRESmp228, TRV_5NTR, TrV_IGR, or TSV_IGR. In some embodiments, the IRES element is at least partially derived from a cellular IRES, such as AML1/RUNX1, Antp-D, Antp-DE, Antp-CDE, Apaf-1, Apaf-1, AQP4, AT1R_var1, AT1R_var2, AT1R_var3, AT1R_var4, BAG1_p36delta236 nt, BAG1_p36, BCL2, BiP_-222_-3, c-IAP1_285-1399, c-IAP1_1313-1462, c-jun, c-myc, Cat-1224, CCND1, DAPS, eIF4G, eIF4GI-ext, eIF4GII, eIF4GII-long, ELG1, ELH, FGF1A,FMR1, Gtx-133-141, Gtx-1-166, Gtx-1-120, Gtx-1-196, hairless, HAP4, HIF1a, hSNM1, Hsp101, hsp70, hsp70, Hsp90, IGF2_leader2, Kv1.4_1.2, L-myc, LamB1_-335_-1, LEF1, MNT_75-267, MNT_36-160, MTG8a, MYB, MYT2_997-1152, n-MYC, NDST1, NDST2, NDST3, NDST4L, NDST4S, NRF_-653_-17, NtHSF1, ODC1, p27kip1, 03_128-269, PDGF2/c-sis, Pim-1, PITSLRE_p58, Rbm3, reaper, Scamper, TFIID, TIF4631, Ubx_1-966, Ubx_373-961, UNR, Ure2, UtrA, VEGF-A-133-1, XIAP_5-464, XIAP_305- 466, or YAP1. [00456] In another embodiment, the IRES is an IRES sequence from Coxsackievirus B3 (CVB3), the protein coding region encodes Guassia luciferase (Gluc) and the spacer sequences are polyA-C. [00457] In some embodiments, the IRES, if present, is at least about 50 nucleotides in length. In one embodiment, the vector comprises an IRES that comprises a natural sequence. In one embodiment, the vector comprises an IRES that comprises a synthetic sequence. [00458] An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA. A polynucleotide containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes (e.g., multicistronic mRNA). When polynucleotides are provided with an IRES, further optionally provided is a second translatable region. Examples of IRES sequences that can be used according to the present disclosure include without limitation, those from picornaviruses (e.g., FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical Swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV). Termination Element [00459] In some embodiments, the oRNA includes one or more coding regions of interest (i.e., also referred to as product expression sequences) which encode polypeptides of interest, including but not limited to vaccine antigens and therapeutic proteins. In various embodiments, the product expression sequences may or may not have a termination element. [00460] In some embodiments, the oRNA includes one or more product expression sequences that lack a termination element, such that the oRNA is continuously translated. [00461] Exclusion of a termination element may result in rolling circle translation or continuous expression of the encoded peptides or polypeptides as the ribosome will not stall or fall- off. In such an embodiment, rolling circle translation expresses continuously through the product expression sequence. [00462] In some embodiments, one or more product expression sequences in the oRNA comprise a termination element. [00463] In some embodiments, not all of the product expression sequences in the oRNA comprise a termination element. In such instances, the product expression sequence may fall off the ribosome when the ribosome encounters the termination element and terminates translation. Rolling Circle Translation [00464] In some embodiments, once translation of the oRNA is initiated, the ribosome bound to the oRNA does not disengage from the oRNA before finishing at least one round of translation of the oRNA. In some embodiments, the oRNA as described herein is competent for rolling circle translation. In some embodiments, during rolling circle translation, once translation of the oRNA is initiated, the ribosome bound to the oRNA does not disengage from the oRNA before finishing at least 2 rounds, at least 3 rounds, at least 4 rounds, at least 5 rounds, at least 6 rounds, at least 7 rounds, at least 8 rounds, at least 9 rounds, at least 10 rounds, at least 11 rounds, at least 12 rounds, at least 13 rounds, at least 14 rounds, at least 15 rounds, at least 20 rounds, at least 30 rounds, at least 40 rounds, at least 50 rounds, at least 60 rounds, at least 70 rounds, at least 80 rounds, at least 90 rounds, at least 100 rounds, at least 150 rounds, at least 200 rounds, at least 250 rounds, at least 500 rounds, at least 1,000 rounds, at least 1,500 rounds, at least 2,000 rounds, at least 5,000 rounds, at least 10,000 rounds, at least 10⁵ rounds, or at least 10⁶ rounds of translation of the oRNA. [00465] In some embodiments, the rolling circle translation of the oRNA leads to generation of polypeptide that is translated from more than one round of translation of the oRNA. In some embodiments, the oRNA comprises a stagger element, and rolling circle translation of the oRNA leads to generation of polypeptide product that is generated from a single round of translation or less than a single round of translation of the oRNA. Circularization [00466] In one embodiment, a linear RNA may be cyclized, or concatemerized. In some embodiments, the linear RNA may be cyclized in vitro prior to formulation and/or delivery. In some embodiments, the linear RNA may be cyclized within a cell. [00467] In some embodiments, the mechanism of cyclization or concatemerization may occur through at least 3 different routes: 1) chemical, 2) enzymatic, and 3) ribozyme catalyzed. The newly formed 5'-/3'-linkage may be intramolecular or intermolecular. [00468] In the first route, the 5'-end and the 3 '-end of the nucleic acid contain chemically reactive groups that, when close together, form a new covalent linkage between the 5 '-end and the 3 '- end of the molecule. The 5 '-end may contain an NHS-ester reactive group and the 3 '-end may contain a 3'-amino-terminated nucleotide such that in an organic solvent the 3'-amino-terminated nucleotide on the 3 '-end of a synthetic mRNA molecule will undergo a nucleophilic attack on the 5 '- NHS-ester moiety forming a new 5 '-/3 '-amide bond. [00469] In the second route, T4 RNA ligase may be used to enzymatically link a 5'- phosphorylated nucleic acid molecule to the 3'-hydroxyl group of a nucleic acid forming a new phosphorodiester linkage. In an example reaction, ^g of a nucleic acid molecule is incubated at 37°C for 1 hour with 1-10 units of T4 RNA ligase (New England Biolabs, Ipswich, MA) according to the manufacturer's protocol. The ligation reaction may occur in the presence of a split oligonucleotide capable of base-pairing with both the 5'-and 3'-region in juxtaposition to assist the enzymatic ligation reaction. [00470] In the third route, either the 5 '-or 3 '-end of the cDNA template encodes a ligase ribozyme sequence such that during in vitro transcription, the resultant nucleic acid molecule can contain an active ribozyme sequence capable of ligating the 5 '-end of a nucleic acid molecule to the 3 '-end of a nucleic acid molecule. The ligase ribozyme may be derived from the Group I Intron, Group I Intron, Hepatitis Delta Virus, Hairpin ribozyme or may be selected by SELEX (systematic evolution of ligands by exponential enrichment). The ribozyme ligase reaction may take 1 to 24 hours at temperatures between 0 and 37°C. [00471] In some embodiments, the oRNA is made via circularization of a linear RNA. [00472] In some embodiments, the following elements are operably connected to each other and, in some embodiments, arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) a protein coding or noncoding region, d.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and e.) a 3′ homology arm. In certain embodiments said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. In some embodiments, the biologically active RNA is, for example, an miRNA sponge, or long noncoding RNA. [00473] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) optionally, a 5′ spacer sequence, d.) optionally, an internal ribosome entry site (IRES), e.) a protein coding or noncoding region, f.) optionally, a 3′ spacer sequence, g.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and h.) a 3′ homology arm. In certain embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00474] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) a 5′ spacer sequence, d.) an internal ribosome entry site (IRES), e.) a protein coding or noncoding region, f.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and g.) a 3′ homology arm. In some embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00475] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) a 5′ spacer sequence, d.) a protein coding or noncoding region, e.) a 3′ spacer sequence, f.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and g.) a 3′ homology arm. In some embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00476] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) an internal ribosome entry site (IRES), d.) a protein coding or noncoding region, e.) a 3′ spacer sequence, f) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and g.) a 3′ homology arm. In some embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00477] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) a protein coding or noncoding region, d.) a 3′ spacer sequence, e.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and f.) a 3′ homology arm. In some embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00478] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) a 5′ spacer sequence, d.) a protein coding or noncoding region, e.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and f.) a 3′ homology arm. In some embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00479] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) an internal ribosome entry site (IRES), d.) a protein coding or noncoding region, e.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and f) a 3′ homology arm. In some embodiments, said vector allows production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00480] In some embodiments, the following elements are operably connected to each other and arranged in the following sequence: a.) a 5′ homology arm, b.) a 3′ group I intron fragment containing a 3′ splice site dinucleotide, c.) a 5′ spacer sequence, d.) an internal ribosome entry site (IRES), e.) a protein coding or noncoding region, f) a 3′ spacer sequence, g.) a 5′ group I intron fragment containing a 5′ splice site dinucleotide, and h.) a 3′ homology arm. In some embodiments, said vector allowing production of a circular RNA that is translatable and/or biologically active inside eukaryotic cells. [00481] In one embodiment, the 3′ group I intron fragment and/or the 5′ group I intron fragment is from a Cyanobacterium Anabaena sp. pre-tRNA-Leu gene or T4 phage Td gene. [00482] In one embodiment, the 3′ group I intron fragment and/or the 5′ group I intron fragment is from a Cyanobacterium Anabaena sp. pre-tRNA-Leu gene. [00483] In one embodiment, the protein coding region encodes a protein of eukaryotic or prokaryotic origin. In another embodiment, the protein coding region encodes human protein or non- human protein. In some embodiments, the protein coding region encodes one or more antibodies. For example, in some embodiments, the protein coding region encodes human antibodies. In one embodiment, the protein coding region encodes a protein selected from hFIX, SP-B, VEGF-A, human methylmalonyl-CoA mutase (hMUT), CFTR, cancer self-antigens, and additional gene editing enzymes like Cpf1, zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). In another embodiment, the protein coding region encodes a protein for therapeutic use. In one embodiment, the human antibody encoded by the protein coding region is an anti-HIV antibody. In one embodiment, the antibody encoded by the protein coding region is a bispecific antibody. In one embodiment, the bispecific antibody is specific for CD19 and CD22. In another embodiment, the bispecific antibody is specific for CD3 and CLDN6. In one embodiment, the protein coding region encodes a protein for diagnostic use. In one embodiment, the protein coding region encodes Gaussia luciferase (Gluc), Firefly luciferase (Fluc), enhanced green fluorescent protein (eGFP), human erythropoietin (hEPO), or Cas9 endonuclease. [00484] In one embodiment, the 5′ homology arm is about 5-50 nucleotides in length. In another embodiment, the 5′ homology arm is about 9-19 nucleotides in length. In some embodiments, the 5′ homology arm is at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 nucleotides in length. In some embodiments, the 5′ homology arm is no more than 50, 45, 40, 35, 30, 25 or 20 nucleotides in length. In some embodiments, the 5′ homology arm is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 nucleotides in length. [00485] In one embodiment, the 3′ homology arm is about 5-50 nucleotides in length. In another embodiment, the 3′ homology arm is about 9-19 nucleotides in length. In some embodiments, the 3′ homology arm is at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 nucleotides in length. In some embodiments, the 3′ homology arm is no more than 50, 45, 40, 35, 30, 25 or 20 nucleotides in length. In some embodiments, the 3′ homology arm is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 nucleotides in length. [00486] In one embodiment, the 5′ spacer sequence is at least 10 nucleotides in length. In another embodiment, the 5′ spacer sequence is at least 15 nucleotides in length. In a further embodiment, the 5′ spacer sequence is at least 30 nucleotides in length. In some embodiments, the 5′ spacer sequence is at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25 or 30 nucleotides in length. In some embodiments, the 5′ spacer sequence is no more than 100, 90, 80, 70, 60, 50, 45, 40, 35 or 30 nucleotides in length. In some embodiments the 5′ spacer sequence is between 20 and 50 nucleotides in length. In certain embodiments, the 5′ spacer sequence is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleotides in length. In one embodiment, the 5′ spacer sequence is a polyA sequence. In another embodiment, the 5′ spacer sequence is a polyA-C sequence. [00487] In one embodiment, the 3′ spacer sequence is at least 10 nucleotides in length. In another embodiment, the 3′ spacer sequence is at least 15 nucleotides in length. In a further embodiment, the 3′ spacer sequence is at least 30 nucleotides in length. In some embodiments, the 3′ spacer sequence is at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25 or 30 nucleotides in length. In some embodiments, the 3′ spacer sequence is no more than 100, 90, 80, 70, 60, 50, 45, 40, 35 or 30 nucleotides in length. In some embodiments the 3′ spacer sequence is between 20 and 50 nucleotides in length. In certain embodiments, the 3′ spacer sequence is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleotides in length. In one embodiment, the 3′ spacer sequence is a polyA sequence. In another embodiment, the 5′ spacer sequence is a polyA-C sequence. Extracellular Circularization [00488] In some embodiments, the linear RNA is cyclized, or concatemerized using a chemical method to form an oRNA. In some chemical methods, the 5'-end and the 3'-end of the nucleic acid (e.g., a linear RNA) includes chemically reactive groups that, when close together, may form a new covalent linkage between the 5'-end and the 3'-end of the molecule. The 5'-end may contain an NHS-ester reactive group and the 3'-end may contain a 3'-amino-terminated nucleotide such that in an organic solvent the 3'-amino-terminated nucleotide on the 3'-end of a linear RNA will undergo a nucleophilic attack on the 5'-NHS-ester moiety forming a new 5'-/3'-amide bond. [00489] In one embodiment, a DNA or RNA ligase may be used to enzymatically link a 5'- phosphorylated nucleic acid molecule (e.g., a linear RNA) to the 3'-hydroxyl group of a nucleic acid (e.g., a linear nucleic acid) forming a new phosphorodiester linkage. In an example reaction, a linear RNA is incubated at 37C for 1 hour with 1-10 units of T4 RNA ligase according to the manufacturer's protocol. The ligation reaction may occur in the presence of a linear nucleic acid capable of base- pairing with both the 5'-and 3'-region in juxtaposition to assist the enzymatic ligation reaction. In one embodiment, the ligation is splint ligation where a single stranded polynucleotide (splint), like a single stranded RNA, can be designed to hybridize with both termini of a linear RNA, so that the two termini can be juxtaposed upon hybridization with the single-stranded splint. Splint ligase can thus catalyze the ligation of the juxtaposed two termini of the linear RNA, generating an oRNA. [00490] In one embodiment, a DNA or RNA ligase may be used in the synthesis of the oRNA. As a non-limiting example, the ligase may be a circ ligase or circular ligase. [00491] In one embodiment, either the 5'-or 3'-end of the linear RNA can encode a ligase ribozyme sequence such that during in vitro transcription, the resultant linear RNA includes an active ribozyme sequence capable of ligating the 5'-end of the linear RNA to the 3'-end of the linear RNA. The ligase ribozyme may be derived from the Group I Intron, Hepatitis Delta Virus, Hairpin ribozyme or may be selected by SELEX (systematic evolution of ligands by exponential enrichment). [00492] In one embodiment, a linear RNA may be cyclized or concatemerized by using at least one non-nucleic acid moiety. In one aspect, the at least one non-nucleic acid moiety may react with regions or features near the 5' terminus and/or near the 3' terminus of the linear RNA in order to cyclize or concatermerize the linear RNA. In another aspect, the at least one non-nucleic acid moiety may be located in or linked to or near the 5' terminus and/or the 3' terminus of the linear RNA. The non-nucleic acid moieties contemplated may be homologous or heterologous. As a non-limiting example, the non-nucleic acid moiety may be a linkage such as a hydrophobic linkage, ionic linkage, a biodegradable linkage and/or a cleavable linkage. As another non-limiting example, the non-nucleic acid moiety is a ligation moiety. As yet another non-limiting example, the non-nucleic acid moiety may be an oligonucleotide or a peptide moiety, such as an aptamer or a non-nucleic acid linker as described herein. [00493] In one embodiment, a linear RNA may be cyclized or concatemerized due to a non- nucleic acid moiety that causes an attraction between atoms, molecular surfaces at, near or linked to the 5' and 3' ends of the linear RNA. As a non-limiting example, one or more linear RNA may be cyclized or concatemerized by intermolecular forces or intramolecular forces. Non-limiting examples of intermolecular forces include dipole-dipole forces, dipole-induced dipole forces, induced dipole- induced dipole forces, Van der Waals forces, and London dispersion forces. Non-limiting examples of intramolecular forces include covalent bonds, metallic bonds, ionic bonds, resonant bonds, agnostic bonds, dipolar bonds, conjugation, hyperconjugation and antibonding. [00494] In one embodiment, the linear RNA may comprise a ribozyme RNA sequence near the 5' terminus and near the 3' terminus. The ribozyme RNA sequence may covalently link to a peptide when the sequence is exposed to the remainder of the ribozyme. In one aspect, the peptides covalently linked to the ribozyme RNA sequence near the 5' terminus and the 3' terminus may associate with each other causing a linear RNA to cyclize or concatemerize. In another aspect, the peptides covalently linked to the ribozyme RNA near the 5' terminus and the 3' terminus may cause the linear RNA to cyclize or concatemerize after being subjected to ligated using various methods known in the art such as, but not limited to, protein ligation. [00495] In some embodiments, the linear RNA may include a 5' triphosphate of the nucleic acid converted into a 5' monophosphate, e.g., by contacting the 5' triphosphate with RNA 5' pyrophosphohydrolase (RppH) or an ATP diphosphohydrolase (apyrase). Alternately, converting the 5' triphosphate of the linear RNA into a 5' monophosphate may occur by a two-step reaction comprising: (a) contacting the 5' nucleotide of the linear RNA with a phosphatase (e.g., Antarctic Phosphatase, Shrimp Alkaline Phosphatase, or Calf Intestinal Phosphatase) to remove all three phosphates; and (b) contacting the 5' nucleotide after step (a) witha kinase (e.g., Polynucleotide Kinase) that adds a single phosphate. [00496] In some embodiments, RNA may be circularized using the methods described in WO2017222911 and WO2016197121, the contents of each of which are herein incorporated by reference in their entirety. [00497] In some embodiments, RNA may be circularized, for example, by back splicing of a non-mammalian exogenous intron or splint ligation of the 5' and 3 ' ends of a linear RNA. In one embodiment, the circular RNA is produced from a recombinant nucleic acid encoding the target RNA to be made circular. As a non-limiting example, the method comprises: a) producing a recombinant nucleic acid encoding the target RNA to be made circular, wherein the recombinant nucleic acid comprises in 5' to 3 ' order: i) a 3 ' portion of an exogenous intron comprising a 3' splice site, ii) a nucleic acid sequence encoding the target RNA, and iii) a 5 ' portion of an exogenous intron comprising a 5 ' splice site; b) performing transcription, whereby RNA is produced from the recombinant nucleic acid; and c) performing splicing of the RNA, whereby the RNA circularizes to produce a oRNA. [00498] While not wishing to be bound by theory, circular RNAs generated with exogenous introns are recognized by the immune system as "non-self" and trigger an innate immune response. On the other hand, circular RNAs generated with endogenous introns are recognized by the immune system as "self" and generally do not provoke an innate immune response, even if carrying an exon comprising foreign RNA. [00499] Accordingly, circular RNAs can be generated with either an endogenous or exogenous intron to control immunological self/non-self discrimination as desired. Numerous intron sequences from a wide variety of organisms and viruses are known and include sequences derived from genes encoding proteins, ribosomal RNA (rRNA), or transfer RNA (tRNA). [00500] Circular RNAs can be produced from linear RNAs in a number of ways. In some embodiments, circular RNAs are produced from a linear RNA by backsplicing of a downstream 5' splice site (splice donor) to an upstream 3' splice site (splice acceptor). Circular RNAs can be generated in this manner by any nonmammalian splicing method. For example, linear RNAs containing various types of introns, including self-splicing group I introns, self-splicing group II introns, spliceosomal introns, and tRNA introns can be circularized. In particular, group I and group II introns have the advantage that they can be readily used for production of circular RNAs in vitro as well as in vivo because of their ability to undergo self-splicing due to their autocatalytic ribozyme activity. [00501] In some embodiments, circular RNAs can be produced in vitro from a linear RNA by chemical or enzymatic ligation of the 5' and 3' ends of the RNA. Chemical ligation can be performed, for example, using cyanogen bromide (BrCN) or ethyl-3-(3'-dimethylaminopropyl) carbodiimide (EDC) for activation of a nucleotide phosphomonoester group to allow phosphodiester bond formation. See e.g., Sokolova (1988) FEBS Lett 232: 153-155; Dolinnaya et al. (1991) Nucleic Acids Res., 19:3067-3072; Fedorova (1996) Nucleosides Nucleotides Nucleic Acids 15: 1137-1147; herein incorporated by reference. Alternatively, enzymatic ligation can be used to circularize RNA. Exemplary ligases that can be used include T4 DNA ligase (T4 Dnl), T4 RNA ligase 1 (T4 Rnl 1), and T4 RNA ligase 2 (T4 Rnl 2). [00502] In some embodiments, splint ligation using an oligonucleotide splint that hybridizes with the two ends of a linear RNA can be used to bring the ends of the linear RNA together for ligation. Hybridization of the splint, which can be either a DNA or a RNA, orientates the 5 '- phosphate and 3' -OH of the RNA ends for ligation. Subsequent ligation can be performed using either chemical or enzymatic techniques, as described above. Enzymatic ligation can be performed, for example, with T4 DNA ligase (DNA splint required), T4 RNA ligase 1 (RNA splint required) or T4 RNA ligase 2 (DNA or RNA splint). Chemical ligation, such as with BrCN or EDC, in some cases is more efficient than enzymatic ligation if the structure of the hybridized splint-RNA complex interferes with enzymatic activity. [00503] In some embodiments, the oRNA may further comprise an internal ribosome entry site (IRES) operably linked to an RNA sequence encoding a polypeptide. Inclusion of an IRES permits the translation of one or more open reading frames from a circular RNA. The IRES element attracts a eukaryotic ribosomal translation initiation complex and promotes translation initiation. See, e.g., Kaufman et al., Nuc. Acids Res. (1991) 19:4485-4490; Gurtu et al., Biochem. Biophys. Res. Comm. (1996) 229:295-298; Rees et al., BioTechniques (1996) 20: 102-110; Kobayashi et al., BioTechniques (1996) 21 :399-402; and Mosser et al., BioTechniques 199722150-161). [00504] In some embodiments, the circularization efficiency of the circularization methods provided herein is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100%. In some embodiments, the circularization efficiency of the circularization methods provided herein is at least about 40%. Splicing Element [00505] In some embodiments, the oRNA includes at least one splicing element. The splicing element can be a complete splicing element that can mediate splicing of the oRNA or the spicing element can be a residual splicing element from a completed splicing event. For instance, in some cases, a splicing element of a linear RNA can mediate a splicing event that results in circularization of the linear RNA, thereby the resultant oRNA comprises a residual splicing element from such splicing- mediated circularization event. In some cases, the residual splicing element is not able to mediate any splicing. In other cases, the residual splicing element can still mediate splicing under certain circumstances. In some embodiments, the splicing element is adjacent to at least one expression sequence. In some embodiments, the oRNA includes a splicing element adjacent each expression sequence. In some embodiments, the splicing element is on one or both sides of each expression sequence, leading to separation of the expression products, e.g., peptide(s) and or polypeptide(s). [00506] In some embodiments, the oRNA includes an internal splicing element that when replicated the spliced ends are joined together. Some examples may include miniature introns (<100 nt) with splice site sequences and short inverted repeats (30-40 nt) such as AluSq2, AluJr, and AluSz, inverted sequences in flanking introns, Alu elements in flanking introns, and motifs found in (suptable4 enriched motifs) cis-sequence elements proximal to backsplice events such as sequences in the 200 bp preceding (upstream of) or following (downstream from) a backsplice site with flanking exons. In some embodiments, the oRNA includes at least one repetitive nucleotide sequence described elsewhere herein as an internal splicing element. In such embodiments, the repetitive nucleotide sequence may include repeated sequences from the Alu family of introns. See, e.g., US Patent No. 11,058,706. [00507] In some embodiments, the oRNA may include canonical splice sites that flank head- to-tail junctions of the oRNA. [00508] In some embodiments, the oRNA may include a bulge-helix-bulge motif, comprising a 4-base pair stem flanked by two 3-nucleotide bulges. Cleavage occurs at a site in the bulge region, generating characteristic fragments with terminal 5'-hydroxyl group and 2', 3'-cyclic phosphate. Circularization proceeds by nucleophilic attack of the 5'-OH group onto the 2', 3'-cyclic phosphate of the same molecule forming a 3', 5'-phosphodiester bridge. [00509] In some embodiments, the oRNA may include a sequence that mediates self-ligation. Non-limiting examples of sequences that can mediate self-ligation include a self-circularizing intron, e.g., a 5' and 3' slice junction, or a self-circularizing catalytic intron such as a Group I, Group II or Group III Introns. Non-limiting examples of group I intron self-splicing sequences may includeself- splicing permuted intron-exon sequences derived from T4 bacteriophage gene td, and the intervening sequence (IVS) rRNA of Tetrahymena. Other Circularization Methods [00510] In some embodiments, linear RNA may include complementary sequences, including either repetitive or nonrepetitive nucleic acid sequences within individual introns or across flanking introns. In some embodiments, the oRNA includes a repetitive nucleic acid sequence. In some embodiments, the repetitive nucleotide sequence includes poly CA or poly UG sequences. In some embodiments, the oRNA includes at least one repetitive nucleic acid sequence that hybridizes to a complementary repetitive nucleic acid sequence in another segment of the oRNA, with the hybridized segment forming an internal double strand. In some embodiments, repetitive nucleic acid sequences and complementary repetitive nucleic acid sequences from two separate oRNA that hybridize to generate a single oRNA, with the hybridized segments forming internal double strands. In some embodiments, the complementary sequences are found at the 5' and 3' ends of the linear RNA. In some embodiments, the complementary sequences include about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or more paired nucleotides. [00511] In some embodiments, chemical methods of circularization may be used to generate the oRNA. Such methods may include, but are not limited to click chemistry (e.g., alkyne- and azide- based methods, or clickable bases), olefin metathesis, phosphoramidate ligation, hemiaminal-imine crosslinking, base modification, and any combination thereof. In some embodiments, enzymatic methods of circularization may be used to generate the oRNA. In some embodiments, a ligation enzyme, e.g., DNA or RNA ligase, may be used to generate a template of the oRNA or complement, a complementary strand of the oRNA, or the oRNA. [00512] Any of the circular polynucleotides as taught in for example U.S. Provisional Application No.61/873,010 filed Sep.3, 2013 or U.S. Patent No.10,709,779, may be used herein. The contents of these references are incorporated herein by reference in their entirety. In addition, any of the circular RNAs, methods for making circular RNAs, circular RNA compositions that are described in the following publications are contemplated herein and are incorporated by reference in their entireties are part of the instant specification: US Patents US 11,352,640, US 11,352,641, US 11,203,767, US 10,683,498, US 5,773,244, and US 5,766,903; US Application Publications US 2022/0177540, US 2021/0371494, US 2022/0090137, US 2019/0345503, and US 2015/0299702; and PCT Application Publications WO 2021/226597, WO 2019/236673, WO 2017/222911, WO2016/187583, WO2014/082644, WO 1997/007825, and WO 2023/182948. [00513] Reference is also made to the following scientific publications that provide information and details on the production of circular RNA molecules: (1) Chen X, Lu Y. Circular RNA: Biosynthesis in vitro. Front Bioeng Biotechnol.2021 Nov 30;9:787881. doi: 10.3389/fbioe.2021.787881. PMID: 34917603; PMCID: PMC8670002; (2) Lee KH, Kim S, Lee SW. Pros and Cons of In Vitro Methods for Circular RNA Preparation. Int J Mol Sci.2022 Oct 31;23(21):13247. doi: 10.3390/ijms232113247. PMID: 36362032; PMCID: PMC9654983; (3) Liu X, Zhang Y, Zhou S, Dain L, Mei L, Zhu G. Circular RNA: An emerging frontier in RNA therapeutic targets, RNA therapeutics, and mRNA vaccines. J Control Release.2022 Aug;348:84-94. doi: 10.1016/j.jconrel.2022.05.043. Epub 2022 Jun 2. PMID: 35649485; PMCID: PMC9644292; (4) Müller S, Appel B. In vitro circularization of RNA. RNA Biol.2017 Aug 3;14(8):1018-1027. doi: 10.1080/15476286.2016.1239009. Epub 2016 Sep 26. PMID: 27668458; PMCID: PMC5680678; (5) Petkovic S, Müller S. Synthesis and Engineering of Circular RNAs. Methods Mol Biol. 2018;1724:167-180. doi: 10.1007/978-1-4939-7562-4_14. PMID: 29322449; (6) Welden JR, Stamm S. Pre-mRNA structures forming circular RNAs. Biochim Biophys Acta Gene Regul Mech.2019 Nov-Dec;1862(11-12):194410. doi: 10.1016/j.bbagrm.2019.194410. Epub 2019 Aug 14. PMID: 31421281; and (7) Prats AC, David F, Diallo LH, Roussel E, Tatin F, Garmy-Susini B, Lacazette E. Circular RNA, the Key for Translation. Int J Mol Sci.2020 Nov 14;21(22):8591. doi: 10.3390/ijms21228591. PMID: 33202605; PMCID: PMC7697609; each of which are incorporated herein by reference in their entireties. D. Gene editing systems [00514] As described herein in various embodiments, the LNPs of the present disclosure may comprise a gene editing system. As used herein, the term “gene editing system” generally refers to a composition having one or more gene editing system components which are capable of independently or co-dependently editing, modifying, or altering a target polynucleotide sequence or a target transcript comprising a nucleic acid sequence and/or modifying the epigenome to effect a change in gene regulation. Gene editing systems for the present disclosure include any editing systems known in the art. [00515] For example, the LNP compositions herein may be used to deliver any gene editing system including CRISPR (clustered regularly interspaced short palindromic repeats) and the associated CRISPR-associated proteins (e.g., CRISPR-Cas9) (Jinek et al., “A programmable dual- RNA-guided DNA endonuclease in adaptive bacterial immunity,” Science, Vol.337 (6096), pp.816- 821), meganuclease editors (Boissel et al., “megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering,” Nucleic Acids Research 42: pp.2591-2601) and bacterial retron systems (Schubert et al., “High-throughput functional variant screens via in vivo production of single- stranded DNA,” PNAS, April 27, 2021, Vol.118(18), pp.1-10). In particular, CRISPR-Cas9 has been derivatized in numerous ways to expand upon its guide RNA-based programmable double-strand cutting activity to form systems ranging from finding alternative CRISPR Cas nuclease enzymes having different PAM requirements and cutting properties (e.g., Cas12a, Cas12f, Cas13a, and Cas13b) to base editing (Komor et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage,” Nature, May 19, 2016, 533 (7603); pp.420-424 [cytosine base editors or CBEs] and Gaudelli et al., “Programmable base editing of A-T to G-C in genomic DNA without DNA cleavage,” Nature, Vol.551, pp.464-471 [adenine base editors or ABEs]) to prime editing (Anzalone et al., “Search-and-replace genome editing without double-strand breaks or donor DNA,” Nature, Dec 2019, 576 (7789): pp.149-157) to twin prime editing (Anzalone et al., “Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing,” Nature Biotechnology, Dec 9, 2021, vol.40, pp.731-740) to epigenetic editing (Kungulovski and Jeltsch, “Epigenome Editing: State of the Art, Concepts, and Perspective,” Trends in Genetics, Vol.32, 206, pp.101-113) to CRISPR-directed integrase editing (Yarnell et al., “Drag- and-drop genome insertion of large sequences without double-stranded DNA cleavage using CRISPR- directed integrases,” Nature Biotechnology, Nov 24, 2022, (“PASTE”). Each of these gene editing systems may be packaged up in the LNP compositions described herein and delivered to target organs, tissues, and cells to bring about the modification of a target sequence or the expression of a target gene. [00516] The gene editing systems deliverable by the herein disclosed LNPs can be any gene editing system. The gene editing systems contemplated herein can include (A) nucleobase gene editing systems which result in one or more the modifications to the sequence of target nucleic acid molecule, (B) an epigenetic editing system which results in one or more modifications to the epigenome to bring about an effect on gene expression without altering the sequence of a nucleic acid molecule, and (C) gene editing systems that combine the features of nucleobase editing systems and epigenetic editing systems. [00517] Nucleobase editing systems include a wide array of configurations with various combinations of protein functionalities and/or nucleic acid molecule components, all of which are contemplated herein. In general, nucleobase editing systems comprise at least a (i) DNA binding domain that is user-programmable to target a specific sequence in a nucleic acid molecule and optionally (ii) one or more effector domains that facilitate the modification of the sequence of the nucleic acid molecule. User-programmability may comprise amino acid sequence-programmable DNA binding domains (e.g., TALENS and zinc finger-binding domains) or nucleic acid sequence- programmable DNA binding domains (e.g., CRISPR Cas9, CRISPR Cas12a, CRISPR Cas12f, CRISPR Cas13a, CRISPR Cas13b, IscB, IsrB, or TnpB). Similarly, epigenetic editing systems comprise at least a (i) DNA binding domain that targets a specific sequence in a nucleic acid molecule and (ii) one or more effector domains that facilitates the modification of one or more epigenomic features of the nucleic acid molecule. [00518] Gene editing systems may also comprise one or more effector domains that provide various functionalities that facilitate changes in nucleotide sequence and/or gene expression, such as, but not limited to, single-strand DNA binding proteins, nucleases, endonucleases, exonucleases, deaminases (e.g., cytidine deaminases or adenosine deaminases), polymerases (e.g., reverse transcriptases), integrases, recombinases, etc., and fusion proteins comprising one or more functional domains linked together). In certain embodiments, the nucleobase editing systems include, but are not limited to, systems comprising a clustered regularly interspaced short palindromic repeats (“CRISPR”)-associated (“Cas”) protein, a zinc finger nuclease (“ZFN”), a transcription activator-like effector nuclease (“TALEN”), an adenosine deaminase acting on RNA (“ADAR”) enzyme, an adenosine deaminase acting on transfer RNA (“ADAT”) enzyme, an activation induced cytidine deaminase (“AID”)/ apolipoprotein B editing complex (“APOBEC”) enzyme, a meganuclease, IscB, IsrB, TnpB, or a restriction enzyme. [00519] In some embodiments, the nucleobase editing system edits, modifies, or alters the target polynucleotide sequence ex vivo. In some embodiments, the nucleobase editing system edits, modifies, or alters the target polynucleotide sequence in vivo. In some embodiments, the nucleobase editing system edits, modifies, or alters the target polynucleotide sequence in a cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. [00520] In some embodiments, the target polynucleotide sequence is a gene or a regulatory sequence that controls transcription of a gene (e.g., a promoter, transcription binding site, enhancer sequence, etc.) or a sequence which controls the translation of a messenger RNA. In some embodiments, the target transcript comprising a nucleic acid sequence is a product of gene transcription. In some embodiments, the target transcript comprising a nucleic acid sequence is an RNA transcript such as a messenger RNA transcript, microRNA transcript or transfer RNA transcript. [00521] The originator constructs and benchmark constructs of the present disclosure may comprise, encode or be conjugated to a cargo which is a nucleobase editing tool. As used herein, the term “nucleobase editing tool” is used interchangeably with “nucleobase editing system component” and generally refers to a compound or substance which is capable of independently or co-dependently editing, modifying, or altering a target polynucleotide sequence or a target transcript comprising a nucleic acid sequence. Nucleobase editing tools for the present disclosure include all nucleobase editing tools known in the art. In certain embodiments, the nucleobase editing tools include, but not limited to, effector proteins which modify DNA or RNA, guide elements which guide effector proteins to specific DNA or RNA sequence, repair elements which encode a nucleic acid sequence template, and supportive elements which activate or modulate the activity of another nucleobase editing tool, or activates or modulates host DNA repair enzymes. [00522] In some embodiments, the cargo may comprise a nucleobase editing tool or a polynucleotide encoding a nucleobase editing tool. In some embodiments, the cargo may comprise one or more polynucleotides encoding a nucleobase editing tool. In some embodiments, the cargo may comprise a polynucleotide encoding one or more nucleobase editing tools. In some embodiments, the cargo may comprise a polynucleotide that is a component of the nucleobase editing tool. In some embodiments, the cargo may comprise a polynucleotide encoding one or more protein or peptide components in the nucleobase editing tool. [00523] In some embodiments, the cargo may comprise an effector protein capable of modifying a target DNA or RNA sequence. In some embodiments, the cargo may comprise a polynucleotide encoding an effector protein. In certain embodiments, the effector proteins include polymerases, nucleases, mutator enzymes, reverse transcriptases, recombinases, integrases, endonucleases, exonucleases, transposases, and deaminases. As used herein, the term “polymerases,” includes enzymes which catalyze the synthesis of DNA or RNA polymers. As used herein, the term “nucleases,” includes enzymes which cleave nucleobases. In certain embodiments, nucleases include enzymes which create single-stranded breaks (“SSB”) or double-stranded breaks (“DSB”) in nucleic acid sequences. As used herein, the term “mutator enzymes,” in its broadest sense, includes enzymes which mutate nucleic acid sequences. In certain embodiments, the cargo may comprise nucleases such as effector proteins include clustered regularly interspaced short palindromic repeats (“CRISPR”)- associated (“Cas”) proteins, zinc finger nucleases (“ZFNs”), transcription activator-like effector nucleases (“TALENs”), adenosine deaminase acting on RNA (“ADAR”) enzymes, adenosine deaminase acting on transfer RNA (“ADAT”) enzymes, activation induced cytidine deaminase (“AID”)/ apolipoprotein B editing complex (“APOBEC”) enzymes, meganucleases, IscB, IsrB, TnpB, or restriction enzymes. [00524] In some embodiments, the cargo may comprise a guide element which guide effector proteins to target a DNA or RNA sequence. In some embodiments, the cargo may comprise a polynucleotide encoding a guide element. In certain embodiments, guide elements include guide RNAs (“gRNAs”), CRISPR RNAs (“crRNAs”), prime editing guide RNAs (“pegRNAs”), transcription activator-like effectors (TALEs), or antisense oligomers. [00525] In some embodiments, the cargo may further comprise a repair element which encodes a sequence repair template. In some embodiments, the cargo may further comprise a polynucleotide encoding a repair element or sequence repair template. [00526] In some embodiments, the cargo may further comprise a supportive element which activates or modulates the editing system. In some embodiments, the cargo may further comprise a supportive element which activates or modulates the effector protein. In some embodiments, the cargo may further comprise a polynucleotide encoding a supportive element. Non-limiting categories of supportive elements include trans-activating RNA (“tracrRNA”). CRISPR-Cas editors [00527] In some embodiments, the LNPs may be used to deliver a CRISPR-Cas gene editing system comprising a CRISPR-Cas programmable nuclease, such as a CRISPR-Cas9 or CRISPR- Cas12a nuclease. [00528] In general, nucleobase editing systems comprise at least a (i) DNA binding domain that is user-programmable to target a specific sequence in a nucleic acid molecule and optionally (ii) one or more effector domains that facilitate the modification of the sequence of the nucleic acid molecule. User-programmability may comprise amino acid sequence-programmable DNA binding domains (e.g., TALENS and zinc finger-binding domains) or nucleic acid sequence-programmable DNA binding domains (e.g., CRISPR Cas9, CRISPR Cas12a, CRISPR Cas12f, CRISPR Cas13a, CRISPR Cas13b, or TnpB), and including a guide RNA which targets the programmable DNA binding protein to target sequence. [00529] In some embodiments, the CRISPR-Cas system comprises a Cas or Cas-derived protein. [00530] In other embodiments, the sequence-programmable DNA binding domains (e.g., RNA-guided nuclease) used for genome modification is a clustered regularly interspersed short palindromic repeats (CRISPR) system Cas nuclease. Any RNA-guided Cas nuclease capable of catalyzing site- directed cleavage of DNA to allow integration of donor polynucleotides by the HDR mechanism can be used in genome editing, including CRISPR system Class 1, Type I, II, or III Cas nucleases; Class 2, Type II nuclease (such as Cas9); a Class 2, Type V nuclease (such as Cpfl), or a Class 2, Type VI nuclease (such as C2c2). Examples of Cas proteins include Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8al, Cas8a2, Cas8b, Cas8c, Cas9 (Csnl or Csxl2), CaslO, CaslOd, CasF, CasG, CasH, Csyl, Csy2, Csy3, Csel (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, and Cul966, and homologs or modified versions thereof. In some embodiments, an LNP of the present disclosure comprises gene editing system is or comprises a Type V nuclease editing system described in International Application Publication WO2024020346A1, which is incorporated by reference herein in its entirety. [00531] In some embodiments, a Class 1, type II CRISPR system Cas9 endonuclease is used. Cas9 nucleases from any species, or biologically active fragments, variants, analogs, or derivatives thereof that retain Cas9 endonuclease activity (i.e., catalyze site-directed cleavage of DNA to generate double-strand breaks) may be used to perform genome modification as described herein. The Cas9 need not be physically derived from an organism but may be synthetically or recombinantly produced. Cas9 sequences from a number of bacterial species are well known in the art and listed in the National Center for Biotechnology Information (NCBI) database. See, for example, NCBI entries for Cas9 from: Streptococcus pyogenes (WP 002989955, WP_038434062, WP_011528583); Campylobacter jejuni (WP_022552435, YP 002344900), Campylobacter coli (WP 060786116); Campylobacter fetus (WP 059434633); Corynebacterium ulcerans (NC_015683, NC_017317); Corynebacterium diphtheria (NC_016782, NC_016786); Enterococcus faecalis (WP 033919308); Spiroplasma syrphidicola (NC 021284); Prevotella intermedia (NC 017861); Spiroplasma taiwanense (NC 021846); Streptococcus iniae (NC 021314); Belliella baltica (NC 018010); Psychroflexus torquisl (NC O 18721); Streptococcus thermophilus (YP 820832), Streptococcus mutans (WP 061046374, WP 024786433); Listeria innocua (NP 472073); Listeria monocytogenes (WP 061665472); Legionella pneumophila (WP 062726656); Staphylococcus aureus (WP_001573634); Francisella tularensis (WP_032729892, WP_014548420), Enterococcus faecalis (WP 033919308); Lactobacillus rhamnosus (WP 048482595, WP_032965177); and Neisseria meningitidis (WP_061704949, YP_002342100); all of which sequences (as entered by the date of filing of this application) are herein incorporated by reference in their entireties. Any of these sequences or a variant thereof comprising a sequence having at least about 70-100% sequence identity thereto, including any percent identity within this range, such as 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity thereto, can be used for genome editing, as described herein. See also Fonfara et al. (2014) Nucleic Acids Res.42(4):2577-90; Kapitonov et al. (2015) J. Bacterid.198(5): 797-807, Shmakov et al. (2015) Mol. Cell.60(3):385- 397, and Chylinski et al. (2014) Nucleic Acids Res.42(10):6091-6105); for sequence comparisons and a discussion of genetic diversity and phylogenetic analysis of Cas9. [00532] In another embodiment, the gene editing system delivered by the LNP-based RNA medicines described herein may comprise a CRISPR-Cas12a (Cpf1) nuclease. Cpf1 was first identified from Prevotella and Francisella 1 (Cpfl, or Cas12a) and published in Zetsche et al., “Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system,” Cell, October 22, 2015, 163, pp.759-711, which is incorporated herein by reference. Cpfl is another class II CRISPR/Cas system RNA-guided nuclease with similarities to Cas9 and may be used analogously. Unlike Cas9, Cpfl does not require a tracrRNA and only depends on a crRNA in its guide RNA, which provides the advantage that shorter guide RNAs can be used with Cpfl for targeting than Cas9. Cpfl is capable of cleaving either DNA or RNA. The PAM sites recognized by Cpfl have the sequences 5ʹ-YTN-3ʹ (where “Y” is a pyrimidine and “N” is any nucleobase) or 5ʹ-TTN-3ʹ, in contrast to the G-rich PAM site recognized by Cas9. Cpfl cleavage of DNA produces double-stranded breaks with a sticky-ends having a 4 or 5 nucleotide overhang. For a discussion of Cpfl, see, e.g., Ledford et al. (2015) Nature. 526 (7571):17-17, Zetsche et al. (2015) Cell.163 (3):759-771, Murovec et al. (2017) Plant Biotechnol. J.15(8):917-926, Zhang et al. (2017) Front. Plant Sci.8:177, Fernandes et al. (2016) Postepy Biochem.62(3):315-326; herein incorporated by reference. [00533] The gene editing systems described herein can include any known Cas12a nuclease, or any variant thereof, such as any Cas12a ortholog described in US Patent Application No. 18/297,346, US Patent Application No.18/481,393, or Intern International Application Publication WO2024020346A1, or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the Cas12a orthologs described in said patent applications. [00534] The gene editing systems described herein can include any known Cas12a nuclease, or any variant thereof, such as any Cas12a ortholog described in (1) Wu J, Gao P, Shi Y, Zhang C, Tong X, Fan H, Zhou X, Zhang Y, Yin H. Characterization of a thermostable Cas12a ortholog. Cell Insight.2023 Oct 11;2(6):100126. doi: 10.1016/j.cellin.2023.100126. PMID: 38047138; PMCID: PMC10692460; (2) Swarts DC, Jinek M. Cas9 versus Cas12a/Cpf1: Structure-function comparisons and implications for genome editing. Wiley Interdiscip Rev RNA.2018 Sep;9(5):e1481. doi: 10.1002/wrna.1481. Epub 2018 May 22. PMID: 29790280; (3) Kleinstiver BP, Sousa AA, Walton RT, Tak YE, Hsu JY, Clement K, Welch MM, Horng JE, Malagon-Lopez J, Scarfò I, Maus MV, Pinello L, Aryee MJ, Joung JK. Engineered CRISPR-Cas12a variants with increased activities and improved targeting ranges for gene, epigenetic and base editing. Nat Biotechnol.2019 Mar;37(3):276- 282. doi: 10.1038/s41587-018-0011-0. Epub 2019 Feb 11. Erratum in: Nat Biotechnol.2020 Jul;38(7):901. PMID: 30742127; PMCID: PMC6401248; (4) Ma E, Chen K, Shi H, Stahl EC, Adler B, Trinidad M, Liu J, Zhou K, Ye J, Doudna JA. Improved genome editing by an engineered CRISPR-Cas12a. Nucleic Acids Res.2022 Dec 9;50(22):12689-12701. doi: 10.1093/nar/gkac1192. PMID: 36537251; PMCID: PMC9825149; (5) Li T, Zhu L, Xiao B, Gong Z, Liao Q, Guo J. CRISPR- Cpf1-mediated genome editing and gene regulation in human cells. Biotechnol Adv.2019 Jan- Feb;37(1):21-27. doi: 10.1016/j.biotechadv.2018.10.013. Epub 2018 Nov 3. PMID: 30399413 (6); Jacobsen T, Liao C, Beisel CL. The Acidaminococcus sp. Cas12a nuclease recognizes GTTV and GCTV as non-canonical PAMs. FEMS Microbiol Lett.2019 Apr 1;366(8):fnz085. doi: 10.1093/femsle/fnz085. PMID: 31004485; PMCID: PMC6604746; (7) Huang H, Huang G, Tan Z, Hu Y, Shan L, Zhou J, Zhang X, Ma S, Lv W, Huang T, Liu Y, Wang D, Zhao X, Lin Y, Rong Z. Engineered Cas12a-Plus nuclease enables gene editing with enhanced activity and specificity. BMC Biol.2022 Apr 25;20(1):91. doi: 10.1186/s12915-022-01296-1. PMID: 35468792; PMCID: PMC9040236; (8) Zhu D, Wang J, Yang D, Xi J, Li J. High-Throughput Profiling of Cas12a Orthologues and Engineered Variants for Enhanced Genome Editing Activity. Int J Mol Sci.2021 Dec 10;22(24):13301. doi: 10.3390/ijms222413301. PMID: 34948095; PMCID: PMC8706968; (9) Gao L, Cox DBT, Yan WX, Manteiga JC, Schneider MW, Yamano T, Nishimasu H, Nureki O, Crosetto N, Zhang F. Engineered Cpf1 variants with altered PAM specificities. Nat Biotechnol.2017 Aug;35(8):789-792. doi: 10.1038/nbt.3900. Epub 2017 Jun 5. PMID: 28581492; PMCID: PMC5548640; (10) Zhang L, Zuris JA, Viswanathan R, Edelstein JN, Turk R, Thommandru B, Rube HT, Glenn SE, Collingwood MA, Bode NM, Beaudoin SF, Lele S, Scott SN, Wasko KM, Sexton S, Borges CM, Schubert MS, Kurgan GL, McNeill MS, Fernandez CA, Myer VE, Morgan RA, Behlke MA, Vakulskas CA. AsCas12a ultra nuclease facilitates the rapid generation of therapeutic cell medicines. Nat Commun.2021 Jun 23;12(1):3908. doi: 10.1038/s41467-021-24017-8. Erratum in: Nat Commun.2021 Jul 19;12(1):4500. PMID: 34162850; PMCID: PMC8222333; (11) Ling X, Chang L, Chen H, Gao X, Yin J, Zuo Y, Huang Y, Zhang B, Hu J, Liu T. Improving the efficiency of CRISPR-Cas12a-based genome editing with site-specific covalent Cas12a-crRNA conjugates. Mol Cell.2021 Nov 18;81(22):4747-4756.e7. doi: 10.1016/j.molcel.2021.09.021. Epub 2021 Oct 13. PMID: 34648747; and (12) Zhou J, Chen P, Wang H, Liu H, Li Y, Zhang Y, Wu Y, Paek C, Sun Z, Lei J, Yin L. Cas12a variants designed for lower genome-wide off-target effect through stringent PAM recognition. Mol Ther.2022 Jan 5;30(1):244-255. doi: 10.1016/j.ymthe.2021.10.010. Epub 2021 Oct 20. PMID: 34687846; PMCID: PMC8753454; each of which are incorporated by reference in their entireties. [00535] Any publicly known Cas12a/Cpf1 may be used as a component of the gene editing systems described herein, including but not limited to, the following publicly available amino acid sequences: GenBank Accession No. QOE76068.1; GenBank Accession No. WKU83685.1; GenBank Accession No. WBC51234.1; GenBank Accession No. QOL02411.1; GenBank Accession No. UVJ64960.1; GenBank Accession No. UVJ64958.1; GenBank Accession No. UVJ64957.1; GenBank Accession No. UVJ64956.1; GenBank Accession No. UVJ64954.1; GenBank Accession No. UVJ64953.1; GenBank Accession No. UVJ64952.1; GenBank Accession No. UVJ64951.1; GenBank Accession No. UVJ64949.1; GenBank Accession No. UVJ64947.1; GenBank Accession No. UVJ64946.1; GenBank Accession No. UVJ64945.1; GenBank Accession No. WP_320869194.1; GenBank Accession No. WOZ85592.1; GenBank Accession No. WOF96262.1; and any amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the aforementioned sequence, or any other publicly available Cas12a sequence. [00536] C2c1 (Cas12b) is another class II CRISPR/Cas system RNA-guided nuclease that may be used. C2cl, similarly to Cas9, depends on both a crRNA and tracrRNA for guidance to target sites. See, e.g., Shmakov et al. (2015) Mol Cell.60(3):385-397, Zhang et al. (2017) Front Plant Sci. 8:177; herein incorporated by reference. [00537] In one aspect, a nucleic acid sequence-programmable DNA binding domain can be associated with or complexed with at least one guide nucleic acid (e.g., guide RNA or a pegRNA), which localizes the DNA binding domain to a DNA sequence that comprises a DNA strand (i.e., a target strand) that is complementary to the guide nucleic acid, or a portion thereof (e.g., the spacer of a guide RNA which anneals to the protospacer of the DNA target). In other words, the guide nucleic- acid “programs” the DNA binding domain (e.g., Cas9 or equivalent) to localize and bind to complementary sequence of the protospacer in the DNA. [00538] Any suitable nucleic acid sequence-programmable DNA binding domain may be used in the prime editors described herein. In various embodiments, the nucleic acid sequence- programmable DNA binding domain may be any Class 2 CRISPR-Cas system, including any type II, type V, or type VI CRISPR-Cas enzyme. Given the rapid development of CRISPR-Cas as a tool for genome editing, there have been constant developments in the nomenclature used to describe and/or identify CRISPR-Cas enzymes, such as Cas9 and Cas9 orthologs. CRISPR-Cas nomenclature is extensively discussed in Makarova et al., “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?,” The CRISPR Journal, Vol.1. No.5, 2018, the entire contents of which are incorporated herein by reference. [00539] Without being bound by theory, the mechanism of action of certain CRISPR Cas enzymes contemplated herein includes the step of forming an R-loop whereby the Cas protein induces the unwinding of a double-strand DNA target, thereby separating the strands in the region bound by the Cas protein. The guide RNA spacer then hybridizes to the “target strand” at a region that is complementary to the protospacer sequence of the DNA. In some embodiments, the Cas protein may include one or more nuclease activities, which then cut the DNA leaving various types of lesions. For example, the Cas protein may comprises a nuclease activity that cuts the non-target strand at a first location, and/ or cuts the target strand at a second location. Depending on the nuclease activity, the target DNA can be cut to form a “double-stranded break” whereby both strands are cut. In other embodiments, the target DNA can be cut at only a single site, i.e., the DNA is “nicked” on one strand. Exemplary Cas proteins with different nuclease activities include “Cas9 nickase” (“nCas9”) and a deactivated Cas9 having no nuclease activities (“dead Cas9” or “dCas9”). [00540] The below description of various Cas proteins which can be used in connection with the presently disclosed LNP-delivered gene editing systems is not meant to be limiting in any way. The gene editing systems may comprise the canonical SpCas9 or Cas12a, or any ortholog Cas9 protein or Cas12a protein, or any variant Cas9 or Cas12a protein—including any naturally occurring variant, mutant, or otherwise engineered version of Cas9—that is known or which can be made or evolved through a directed evolutionary or otherwise mutagenic process. In various embodiments, the Cas9 or Cas9 variants have a nickase activity, i.e., only cleave one strand of the target DNA sequence. In other embodiments, the Cas9 or Cas9 variants have inactive nucleases, i.e., are “dead” Cas9 proteins. Other variant Cas9 proteins that may be used are those having a smaller molecular weight than the canonical SpCas9 (e.g., for easier delivery) or having modified or rearranged primary amino acid structure. [00541] The gene editing systems described herein may also comprise Cas9 equivalents, including Cas12a (Cpf1) and Cas12b1 proteins. The Cas proteins usable herein (e.g., SpCas9, Cas9 variant, or Cas9 equivalents) may also contain various modifications that alter/enhance their PAM specificities. The present disclosure contemplates any Cas9, Cas9 variant, or Cas9 equivalent which has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% sequence identity to a reference Cas9 sequence, such as a reference SpCas9 canonical sequence of Streptococcus pyogenes M1 (Accession No. Q99ZW2). [00542] The Cas proteins contemplated herein embrace CRISPR Cas 9 proteins, as well as Cas9 equivalents, variants (e.g., Cas9 nickase (nCas9) or nuclease inactive Cas9 (dCas9)) homologs, orthologs, or paralogs, whether naturally occurring or non-naturally occurring (e.g., engineered or recombinant), and may include a Cas9 equivalent from any Class 2 CRISPR system (e.g., type II, V, VI), including Cas12a (Cpf1), Cas12e (CasX), Cas12b1 (C2c1), Cas12b2, Cas12c (C2c3), C2c4, C2c8, C2c5, C2c10, C2c9 Cas13a (C2c2), Cas13d, Cas13c (C2c7), Cas13b (C2c6), and Cas13b. Further Cas-equivalents are described in Makarova et al., “C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector,” Science 2016; 353(6299) and Makarova et al., “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?,” The CRISPR Journal, Vol.1. No.5, 2018, the contents of which are incorporated herein by reference. [00543] The terms “Cas9” or “Cas9 nuclease” or “Cas9 moiety” or “Cas9 domain” embrace any naturally occurring Cas9 from any organism, any naturally-occurring Cas9 equivalent or functional fragment thereof, any Cas9 homolog, ortholog, or paralog from any organism, and any mutant or variant of a Cas9, naturally-occurring or engineered. The term Cas9 is not meant to be particularly limiting and may be referred to as a “Cas9 or equivalent.” Exemplary Cas9 proteins are further described in the art and are incorporated herein by reference. As noted herein, Cas9 nuclease sequences and structures are well known to those of skill in the art (see, e.g., “Complete genome sequence of an M1 strain of Streptococcus pyogenes.” Ferretti et al., J.J., McShan W.M., Ajdic D.J., Savic D.J., Savic G., Lyon K., Primeaux C., Sezate S., Suvorov A.N., Kenton S., Lai H.S., Lin S.P., Qian Y., Jia H.G., Najar F.Z., Ren Q., Zhu H., Song L., White J., Yuan X., Clifton S.W., Roe B.A., McLaughlin R.E., Proc. Natl. Acad. Sci. U.S.A.98:4658-4663(2001); “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.” Deltcheva E., Chylinski K., Sharma C.M., Gonzales K., Chao Y., Pirzada Z.A., Eckert M.R., Vogel J., Charpentier E., Nature 471:602- 607(2011); and “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E.Science 337:816-821(2012), the entire contents of each of which are incorporated herein by reference). [00544] In certain embodiments, a polynucleotide programmable nucleotide binding domain of a nucleobase editor itself comprises one or more domains. In one embodiment, a polynucleotide programmable nucleotide binding domain comprises one or more nuclease domains. In some embodiments, the nuclease domain of a polynucleotide programmable nucleotide binding domain comprises an endonuclease or an exonuclease. In some embodiments, the endonuclease cleaves a single strand of a double-stranded nucleobase. In some embodiments, the endonuclease cleaves both strands of a double-stranded nucleobase molecule. In some embodiments, the polynucleotide programmable nucleotide binding domain is a deoxyribonuclease. In some embodiments, the polynucleotide programmable nucleotide binding domain is a ribonuclease. [00545] In some embodiments, the nuclease domain of a polynucleotide programmable nucleotide binding domain can cut zero, one, or two strands of a target polynucleotide. In some embodiments, the polynucleotide programmable nucleotide binding domain comprises a nickase domain. Herein the term “nickase” refers to a polynucleotide programmable nucleotide binding domain comprising a nuclease domain that is capable of cleaving only one strand of the two strands in a duplexed nucleobase molecule (e.g., DNA). In some embodiments, the nickase is derived from a fully catalytically active (e.g., natural) form of a polynucleotide programmable nucleotide binding domain by introducing one or more mutations into the active polynucleotide programmable nucleotide binding domain. In certain embodiments, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9. Cas12a and Cas9 nickases are known in the art and contemplated for use herein, for example as discussed in (1) Schubert MS, Thommandru B, Woodley J, Turk R, Yan S, Kurgan G, McNeill MS, Rettig GR. Optimized design parameters for CRISPR Cas9 and Cas12a homology-directed repair. Sci Rep.2021 Sep 30;11(1):19482. doi: 10.1038/s41598-021-98965-y. PMID: 34593942; PMCID: PMC8484621; (2) Fu BXH, Smith JD, Fuchs RT, Mabuchi M, Curcuru J, Robb GB, Fire AZ. Target-dependent nickase activities of the CRISPR-Cas nucleases Cpf1 and Cas9. Nat Microbiol.2019 May;4(5):888-897. doi: 10.1038/s41564- 019-0382-0. Epub 2019 Mar 4. PMID: 30833733; PMCID: PMC6512873; (3) Xu T, Tao X, Kempher ML, Zhou J. Cas9 Nickase-Based Genome Editing in Clostridium cellulolyticum. Methods Mol Biol. 2022;2479:227-243. doi: 10.1007/978-1-0716-2233-9_15. PMID: 35583742; (4) Wu WH, Ma XM, Huang JQ, Lai Q, Jiang FN, Zou CY, Chen LT, Yu L. CRISPR/Cas9 (D10A) nickase-mediated Hb CS gene editing and genetically modified fibroblast identification. Bioengineered.2022 May;13(5):13398-13406. doi: 10.1080/21655979.2022.2069940. PMID: 36700476; PMCID: PMC9276056; each of which are incorporated herein by reference in their entireties. [00546] In some embodiments, the Cas9-derived nickase has one or more mutations in the RuvC-1 domain. In one embodiment, the Cas9-derived nickase has a D10A mutation in the RuvC-1 domain. In some embodiments, the Cas9-derived nickase has one or more mutations in the REC Lobe domain. In one embodiment, the Cas9-derived nickase has a N497A, R661A, and/or Q695A mutation in the REC Lobe domain. In some embodiment, the Cas9-derived nickase has one or more mutations in the HNH domain. In one embodiment, the Cas9-derived nickase has H840A, N863A, and/or D839A in the HNH domain. [00547] In certain embodiments, in the SpCas9-derived nickase, the residue H840 retains catalytic activity and can thereby cleave a single strand of the nucleobase duplex. In certain embodiments, a Cas9-derived nickase domain can comprise an H840A mutation, while the amino acid residue at position 10 remains a D. In certain embodiments, a Cas9-derived nickase domain can comprise an N863A mutation, while the amino acid residue at position 10 remains a D. In some embodiments, the nickase is derived from a fully catalytically active (e.g., natural) form of a polynucleotide programmable nucleotide binding domain by removing all or a portion of a nuclease domain that is not required for the nickase activity. In certain embodiments, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9- derived nickase domain comprises a deletion of all or a portion of the RuvC domain or the HNH domain. [00548] Any of the above CRISPR-Cas editor embodiments or any variants, modifications, or derivatives thereof are contemplated herein to be delivered by the LNP systems disclosed in this specification for gene editing in cells, tissues, and/or organs under in vitro, ex vivo, or in vivo conditions. The various components described herein may be configured and delivered in any suitable manner. Any of the descriptions presented in this section are not intended to be strictly limiting. Base editors [00549] In other embodiments, the LNPs may be used to deliver a base editing system. Base editors are generally composed of an engineered deaminase and a catalytically impaired CRISPR– Cas9 variant and enzymatically convert one base to another base at a specific target site with the assistance of endogenous DNA repair systems in the cell. However, base editors may also comprise Cas12a enzymes and/or other programmable nucleases. For example, Cas12a-configured base editors are described in (1) Chen F, Lian M, Ma B, Gou S, Luo X, Yang K, Shi H, Xie J, Ge W, Ouyang Z, Lai C, Li N, Zhang Q, Jin Q, Liang Y, Chen T, Wang J, Zhao X, Li L, Yu M, Ye Y, Wang K, Wu H, Lai L. Multiplexed base editing through Cas12a variant-mediated cytosine and adenine base editors. Commun Biol.2022 Nov 2;5(1):1163. doi: 10.1038/s42003-022-04152-8. PMID: 36323848; PMCID: PMC9630288; (2) Wang X, Ding C, Yu W, Wang Y, He S, Yang B, Xiong YC, Wei J, Li J, Liang J, Lu Z, Zhu W, Wu J, Zhou Z, Huang X, Liu Z, Yang L, Chen J. Cas12a Base Editors Induce Efficient and Specific Editing with Low DNA Damage Response. Cell Rep.2020 Jun 2;31(9):107723. doi: 10.1016/j.celrep.2020.107723. PMID: 32492431; and (3) Swartjes T, Staals RHJ, van der Oost J. Editor's cut: DNA cleavage by CRISPR RNA-guided nucleases Cas9 and Cas12a. Biochem Soc Trans.2020 Feb 28;48(1):207-219. doi: 10.1042/BST20190563. PMID: 31872209; PMCID: PMC7054755; (4) Gaillochet C, Peña Fernández A, Goossens V, D'Halluin K, Drozdzecki A, Shafie M, Van Duyse J, Van Isterdael G, Gonzalez C, Vermeersch M, De Saeger J, Develtere W, Audenaert D, De Vleesschauwer D, Meulewaeter F, Jacobs TB. Systematic optimization of Cas12a base editors in wheat and maize using the ITER platform. Genome Biol.2023 Jan 13;24(1):6. doi: 10.1186/s13059-022-02836-2. PMID: 36639800; PMCID: PMC9838060; each of which are incorporated herein by reference in their entireties. [00550] Base editing was first described in Komor et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage,” Nature, May 19, 2016, 533 (7603); pp.420-424 in the form of cytosine base editors or CBEs followed by the disclosure of Gaudelli et al., “Programmable base editing of A-T to G-C in genomic DNA without DNA cleavage,” Nature, Vol. 551, pp.464-471 describing adenine base editors or ABEs. Subsequently, base editing has been described in numerous scientific publications, including, but not limited to (i) Kim JS. Precision genome engineering through adenine and cytosine base editing. Nat Plants.2018 Mar;4(3):148-151. doi: 10.1038/s41477-018-0115-z. Epub 2018 Feb 26. PMID: 29483683.; (ii) Wei Y, Zhang XH, Li DL. The "new favorite" of gene editing technology-single base editors. Yi Chuan.2017 Dec 20;39(12):1115-1121. doi: 10.16288/j.yczz.17-389. PMID: 29258982; (iii) Tang J, Lee T, Sun T. Single-nucleotide editing: From principle, optimization to application. Hum Mutat.2019 Dec;40(12):2171-2183. doi: 10.1002/humu.23819. Epub 2019 Sep 15. PMID: 31131955; PMCID: PMC6874907; (iv) Grünewald J, Zhou R, Lareau CA, Garcia SP, Iyer S, Miller BR, Langner LM, Hsu JY, Aryee MJ, Joung JK. A dual-deaminase CRISPR base editor enables concurrent adenine and cytosine editing. Nat Biotechnol.2020 Jul;38(7):861-864. doi: 10.1038/s41587-020-0535-y. Epub 2020 Jun 1. PMID: 32483364; PMCID: PMC7723518; (v) Sakata RC, Ishiguro S, Mori H, Tanaka M, Tatsuno K, Ueda H, Yamamoto S, Seki M, Masuyama N, Nishida K, Nishimasu H, Arakawa K, Kondo A, Nureki O, Tomita M, Aburatani H, Yachie N. Base editors for simultaneous introduction of C-to-T and A-to-G mutations. Nat Biotechnol.2020 Jul;38(7):865-869. doi: 10.1038/s41587-020- 0509-0. Epub 2020 Jun 2. Erratum in: Nat Biotechnol.2020 Jun 5;: PMID: 32483365; (vi) Fan J, Ding Y, Ren C, Song Z, Yuan J, Chen Q, Du C, Li C, Wang X, Shu W. Cytosine and adenine deaminase base-editors induce broad and nonspecific changes in gene expression and splicing. Commun Biol.2021 Jul 16;4(1):882. doi: 10.1038/s42003-021-02406-5. PMID: 34272468; PMCID: PMC8285404; (vii) Zhang S, Yuan B, Cao J, Song L, Chen J, Qiu J, Qiu Z, Zhao XM, Chen J, Cheng TL. TadA orthologs enable both cytosine and adenine editing of base editors. Nat Commun.2023 Jan 26;14(1):414. doi: 10.1038/s41467-023-36003-3. PMID: 36702837; PMCID: PMC988000; and (viii) Zhang S, Song L, Yuan B, Zhang C, Cao J, Chen J, Qiu J, Tai Y, Chen J, Qiu Z, Zhao XM, Cheng TL. TadA reprogramming to generate potent miniature base editors with high precision. Nat Commun.2023 Jan 26;14(1):413. doi: 10.1038/s41467-023-36004-2. PMID: 36702845; PMCID: PMC987999, each of which are incorporated herein by reference in their entireties. [00551] Amino acid and nucleotide sequences of base editors, including adenosine base editors, cytidine base editors, and others are readily available in the art. For example, exemplary base editors that may be delivered using the LNP compositions described herein can be found in the following published patent applications, each of their contents (including any and all biological sequences) are incorporated herein by reference: US 2023/0021641 A1 CAS9 VARIANTS HAVING NON-CANONICAL PAM SPECIFICITIES AND USES THEREOF US 11542496 B2 Cytosine to guanine base editor US 11542509 B2 Incorporation of unnatural amino acids into proteins using base editing US 2022/0315906 A1 BASE EDITORS WITH DIVERSIFIED TARGETING SCOPE US 2022/0282275 A1 G-TO-T BASE EDITORS AND USES THEREOF US 2022/0249697 A1 AAV DELIVERY OF NUCLEOBASE EDITORS [00552] In some embodiments, the LNP cargo comprises a base editing system or a polynucleotide encoding a CRISPR-Cas base editing system. In some embodiments, the cargo comprises a component of a base editing system or a polynucleotide encoding a component of a base editing system. [00553] Base editing does not require double-stranded DNA breaks or a DNA donor template. In some embodiments, base editing comprises creating an SSB in a target double-stranded DNA sequence and then converting a nucleobase. In some embodiments, the nucleobase conversion is an adenosine to a guanine. In some embodiments, the nucleobase conversion is a thymine to a cytosine. In some embodiments, the nucleobase conversion is a cytosine to a thymine. In some embodiments, the nucleobase conversion is a guanine to an adenosine. In some embodiments, the nucleobase conversion is an adenosine to inosine. In some embodiments, the nucleobase conversion is a cytosine to uracil. [00554] A base editing system comprises a base editor which can convert a nucleobase. The base editor (“BE”) comprises a partially inactive Cas protein which is connected to a deaminase that precisely and permanently edits a target nucleobase in a polynucleotide sequence. A base editor comprises a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain (e.g., adenosine deaminase or cytosine deaminase). In some embodiments, the partially inactive Cas protein is a Cas nickase. In some embodiments, the partially inactive Cas protein is a Cas9 nickase (also referred to as “nCas9”). [00555] A polynucleotide programmable nucleotide binding domain, when in conjunction with a bound guide polynucleotide (e.g., gRNA), can specifically bind to a target polynucleotide sequence (i.e., via complementary base pairing between bases of the bound guide nucleobase and bases of the target polynucleotide sequence) and thereby localize the nucleobase editor to the target polynucleotide sequence desired to be edited. In some embodiments, the target polynucleotide sequence comprises single-stranded DNA or double-stranded DNA. In some embodiments, the target polynucleotide sequence comprises RNA. In some embodiments, the target polynucleotide sequence comprises a DNA-RNA hybrid. [00556] In certain embodiments, polynucleotide programmable nucleotide binding domains also include nucleobase programmable proteins that bind RNA. In certain embodiments, the polynucleotide programmable nucleotide binding domain can be associated with a nucleobase that guides the polynucleotide programmable nucleotide binding domain to an RNA. [00557] In some embodiments, the LNP-deliverable base editors may comprise a deaminase domain that is a cytidine deaminase domain. A cytidine deaminase domain may also be referred to interchangeably as a cytosine deaminase domain. In some embodiments, the cytidine deaminase catalyzes the hydrolytic deamination of cytidine (C) or deoxycytidine (dC) to uridine (U) or deoxyuridine (dU), respectively. In some embodiments, the cytidine deaminase domain catalyzes the hydrolytic deamination of cytosine (C) to uracil (U). In some embodiments, the cytidine deaminase catalyzes the hydrolytic deamination of cytidine or cytosine in deoxyribonucleic acid (DNA). Without wishing to be bound by any particular theory, fusion proteins comprising a cytidine deaminase are useful inter alia for targeted editing, referred to herein as “base editing,” of nucleic acid sequences in vitro and in vivo. [00558] One exemplary suitable type of cytidine deaminase is a cytidine deaminase, for example, of the APOBEC family. The apolipoprotein B mRNA-editing complex (APOBEC) family of cytidine deaminase enzymes encompasses eleven proteins that serve to initiate mutagenesis in a controlled and beneficial manner (see, e.g., Conticello S G. The AID/APOBEC family of nucleic acid mutators. Genome Biol.2008; 9(6):229). One family member, activation-induced cytidine deaminase (AID), is responsible for the maturation of antibodies by converting cytosines in ssDNA to uracils in a transcription-dependent, strand-biased fashion (see, e.g., Reynaud C A, et al. What role for AID: mutator, or assembler of the immunoglobulin mutasome, Nat Immunol.2003; 4(7):631-638). The apolipoprotein B editing complex 3 (APOBEC3) enzyme provides protection to human cells against a certain HIV-1 strain via the deamination of cytosines in reverse-transcribed viral ssDNA (see, e.g., Bhagwat A S. DNA-cytosine deaminases: from antibody maturation to antiviral defense. DNA Repair (Amst).2004; 3(1):85-89). [00559] Some aspects of this disclosure relate to the recognition that the activity of cytidine deaminase enzymes such as APOBEC enzymes can be directed to a specific site in genomic DNA. Without wishing to be bound by any particular theory, advantages of using a nucleic acid programmable binding protein (e.g., a Cas9 domain) as a recognition agent include (1) the sequence specificity of nucleic acid programmable binding protein (e.g., a Cas9 domain) can be easily altered by simply changing the sgRNA sequence; and (2) the nucleic acid programmable binding protein (e.g., a Cas9 domain) may bind to its target sequence by denaturing the dsDNA, resulting in a stretch of DNA that is single-stranded and therefore a viable substrate for the deaminase. It should be understood that other catalytic domains of napDNAbps, or catalytic domains from other nucleic acid editing proteins, can also be used to generate fusion proteins with Cas9, and that the disclosure is not limited in this regard. [00560] In some embodiments, the cytidine deaminase is an apolipoprotein B mRNA-editing complex (APOBEC) family deaminase. In some embodiments, the cytidine deaminase is an APOBEC1 deaminase. In some embodiments, the cytidine deaminase is an APOBEC2 deaminase. In some embodiments, the cytidine deaminase is an APOBEC3 deaminase. In some embodiments, the cytidine deaminase is an APOBEC3A deaminase. In some embodiments, the cytidine deaminase is an APOBEC3B deaminase. In some embodiments, the cytidine deaminase is an APOBEC3C deaminase. In some embodiments, the cytidine deaminase is an APOBEC3D deaminase. In some embodiments, the cytidine deaminase is an APOBEC3E deaminase. In some embodiments, the cytidine deaminase is an APOBEC3F deaminase. In some embodiments, the cytidine deaminase is an APOBEC3G deaminase. In some embodiments, the cytidine deaminase is an APOBEC3H deaminase. In some embodiments, the cytidine deaminase is an APOBEC4 deaminase. In some embodiments, the cytidine deaminase is an activation-induced deaminase (AID). In some embodiments, the cytidine deaminase is a vertebrate cytidine deaminase. In some embodiments, the cytidine deaminase is an invertebrate cytidine deaminase. In some embodiments, the cytidine deaminase is a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse deaminase. In some embodiments, the cytidine deaminase is a human cytidine deaminase. In some embodiments, the cytidine deaminase is a rat cytidine deaminase, e.g., rAPOBEC1. [00561] In some embodiments, the nucleic acid editing domain is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any of the cytidine deaminase domain examples above. [00562] In other embodiments, the LNP-deliverable base editors may comprise a deaminase domain that is an adenosine deaminase domain. [00563] The disclosure provides fusion proteins that comprise one or more adenosine deaminases. In some aspects, such fusion proteins are capable of deaminating adenosine in a nucleic acid sequence (e.g., DNA or RNA). As one example, any of the fusion proteins provided herein may be base editors, (e.g., adenine base editors). Without wishing to be bound by any particular theory, dimerization of adenosine deaminases (e.g., in cis or in trans) may improve the ability (e.g., efficiency) of the fusion protein to modify a nucleic acid base, for example to deaminate adenine. In some embodiments, any of the fusion proteins may comprise 2, 3, 4 or 5 adenosine deaminases. In some embodiments, any of the fusion proteins provided herein comprise two adenosine deaminases. Exemplary, non-limiting, embodiments of adenosine deaminases are provided herein. It should be appreciated that the mutations provided herein (e.g., mutations in ecTadA) may be applied to adenosine deaminases in other adenosine base editors, for example those provided in U.S. Patent Publication No.2018/0073012, published Mar.15, 2018, which issued as U.S. Pat. No.10,113,163, on Oct.30, 2018; U.S. Patent Publication No.2017/0121693, published May 4, 2017, which issued as U.S. Pat. No.10,167,457 on Jan.1, 2019; International Publication No. WO 2017/070633, published Apr.27, 2017; U.S. Patent Publication No.2015/0166980, published Jun.18, 2015; U.S. Pat. No. 9,840,699, issued Dec.12, 2017; and U.S. Pat. No.10,077,453, issued Sep.18, 2018, all of which are incorporated herein by reference in their entireties. [00564] In some embodiments, any of the adenosine deaminases provided herein is capable of deaminating adenine. In some embodiments, the adenosine deaminases provided herein are capable of deaminating adenine in a deoxyadenosine residue of DNA. The adenosine deaminase may be derived from any suitable organism (e.g., E. coli). In some embodiments, the adenosine deaminase is a naturally-occurring adenosine deaminase that includes one or more mutations corresponding to any of the mutations provided herein (e.g., mutations in ecTadA). One of skill in the art will be able to identify the corresponding residue in any homologous protein and in the respective encoding nucleic acid by methods well known in the art, e.g., by sequence alignment and determination of homologous residues. Accordingly, one of skill in the art would be able to generate mutations in any naturally- occurring adenosine deaminase (e.g., having homology to ecTadA) that corresponds to any of the mutations described herein, e.g., any of the mutations identified in ecTadA. In some embodiments, the adenosine deaminase is from a prokaryote. In some embodiments, the adenosine deaminase is from a bacterium. In some embodiments, the adenosine deaminase is from Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shewanella putrefaciens, Haemophilus influenzae, Caulobacter crescentus, or Bacillus subtilis. In some embodiments, the adenosine deaminase is from E. coli. [00565] Any two or more of the adenosine deaminases described herein may be connected to one another (e.g. by a linker) within an adenosine deaminase domain of the fusion proteins provided herein. For instance, the fusion proteins provided herein may contain only two adenosine deaminases. In some embodiments, the adenosine deaminases are the same. In some embodiments, the adenosine deaminases are any of the adenosine deaminases provided herein. In some embodiments, the adenosine deaminases are different. In some embodiments, the first adenosine deaminase is any of the adenosine deaminases provided herein, and the second adenosine is any of the adenosine deaminases provided herein, but is not identical to the first adenosine deaminase. In some embodiments, the fusion protein comprises two adenosine deaminases (e.g., a first adenosine deaminase and a second adenosine deaminase). In some embodiments, the fusion protein comprises a first adenosine deaminase and a second adenosine deaminase. In some embodiments, the first adenosine deaminase is N-terminal to the second adenosine deaminase in the fusion protein. In some embodiments, the first adenosine deaminase is C-terminal to the second adenosine deaminase in the fusion protein. In some embodiments, the first adenosine deaminase and the second deaminase are fused directly or via a linker. [00566] In some embodiments, the base editor comprises a deaminase enzyme. In some embodiments, the base editor comprises a cytidine deaminase. In some embodiments, the base editor comprises a Cas9 protein fused to a cytidine deaminase enzyme. In some embodiments, the base editor comprises an adenosine deaminase. In some embodiments, the base editor comprises a Cas9 protein fused to an adenosine deaminase enzyme. [00567] In some embodiments, the base editing system comprises an uracil glycosylase inhibitor. In some embodiments, the base editing system comprises a Cas9 protein fused to an uracil glycosylase inhibitor. In some embodiments, the cargo comprises an uracil glycosylase inhibitor or a polynucleotide encoding an uracil glycosylase inhibitor. In some embodiments, the cargo comprises a Cas9 protein fused to an uracil glycosylase inhibitor or a polynucleotide encoding a Cas9 protein fused to an uracil glycosylase inhibitor. [00568] A variety of nucleobase modifying enzymes are suitable for use in the nucleobase systems disclosed herein. In some embodiments, the nucleobase modifying enzyme is a RNA base editor. In some embodiments, the RNA base editor can be a cytidine deaminase, which converts cytidine into uridine. Non-limiting examples of cytidine deaminases include cytidine deaminase 1 (CDA1), cytidine deaminase 2 (CDA2), activation-induced cytidine deaminase (AICDA), apolipoprotein B mRNA-editing complex (APOBEC) family cytidine deaminase (e.g., APOBEC1, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D/E, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4), APOBEC1 complementation factor/APOBEC1 stimulating factor (ACF1/ASF) cytidine deaminase, cytosine deaminase acting on RNA (CDAR), bacterial long isoform cytidine deaminase (CDDL), and cytosine deaminase acting on tRNA (CDAT). In other embodiments, the RNA base editor can be an adenosine deaminase, which converts adenosine into inosine, which is read by polymerase enzymes as guanosine. In certain embodiments, adenosine deaminases include tRNA adenine deaminase, adenosine deaminase, adenosine deaminase acting on RNA (ADAR), and adenosine deaminase acting on tRNA (ADAT). [00569] In some embodiments, in the nucleobase editing systems disclosed herein, the Cas effector may associate with one or more functional domains (e.g., via fusion protein or suitable linkers). In some embodiments, the effector domain comprises one or more cytidine or nucleotide deaminases that mediate editing of via hydrolytic deamination. In certain embodiments, the effector domain comprises the adenosine deaminase acting on RNA (ADAR) family of enzymes. In certain embodiments, the adenosine deaminase protein or catalytic domain thereof capable of deaminating adenosine or cytidine in RNA or is an RNA specific adenosine deaminase and/or is a bacterial, human, cephalopod, or Drosophila adenosine deaminase protein or catalytic domain thereof, preferably TadA, more preferably ADAR, optionally huADAR, optionally (hu)ADAR1 or (hu)ADAR2, preferably huADAR2 or catalytic domain thereof. [00570] In some embodiments, the cytidine deaminase is a human, rat or lamprey cytidine deaminase. In some embodiments, the cytidine deaminase is an apolipoprotein B mRNA-editing complex (APOBEC) family deaminase, an activation-induced deaminase (AID), or a cytidine deaminase 1 (CDA1). [00571] In certain embodiments, the adenosine deaminase is adenosine deaminase acting on RNA (ADAR). In certain embodiments, the ADAR is ADAR (ADAR1), ADARB1 (ADAR2) or ADARB2 (ADAR3) (see, e.g., Savva et al. Genon. Biol.2012, 13(12):252). [00572] In some embodiments, the gene editing system comprises AID/APOBEC (apolipoprotein B editing complex) family of enzymes deaminates cytidine to uridine, leading to mutations in RNA and DNA. [00573] In some embodiments, the nucleobase editing system comprises ADAR and an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is chemically optimized antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is administered for the nucleobase editing, wherein the antisense oligonucleotide activates human endogenous ADAR for nucleobase editing. Such ADAR and antisense oligonucleotide editing system provides a safer site-directed RNA editing with low off-target effect. See, e.g., Merkle et al., Nature Biotechnology, 2019, 37, 133-138. [00574] Any of the above base editor embodiments or variants, modifications, or derivatives thereof are contemplated herein to be delivered by the LNP systems disclosed in this specification for gene editing in cells, tissues, and/or organs under in vitro, ex vivo, or in vivo conditions. The various components described herein may be configured and delivered in any suitable manner. Any of the descriptions presented in this section are not intended to be strictly limiting. Prime editors [00575] In various embodiments, the herein disclosed LNPs may contain a prime editing system or components thereof and which may be used to conduct prime editing of target nucleic acid sequences in cells, tissues, and organs in an ex vivo or in vivo manner. [00576] Prime editing technology is a gene editing technology that can make targeted insertions, deletions, and all transversion and transition point mutations in a target genome. Without wishing to be bound by any particular theory, the prime editing process may search and replace endogenous sequences in a target polynucleotide. The spacer sequence of a prime editing guide RNA (“PEgRNA” or “pegRNA”) recognizes and anneals with a search target sequence in a target strand of a double stranded target polynucleotide, e.g., a double stranded target DNA. A prime editing complex may generate a nick in the target DNA on the edit strand which is the complementary strand of the target strand. The prime editing complex may then use a free 3’ end formed at the nick site of the edit strand to initiate DNA synthesis, where a “primer binding site sequence” (PBS) of the PEgRNA complexes with the free 3’ end, and a single stranded DNA is synthesized (by reverse transcriptase) using an editing template of the PEgRNA as a template. As used herein, a “primer binding site” is a single-stranded portion of the PEgRNA that comprises a region of complementarity to the PAM strand (i.e., the non-target strand or the edit strand). The PBS is complementary or substantially complementary to a sequence on the PAM strand of the double stranded target DNA that is immediately upstream of the nick site. [00577] The term “prime editor (PE)” refers to the polypeptide or polypeptide components involved in prime editing, or any polynucleotide(s) encoding the polypeptide or polypeptide components. In various embodiments, a prime editor includes a polypeptide domain having DNA binding activity and a polypeptide domain having DNA polymerase activity. In some embodiments, the prime editor further comprises a polypeptide domain having nuclease activity. In some embodiments, the polypeptide domain having DNA binding activity comprises a nuclease domain or nuclease activity. In some embodiments, the polypeptide domain having nuclease activity comprises a nickase, or a fully active nuclease. As used herein, the term “nickase” refers to a nuclease capable of cleaving only one strand of a double-stranded DNA target. In some embodiments, the prime editor comprises a polypeptide domain that is an inactive nuclease. In some embodiments, the polypeptide domain having programmable DNA binding activity comprises a nucleic acid guided DNA binding domain, for example, a CRISPR-Cas protein, for example, a Cas9 nickase, a Cpf1 nickase, or another CRISPR-Cas nuclease. In some embodiments, the polypeptide domain having DNA polymerase activity comprises a template-dependent DNA polymerase, for example, a DNA-dependent DNA polymerase or an RNA-dependent DNA polymerase. In some embodiments, the DNA polymerase is a reverse transcriptase. In some embodiments, the prime editor comprises additional polypeptides involved in prime editing, for example, a polypeptide domain having 5’ endonuclease activity, e.g., a 5' endogenous DNA flap endonucleases (e.g., FEN1), for helping to drive the prime editing process towards the edited product formation. In some embodiments, the prime editor further comprises an RNA-protein recruitment polypeptide, for example, a MS2 coat protein. [00578] A prime editor may be engineered. In some embodiments, the polypeptide components of a prime editor do not naturally occur in the same organism or cellular environment. In some embodiments, the polypeptide components of a prime editor may be of different origins or from different organisms. In some embodiments, a prime editor comprises a DNA binding domain and a DNA polymerase domain that are derived from different species. In some embodiments, a prime editor comprises a Cas polypeptide (DNA binding domain) and a reverse transcriptase polypeptide (DNA polymerase) that are derived from different species. For example, a prime editor may comprise a S. pyogenes Cas9 polypeptide and a Moloney murine leukemia virus (M-MLV) reverse transcriptase polypeptide. [00579] In some embodiments, polypeptide domains of a prime editor may be fused or linked by a peptide linker to form a fusion protein. In other embodiments, a prime editor comprises one or more polypeptide domains provided in trans as separate proteins, which are capable of being associated to each other through non-peptide linkages or through aptamers or recruitment sequences. For example, a prime editor may comprise a DNA binding domain and a reverse transcriptase domain associated with each other by an RNA-protein recruitment aptamer, e.g., a MS2 aptamer, which may be linked to a PEgRNA. Prime editor polypeptide components may be encoded by one or more polynucleotides in whole or in part. In some embodiments, a single polynucleotide, construct, or vector encodes the prime editor fusion protein. In some embodiments, multiple polynucleotides, constructs, or vectors each encode a polypeptide domain or portion of a domain of a prime editor, or a portion of a prime editor fusion protein. For example, a prime editor fusion protein may comprise an N-terminal portion fused to an intein-N and a C-terminal portion fused to an intein-C, each of which is individually encoded by an AAV vector. [00580] The editing template may comprise one or more intended nucleotide edits compared to the endogenous double stranded target DNA sequence. Accordingly, the newly synthesized single stranded DNA also comprises the nucleotide edit(s) encoded by the editing template. Through removal of the editing target sequence on the edit strand of the double stranded target DNA and DNA repair mechanism, the newly synthesized single stranded DNA replaces the editing target sequence, and the desired nucleotide edit(s) are incorporated into the double stranded target DNA. [00581] Prime editing was first described in Anzalone et al., “Search-and-replace genome editing without double-strand breaks or donor DNA,” Nature, Dec 2019, 576 (7789): pp.149-157, which is incorporated herein in its entirety. Prime editing has subsequently been described and detailed in numerous follow-on publications, including, for example, (i) Liu et al., “Prime editing: a search and replace tool with versatile base changes,” Yi Chuan, Nov.20, 2022, 44(11): 993-1008; (ii) Lu C et al., “Prime Editing: An All-Rounder for Genome Editing. Int J Mol Sci.2022 Aug 30;23(17):9862; (iii) Velimirovic M, Zanetti LC, Shen MW, Fife JD, Lin L, Cha M, Akinci E, Barnum D, Yu T, Sherwood RI. Peptide fusion improves prime editing efficiency. Nat Commun. 2022 Jun 18;13(1):3512. doi: 10.1038/s41467-022-31270-y. PMID: 35717416; PMCID: PMC9206660; (iv) Velimirovic M, Zanetti LC, Shen MW, Fife JD, Lin L, Cha M, Akinci E, Barnum D, Yu T, Sherwood RI. Peptide fusion improves prime editing efficiency. Nat Commun.2022 Jun 18;13(1):3512. doi: 10.1038/s41467-022-31270-y. PMID: 35717416; PMCID: PMC9206660; (v) Habib O, Habib G, Hwang GH, Bae S. Comprehensive analysis of prime editing outcomes in human embryonic stem cells. Nucleic Acids Res.2022 Jan 25;50(2):1187-1197. doi: 10.1093/nar/gkab1295. PMID: 35018468; PMCID: PMC8789035; (vi) Marzec M, Brąszewska-Zalewska A, Hensel G. Prime Editing: A New Way for Genome Editing. Trends Cell Biol.2020 Apr;30(4):257-259. doi: 10.1016/j.tcb.2020.01.004. Epub 2020 Jan 27. PMID: 32001098; (vii) Tao R, Wang Y, Jiao Y, Hu Y, Li L, Jiang L, Zhou L, Qu J, Chen Q, Yao S. Bi-PE: bi-directional priming improves CRISPR/Cas9 prime editing in mammalian cells. Nucleic Acids Res.2022 Jun 24;50(11):6423-6434. doi: 10.1093/nar/gkac506. PMID: 35687127; PMCID: PMC9226529; (viii) Nelson JW, Randolph PB, Shen SP, Everette KA, Chen PJ, Anzalone AV, An M, Newby GA, Chen JC, Hsu A, Liu DR. Engineered pegRNAs improve prime editing efficiency. Nat Biotechnol.2022 Mar;40(3):402-410. doi: 10.1038/s41587-021-01039-7. Epub 2021 Oct 4. Erratum in: Nat Biotechnol.2021 Dec 8; PMID: 34608327; PMCID: PMC8930418; (ix) Doman JL, Sousa AA, Randolph PB, Chen PJ, Liu DR. Designing and executing prime editing experiments in mammalian cells. Nat Protoc.2022 Nov;17(11):2431-2468. doi: 10.1038/s41596-022-00724-4. Epub 2022 Aug 8. PMID: 35941224; PMCID: PMC9799714; (x) Jiao Y, Zhou L, Tao R, Wang Y, Hu Y, Jiang L, Li L, Yao S. Random- PE: an efficient integration of random sequences into mammalian genome by prime editing. Mol Biomed.2021 Nov 18;2(1):36. doi: 10.1186/s43556-021-00057-w. PMID: 35006470; PMCID: PMC8607425; and (xi) Awan MJA, Ali Z, Amin I, Mansoor S. Twin prime editor: seamless repair without damage. Trends Biotechnol.2022 Apr;40(4):374-376. doi: 10.1016/j.tibtech.2022.01.013. Epub 2022 Feb 10. PMID: 35153078, all of which are incorporated herein by reference. [00582] In addition, prime editing has been described and disclosed in numerous published patent applications, each of which their entire contents, amino acid sequences, nucleotide sequences, and all disclosures therein are incorporated herein by reference in their entireties:

[00583] In some embodiments, the cargo comprises a prime editing system or a polynucleotide encoding a prime editing system. In some embodiments, the cargo comprises a component of a prime editing system or a polynucleotide encoding a component of a prime editing system. [00584] Prime editing is a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas fused to an engineered reverse transcriptase, also referred to as a prime editor, which is programmable using a prime editing guide RNA (“pegRNA”) that both specifies the target site and encodes the desired edit (see, e.g., Anzalone et al., Nature 2019). Prime editing bypasses the need for DNA donor templates by using a prime editor having nickase or catalytically impaired enzymatic activity. [00585] A prime editing system comprises a prime editor. The prime editor (“PE”) comprises a catalytically impaired Cas protein fused to an engineered reverse transcriptase which can precisely and permanently edit one or more target nucleobases in a target polynucleotide. [00586] In some embodiments, the prime editor comprises an engineered Moloney murine leukemia virus (“M-MLV”) reverse transcriptase (“RT”) fused to a Cas-H840A nickase (called “PE2”). In some embodiments, the prime editor comprises an engineered M-MLV RT fused to a Cas9-H840A nickase. In some embodiments, the prime editor comprises an engineered M-MLV RT fused to a Streptococcus pyogenes Cas9 (spCas9)-H840A nickase. PE modifications include increased PAM flexibility to increase the utility of PE2 editing, expanding the coverage of targetable pathogenic variants in the ClinVar database that can now be prime edited to 94.4%. [00587] In some embodiments, the prime editing system further comprises a prime editing guide RNA (“pegRNA”). In some embodiments, the cargo comprises a pegRNA or a polynucleotide encoding a pegRNA. [00588] pegRNAs may be designed and synthesized using methods, software, and commercial sources which are well known to those having ordinary skill in the art such that guide RNAs for any given naspDBP or prime editor may be obtained without undue experimentation. [00589] Reference may be made to the following references providing information and tools for the design, synthesis, modification, and structural configuration of pegRNAs, and guide RNAs in general: (1) Mohr SE, Hu Y, Ewen-Campen B, Housden BE, Viswanatha R, Perrimon N. CRISPR guide RNA design for research applications. FEBS J.2016 Sep;283(17):3232-8. doi: 10.1111/febs.13777. Epub 2016 Jun 22. PMID: 27276584; PMCID: PMC5014588; (2) Hoberecht L, Perampalam P, Lun A, Fortin JP. A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies. Nat Commun.2022 Nov 2;13(1):6568. doi: 10.1038/s41467-022-34320-7. PMID: 36323688; PMCID: PMC9630310; (3) Cram D, Kulkarni M, Buchwaldt M, Rajagopalan N, Bhowmik P, Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRISPR/Cas9-mediated genome editing in wheat. BMC Plant Biol.2019 Nov 6;19(1):474. doi: 10.1186/s12870-019-2097-z. PMID: 31694550; PMCID: PMC6836449; (4) Pliatsika V, Rigoutsos I. "Off-Spotter": very fast and exhaustive enumeration of genomic lookalikes for designing CRISPR/Cas guide RNAs. Biol Direct.2015 Jan 29;10:4. doi: 10.1186/s13062-015-0035-z. PMID: 25630343; PMCID: PMC4326336; (5) Hoof JB, Nødvig CS, Mortensen UH. Genome Editing: CRISPR-Cas9. Methods Mol Biol.2018;1775:119-132. doi: 10.1007/978-1-4939-7804-5_11. PMID: 29876814; (6) Labun K, Krause M, Torres Cleuren Y, Valen E. CRISPR Genome Editing Made Easy Through the CHOPCHOP Website. Curr Protoc.2021 Apr;1(4):e46. doi: 10.1002/cpz1.46. PMID: 33905612; (7) Lee CM, Davis TH, Bao G. Examination of CRISPR/Cas9 design tools and the effect of target site accessibility on Cas9 activity. Exp Physiol. 2018 Apr 1;103(4):456-460. doi: 10.1113/EP086043. Epub 2017 Apr 12. PMID: 28303677; PMCID: PMC7266697; (8) Ma S, Lv J, Feng Z, Rong Z, Lin Y. Get ready for the CRISPR/Cas system: A beginner's guide to the engineering and design of guide RNAs. J Gene Med.2021 Nov;23(11):e3377. doi: 10.1002/jgm.3377. Epub 2021 Jul 28. PMID: 34270141; (9) Hiranniramol K, Chen Y, Wang X. CRISPR/Cas9 Guide RNA Design Rules for Predicting Activity. Methods Mol Biol.2020;2115:351- 364. doi: 10.1007/978-1-0716-0290-4_19. PMID: 32006410; (10) Wiles MV, Qin W, Cheng AW, Wang H. CRISPR-Cas9-mediated genome editing and guide RNA design. Mamm Genome.2015 Oct;26(9-10):501-10. doi: 10.1007/s00335-015-9565-z. Epub 2015 May 20. PMID: 25991564; PMCID: PMC4602062; (11) Creutzburg SCA, Wu WY, Mohanraju P, Swartjes T, Alkan F, Gorodkin J, Staals RHJ, van der Oost J. Good guide, bad guide: spacer sequence-dependent cleavage efficiency of Cas12a. Nucleic Acids Res.2020 Apr 6;48(6):3228-3243. doi: 10.1093/nar/gkz1240. PMID: 31989168; PMCID: PMC7102956; (12) Heigwer F, Boutros M. Cloud-Based Design of Short Guide RNA (sgRNA) Libraries for CRISPR Experiments. Methods Mol Biol.2021;2162:3-22. doi: 10.1007/978-1-0716-0687-2_1. PMID: 32926374; (13) Dronina J, Samukaite-Bubniene U, Ramanavicius A. Towards application of CRISPR-Cas12a in the design of modern viral DNA detection tools (Review). J Nanobiotechnology.2022 Jan 21;20(1):41. doi: 10.1186/s12951-022- 01246-7. PMID: 35062978; PMCID: PMC8777428; (14) Krysler AR, Cromwell CR, Tu T, Jovel J, Hubbard BP. Guide RNAs containing universal bases enable Cas9/Cas12a recognition of polymorphic sequences. Nat Commun.2022 Mar 25;13(1):1617. doi: 10.1038/s41467-022-29202-x. PMID: 35338140; PMCID: PMC8956631; (15) Shin HR, Kweon J, Kim Y. Gene Manipulation Using Fusion Guide RNAs for Cas9 and Cas12a. Methods Mol Biol.2021;2162:185-193. doi: 10.1007/978- 1-0716-0687-2_10. PMID: 32926383; (16) Schubert MS, Thommandru B, Woodley J, Turk R, Yan S, Kurgan G, McNeill MS, Rettig GR. Optimized design parameters for CRISPR Cas9 and Cas12a homology-directed repair. Sci Rep.2021 Sep 30;11(1):19482. doi: 10.1038/s41598-021-98965-y. PMID: 34593942; PMCID: PMC8484621; (17) Crone MA, MacDonald JT, Freemont PS, Siciliano V. gDesigner: computational design of synthetic gRNAs for Cas12a-based transcriptional repression in mammalian cells. NPJ Syst Biol Appl.2022 Sep 16;8(1):34. doi: 10.1038/s41540-022-00241-w. PMID: 36114193; PMCID: PMC9481559; (18) Konstantakos V, Nentidis A, Krithara A, Paliouras G. CRISPR-Cas9 gRNA efficiency prediction: an overview of predictive tools and the role of deep learning. Nucleic Acids Res.2022 Apr 22;50(7):3616-3637. doi: 10.1093/nar/gkac192. PMID: 35349718; PMCID: PMC9023298; (19) Wang J, Zhang X, Cheng L, Luo Y. An overview and metanalysis of machine and deep learning-based CRISPR gRNA design tools. RNA Biol.2020 Jan;17(1):13-22. doi: 10.1080/15476286.2019.1669406. Epub 2019 Sep 27. PMID: 31533522; PMCID: PMC6948960; and (20) Cram D, Kulkarni M, Buchwaldt M, Rajagopalan N, Bhowmik P, Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRISPR/Cas9-mediated genome editing in wheat. BMC Plant Biol.2019 Nov 6;19(1):474. doi: 10.1186/s12870-019-2097-z. PMID: 31694550; PMCID: PMC6836449; each of which are incorporated herein by reference in their entireties. [00590] In the specific case of prime editing, in particular, further reference may be made to the following references providing information and tools for the design, synthesis, modification, and structural configuration of pegRNAs: (1) Hsu JY, Grünewald J, Szalay R, Shih J, Anzalone AV, Lam KC, Shen MW, Petri K, Liu DR, Joung JK, Pinello L. PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nat Commun.2021 Feb 15;12(1):1034. doi: 10.1038/s41467- 021-21337-7. PMID: 33589617; PMCID: PMC7884779; (2) Li Y, Chen J, Tsai SQ, Cheng Y. Easy- Prime: a machine learning-based prime editor design tool. Genome Biol.2021 Aug 19;22(1):235. doi: 10.1186/s13059-021-02458-0. PMID: 34412673; PMCID: PMC8377858; (3) Zhang W, Petri K, Ma J, Lee H, Tsai CL, Joung JK, Yeh JJ. Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions. bioRxiv [Preprint].2023 Aug 15:2023.08.14.553324. doi: 10.1101/2023.08.14.553324. PMID: 37645936; PMCID: PMC10462064; (4) Jin S, Lin Q, Gao Q, Gao C. Optimized prime editing in monocot plants using PlantPegDesigner and engineered plant prime editors (ePPEs). Nat Protoc.2023 Mar;18(3):831-853. doi: 10.1038/s41596-022-00773-9. Epub 2022 Nov 25. PMID: 36434096; (5) Lin Q, Jin S, Zong Y, Yu H, Zhu Z, Liu G, Kou L, Wang Y, Qiu JL, Li J, Gao C. High-efficiency prime editing with optimized, paired pegRNAs in plants. Nat Biotechnol.2021 Aug;39(8):923-927. doi: 10.1038/s41587-021-00868-w. Epub 2021 Mar 25. PMID: 33767395; (6) Standage-Beier K, Tekel SJ, Brafman DA, Wang X. Prime Editing Guide RNA Design Automation Using PINE-CONE. ACS Synth Biol.2021 Feb 19;10(2):422-427. doi: 10.1021/acssynbio.0c00445. Epub 2021 Jan 19. PMID: 33464043; PMCID: PMC7901017; (7) Zhang W, Petri K, Ma J, Lee H, Tsai CL, Joung JK, Yeh JJ. Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions. bioRxiv [Preprint].2023 Aug 15:2023.08.14.553324. doi: 10.1101/2023.08.14.553324. PMID: 37645936; PMCID: PMC10462064; (8) Chow RD, Chen JS, Shen J, Chen S. A web tool for the design of prime-editing guide RNAs. Nat Biomed Eng.2021 Feb;5(2):190-194. doi: 10.1038/s41551-020-00622-8. Epub 2020 Sep 28. PMID: 32989284; PMCID: PMC7882013; each of which are incorporated herein by reference in their entireties. [00591] Reference may also be made to the following commercial vendors which synthesize pegRNAs for prime editing applications and provide various tools and instruction for the ordering, design, synthesis, modification, and structural configuration of pegRNAs: GENSCRIPT, SYNTHEGO, TAKARA BIO, INTEGRATED DNA TECHNOLOGIES, LC SCIENCES, HORIZON DISCOVERY; SIGMA-ALDRICH; ORIGENE, and TWIST BIOSCIENCES, among others. [00592] In addition, pegRNAs may be modified with chemical modifications and/or structural modifications for enhancing various properties thereof, including specificity, stability, and limiting off-target activity. One of ordinary skill in the art will be able to modify a guide RNA with any known modification without undue experimentation. Guide modifications are discussed in the following references: (1) Ke Y, Ghalandari B, Huang S, Li S, Huang C, Zhi X, Cui D, Ding X.2'-O- Methyl modified guide RNA promotes the single nucleotide polymorphism (SNP) discrimination ability of CRISPR-Cas12a systems. Chem Sci.2022 Feb 1;13(7):2050-2061. doi: 10.1039/d1sc06832f. PMID: 35308857; PMCID: PMC8848812; (2) Allen D, Rosenberg M, Hendel A. Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells. Front Genome Ed.2021 Jan 28;2:617910. doi: 10.3389/fgeed.2020.617910. PMID: 34713240; PMCID: PMC8525374; (3) Basila M, Kelley ML, Smith AVB. Minimal 2'-O-methyl phosphorothioate linkage modification pattern of synthetic guide RNAs for increased stability and efficient CRISPR-Cas9 gene editing avoiding cellular toxicity. PLoS One.2017 Nov 27;12(11):e0188593. doi: 10.1371/journal.pone.0188593. PMID: 29176845; PMCID: PMC5703482; (4) Sakovina L, Vokhtantsev I, Vorobyeva M, Vorobyev P, Novopashina D. Improving Stability and Specificity of CRISPR/Cas9 System by Selective Modification of Guide RNAs with 2'-fluoro and Locked Nucleic Acid Nucleotides. Int J Mol Sci.2022 Nov 3;23(21):13460. doi: 10.3390/ijms232113460. PMID: 36362256; PMCID: PMC9655745; (5) Shapiro J, Tovin A, Iancu O, Allen D, Hendel A. Chemical Modification of Guide RNAs for Improved CRISPR Activity in CD34+ Human Hematopoietic Stem and Progenitor Cells. Methods Mol Biol.2021;2162:37-48. doi: 10.1007/978-1-0716-0687-2_3. PMID: 32926376; (6) Filippova J, Matveeva A, Zhuravlev E, Stepanov G. Guide RNA modification as a way to improve CRISPR/Cas9-based genome-editing systems. Biochimie.2019 Dec;167:49-60. doi: 10.1016/j.biochi.2019.09.003. Epub 2019 Sep 4. PMID: 31493470; (7) Hendel A, Bak RO, Clark JT, Kennedy AB, Ryan DE, Roy S, Steinfeld I, Lunstad BD, Kaiser RJ, Wilkens AB, Bacchetta R, Tsalenko A, Dellinger D, Bruhn L, Porteus MH. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol.2015 Sep;33(9):985-989. doi: 10.1038/nbt.3290. Epub 2015 Jun 29. PMID: 26121415; PMCID: PMC4729442; (8)_ Ryan DE, Taussig D, Steinfeld I, Phadnis SM, Lunstad BD, Singh M, Vuong X, Okochi KD, McCaffrey R, Olesiak M, Roy S, Yung CW, Curry B, Sampson JR, Bruhn L, Dellinger DJ. Improving CRISPR-Cas specificity with chemical modifications in single-guide RNAs. Nucleic Acids Res.2018 Jan 25;46(2):792-803. doi: 10.1093/nar/gkx1199. Erratum in: Nucleic Acids Res.2022 Mar 21;50(5):2986. PMID: 29216382; PMCID: PMC5778453; (9) Palumbo CM, Gutierrez-Bujari JM, O'Geen H, Segal DJ, Beal PA. Versatile 3' Functionalization of CRISPR Single Guide RNA. Chembiochem.2020 Jun 2;21(11):1633-1640. doi: 10.1002/cbic.201900736. Epub 2020 Mar 5. PMID: 31943634; PMCID: PMC7323579; (10) Mullally G, van Aelst K, Naqvi MM, Diffin FM, Karvelis T, Gasiunas G, Siksnys V, Szczelkun MD.5' modifications to CRISPR-Cas9 gRNA can change the dynamics and size of R-loops and inhibit DNA cleavage. Nucleic Acids Res.2020 Jul 9;48(12):6811-6823. doi: 10.1093/nar/gkaa477. PMID: 32496535; PMCID: PMC7337959; (12) Lu S, Zhang Y, Yin H. Chimeric DNA-RNA Guide RNA Designs. Methods Mol Biol.2021;2162:79-85. doi: 10.1007/978-1-0716-0687-2_6. PMID: 32926379; each of which are incorporated by reference herein in their entireties. [00593] In the specific case of prime editing, pegRNAs may be further modified with chemical modifications and/or structural modifications for enhancing various properties thereof, including specificity, stability, and limiting off-target activity. One of ordinary skill in the art will be able to modify a pegRNA for prime editing with any known modification without undue experimentation. pegRNA modifications are discussed in the following references: (1) Nelson JW, Randolph PB, Shen SP, Everette KA, Chen PJ, Anzalone AV, An M, Newby GA, Chen JC, Hsu A, Liu DR. Engineered pegRNAs improve prime editing efficiency. Nat Biotechnol.2022 Mar;40(3):402-410. doi: 10.1038/s41587-021-01039-7. Epub 2021 Oct 4. Erratum in: Nat Biotechnol. 2021 Dec 8;: PMID: 34608327; PMCID: PMC8930418; (2) Liu B, Dong X, Cheng H, Zheng C, Chen Z, Rodríguez TC, Liang SQ, Xue W, Sontheimer EJ. A split prime editor with untethered reverse transcriptase and circular RNA template. Nat Biotechnol.2022 Sep;40(9):1388-1393. doi: 10.1038/s41587-022-01255-9. Epub 2022 Apr 4. PMID: 35379962; each of which are incorporated by reference herein in their entireties. [00594] In some embodiments, the prime editing system further comprises a second guide RNA targeting the complementary strand, allowing the Cas9 nickase to also nick the non-edited strand (called “PE3”), which biases mismatch DNA repair in favor of the edited sequence. In some embodiments, the second guide RNA is designed to recognize the complementary strand of DNA only after the PE3 edit has occurred (called “PE3b”), which reduces indel formation. [00595] In some embodiments, the prime editing system comprises an uracil glycosylase inhibitor. In some embodiments, the prime editing system comprises a Cas9 protein fused to an uracil glycosylase inhibitor. In some embodiments, the cargo comprises an uracil glycosylase inhibitor or a polynucleotide encoding an uracil glycosylase inhibitor. In some embodiments, the cargo comprises a Cas9 protein fused to an uracil glycosylase inhibitor or a polynucleotide encoding a Cas9 protein fused to an uracil glycosylase inhibitor. [00596] Any of the above prime editor embodiments or variants, modifications, or derivatives thereof are contemplated herein to be delivered by the LNP systems disclosed in this specification for gene editing in cells, tissues, and/or organs under in vitro, ex vivo, or in vivo conditions. The various components described herein may be configured and delivered in any suitable manner. Any of the descriptions presented in this section are not intended to be strictly limiting. [00597] In embodiments, the reverse transcriptase component of the prime editor can be any reverse transcriptase known in the art, or any variant thereof, such as those described in the above published prime editing application or in the scientific literature, such as in: (1) Gao Z, Ravendran S, Mikkelsen NS, Haldrup J, Cai H, Ding X, Paludan SR, Thomsen MK, Mikkelsen JG, Bak RO. A truncated reverse transcriptase enhances prime editing by split AAV vectors. Mol Ther.2022 Sep 7;30(9):2942-2951. doi: 10.1016/j.ymthe.2022.07.001. Epub 2022 Jul 8. PMID: 35808824; PMCID: PMC9481986; (2) Lan T, Chen H, Tang C, Wei Y, Liu Y, Zhou J, Zhuang Z, Zhang Q, Chen M, Zhou X, Chi Y, Wang J, He Y, Lai L, Zou Q. Mini-PE, a prime editor with compact Cas9 and truncated reverse transcriptase. Mol Ther Nucleic Acids.2023 Aug 18;33:890-897. doi: 10.1016/j.omtn.2023.08.018. PMID: 37680986; PMCID: PMC10480570; (3) or available biological sequence databases, all of which are incorporated herein by reference. [00598] In addition, the reverse transcriptase may be a retron reverse transcriptase (retron RT), such as any of those described in: (1) US Patent Application Serial No.18/087,673; (2) International PCT Application No. PCT/US2023/061038; (3) International Application No. PCT/US2023/072872; (4) Mestre et al., Nucleic Acids Research, Volume 48, Issue 22, 16 December 2020, Pages 12632-12647; (5) Mestre et al., UG/Abi: “A Highly Diverse Family of Prokaryotic Reverse Transcriptases Associated With Defense Functions,” doi.org/10.1101/2021.12.02.470933; (6) International Application No. PCT/US2023/016262; (7) International Application No. PCT/US2023/016263; (8) International Application No. PCT/US23/72799; (9) International Application NO. PCT/US2022/079220; (10) International Application No. PCT/US2023/016317; and (10) may particularly be any retron selected from Table A of International Application No. PCT/US2023/072872, or any amino acid sequence having at having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% sequence identity to a polypeptide listed in Table A of International Application No. PCT/US2023/072872. The contents of each of the documents in this paragraph are incorporated herein by reference in their entireties. Retron editors [00599] In still other embodiments, the herein disclosed LNPs may be used to encapsulate and deliver a retron editing system. A retron editing system in various embodiments may comprise (a) a retron reverse transcriptase, or a nucleic acid molecule encoding a retron reverse transcriptase, (b) a retron ncRNA (or a nucleic acid molecule encoding same) comprising a modified msd region to include a sequence that is reverse transcribed to form a single strand template DNA sequence (RT- DNA), (c) a nucleic acid programmable nuclease (e.g., a CRISPR Cas9 or Cas12a), and (d) a guide RNA to target the nuclease to a desired target site. [00600] Retrons are defined by their unique ability to produce an unusual satellite DNA known as msDNA (multicopy single-stranded DNA). DNA encoding retrons includes a reverse trancriptase (RT)-coding gene (ret) and a nucleic acid sequence encoding the non-coding RNA (ncRNA), which contains two contiguous and inverted non-coding sequences referred to as the msr and msd. The ret gene and the non-coding RNA (including the msr and msd) are transcribed as a single RNA transcript, which becomes folded into a specific secondary structure following post- transcriptional processing. Once translated, the RT binds the RNA template downstream from the msd locus, initiating reverse transcription of the RNA towards its 5ʹ end, assisted by the 2’OH group present in a conserved branching guanosine residue that acts as a primer. Reverse transcription halts before reaching the msr locus, and the resulting DNA, the msDNA, remains covalently attached to the RNA template via a 2’-5ʹ phosphodiester bond and base-pairing between the 3ʹ ends of the msDNA and the RNA template. The external regions, at the 5ʹ and 3ʹ ends of the msd/msr transcript (a1 and a2, respectively) are complementary and can hybridize, leaving the structures located in the msr and msd regions in internal positions. The msr locus, which is not reverse transcribed, forms one to three short stem-loops of variable size, ranging from 3 to 10 base pairs, whereas the msd locus folds into a single/double long hairpin with a highly variable long stem of 10-50 bp in length that is also present in the final msDNA form. [00601] It has recently been reported that retrons may be utilized as a means to provide donor DNA template for HDR-dependent genome editing (e.g., see Lopez et al., “Precise genome editing across kingdoms of life using retron-derived DNA,” Nature Chemical Biology, December 12, 2021, 18, pages 199–206 (2022)), however, producing sufficient levels of donor DNA template intracellularly to sufficiently support efficient HDR-dependent editing remains a significant challenge. [00602] Retrons have previously been described in the scientific literature, including in the context of retron editing. For example, retrons have been described in the following references, each of which are incorporated herein by reference:

[00603] In addition, retrons have previously been described in the patent literature, including in the context of retron editing. For example, retrons have been described in the following references, each of which are incorporated herein by reference:

[00604] In some embodiments, the LNP-based retron editing system can be used for genome editing a desired site. A retron is engineered with a heterologous nucleic acid sequence encoding a donor polynucleotide (“template or donor nucleotide sequence” or “template DNA”) suitable for use with nuclease genome editing system. The nuclease is designed to specifically target a location proximal to the desired edit (the nuclease should be designed such that it will not cut the target once the edit is properly installed). The nuclease (e.g., CAS or non-CAS) is linked to the retron, either by direct fusion to the RT or by fusion of the msDNA to the gRNA (only applicable for RNA-guided nucleases). A heterologous nucleic acid sequence is inserted into the retron msd. [00605] In some embodiments, the heterologous nucleic acid sequence has 10-100 or more bp of homologous nucleic acid sequence to the genome on both sides of the desired edit. The desired edit (insertion, deletion, or mutation) is in between the homologous sequence. [00606] In some embodiments, donor polynucleotides comprise a sequence comprising an intended genome edit flanked by a pair of homology arms responsible for targeting the donor polynucleotide to the target locus to be edited in a cell. The donor polynucleotide typically comprises a 5ʹ homology arm that hybridizes to a 5ʹ genomic target sequence and a 3ʹ homology arm that hybridizes to a 3ʹ genomic target sequence. The homology arms are referred to herein as 5ʹ and 3ʹ (i.e., upstream and downstream) homology arms, which relate to the relative position of the homology arms to the nucleotide sequence comprising the intended edit within the donor polynucleotide. The 5ʹ and 3ʹ homology arms hybridize to regions within the target locus in the genomic DNA to be modified, which are referred to herein as the “5ʹ target sequence” and “3ʹ target sequence,” respectively. [00607] The homology arm must be sufficiently complementary for hybridization to the target sequence to mediate homologous recombination between the donor polynucleotide and genomic DNA at the target locus. For example, a homology arm may comprise a nucleotide sequence having at least about 80-100% sequence identity to the corresponding genomic target sequence, including any percent identity within this range, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto, wherein the nucleotide sequence comprising the intended edit can be integrated into the genomic DNA by HDR at the genomic target locus recognized (i.e., having sufficient complementary for hybridization) by the 5ʹ and 3ʹ homology arms. [00608] In some embodiments, the corresponding homologous nucleotide sequences in the genomic target sequence (i.e., the “5ʹ target sequence” and “3ʹ target sequence”) flank a specific site for cleavage and/or a specific site for introducing the intended edit. The distance between the specific cleavage site and the homologous nucleotide sequences (e.g., each homology arm) can be several hundred nucleotides. In some embodiments, the distance between a homology arm and the cleavage site is 200 nucleotides or less (e.g., 0, 10, 20, 30, 50, 75, 100, 125, 150, 175, and 200 nucleotides). In most cases, a smaller distance may give rise to a higher gene targeting rate. In some embodiments, the donor polynucleotide is substantially identical to the target genomic sequence, across its entire length except for the sequence changes to be introduced to a portion of the genome that encompasses both the specific cleavage site and the portions of the genomic target sequence to be altered. [00609] A homology arm can be of any length, e.g.10 nucleotides or more, 15 nucleotides or more, 20 nucleotides or more, 50 nucleotides or more, 100 nucleotides or more, 250 nucleotides or more, 300 nucleotides or more, 350 nucleotides or more, 400 nucleotides or more, 450 nucleotides or more, 500 nucleotides or more, 1000 nucleotides (1 kb) or more, 5000 nucleotides (5 kb) or more, 10000 nucleotides (10 kb) or more, etc. In some instances, the 5ʹ and 3ʹ homology arms are substantially equal in length to one another. However, in some instances the 5ʹ and 3ʹ homology arms are not necessarily equal in length to one another. For example, one homology arm may be 30% shorter or less than the other homology arm, 20% shorter or less than the other homology arm, 10% shorter or less than the other homology arm, 5% shorter or less than the other homology arm, 2% shorter or less than the other homology arm, or only a few nucleotides less than the other homology arm. In other instances, the 5ʹ and 3ʹ homology arms are substantially different in length from one another, e.g. one may be 40% shorter or more, 50% shorter or more, sometimes 60% shorter or more, 70% shorter or more, 80% shorter or more, 90% shorter or more, or 95% shorter or more than the other homology arm. [00610] The donor polynucleotide may be used in combination with an RNA-guided nuclease, which is targeted to a particular genomic sequence (i.e., genomic target sequence to be modified) by a guide RNA. A target-specific guide RNA comprises a nucleotide sequence that is complementary to a genomic target sequence, and thereby mediates binding of the nuclease-gRNA complex by hybridization at the target site. For example, the gRNA can be designed with a sequence complementary to the sequence of a minor allele to target the nuclease-gRNA complex to the site of a mutation. The mutation may comprise an insertion, a deletion, or a substitution. For example, the mutation may include a single nucleotide variation, gene fusion, translocation, inversion, duplication, frameshift, missense, nonsense, or other mutation associated with a phenotype or disease of interest. The targeted minor allele may be a common genetic variant or a rare genetic variant. In some embodiments, the gRNA is designed to selectively bind to a minor allele with single base-pair discrimination, for example, to allow binding of the nuclease-gRNA complex to a single nucleotide polymorphism (SNP). In particular, the gRNA may be designed to target disease-relevant mutations of interest for the purpose of genome editing to remove the mutation from a gene. Alternatively, the gRNA can be designed with a sequence complementary to the sequence of a major or wild-type allele to target the nuclease-gRNA complex to the allele for the purpose of genome editing to introduces a mutation into a gene in the genomic DNA of the cell, such as an insertion, deletion, or substitution. Such genetically modified cells can be used, for example, to alter phenotype, confer new properties, or produce disease models for drug screening. [00611] In some embodiments, the RNA-guided nuclease used for genome modification is a clustered regularly interspersed short palindromic repeats (CRISPR) system Cas nuclease. Any RNA- guided Cas nuclease capable of catalyzing site- directed cleavage of DNA to allow integration of donor polynucleotides by the HDR mechanism can be used in genome editing, including CRISPR system Class 1, Type I, II, or III Cas nucleases; Class 2, Type II nuclease (such as Cas9); a Class 2, Type V nuclease (such as Cpfl), or a Class 2, Type VI nuclease (such as C2c2). Examples of Cas proteins include Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8al, Cas8a2, Cas8b, Cas8c, Cas9 (Csnl or Csxl2), CaslO, CaslOd, CasF, CasG, CasH, Csyl, Csy2, Csy3, Csel (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, and Cul966, and homologs or modified versions thereof. [00612] In some embodiments, a Class 1, type II CRISPR system Cas9 endonuclease is used. Cas9 nucleases from any species, or biologically active fragments, variants, analogs, or derivatives thereof that retain Cas9 endonuclease activity (i.e., catalyze site-directed cleavage of DNA to generate double-strand breaks) may be used to perform genome modification as described herein. The Cas9 need not be physically derived from an organism but may be synthetically or recombinantly produced. Cas9 sequences from a number of bacterial species are well known in the art and listed in the National Center for Biotechnology Information (NCBI) database. See, for example, NCBI entries for Cas9 from: Streptococcus pyogenes (WP 002989955, WP_038434062, WP_011528583); Campylobacter jejuni (WP_022552435, YP 002344900), Campylobacter coli (WP 060786116); Campylobacter fetus (WP 059434633); Corynebacterium ulcerans (NC_015683, NC_017317); Corynebacterium diphtheria (NC_016782, NC_016786); Enterococcus faecalis (WP 033919308); Spiroplasma syrphidicola (NC 021284); Prevotella intermedia (NC 017861); Spiroplasma taiwanense (NC 021846); Streptococcus iniae (NC 021314); Belliella baltica (NC 018010); Psychroflexus torquisl (NC O 18721); Streptococcus thermophilus (YP 820832), Streptococcus mutans (WP 061046374, WP 024786433); Listeria innocua (NP 472073); Listeria monocytogenes (WP 061665472); Legionella pneumophila (WP 062726656); Staphylococcus aureus (WP_001573634); Francisella tularensis (WP_032729892, WP_014548420), Enterococcus faecalis (WP 033919308); Lactobacillus rhamnosus (WP 048482595, WP_032965177); and Neisseria meningitidis (WP_061704949, YP_002342100); all of which sequences (as entered by the date of filing of this application) are herein incorporated by reference in their entireties. Any of these sequences or a variant thereof comprising a sequence having at least about 70-100% sequence identity thereto, including any percent identity within this range, such as 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity thereto, can be used for genome editing, as described herein. See also Fonfara et al. (2014) Nucleic Acids Res.42(4):2577-90; Kapitonov et al. (2015) J. Bacterid.198(5): 797-807, Shmakov et al. (2015) Mol. Cell.60(3):385- 397, and Chylinski et al. (2014) Nucleic Acids Res.42(10):6091-6105); for sequence comparisons and a discussion of genetic diversity and phylogenetic analysis of Cas9. [00613] The genomic target site will typically comprise a nucleotide sequence that is complementary to the gRNA and may further comprise a protospacer adjacent motif (PAM). In some embodiments, the target site comprises 20-30 base pairs in addition to a 3 or more base pair PAM. Typically, the first nucleotide of a PAM can be any nucleotide, while the two or more other nucleotides will depend on the specific Cas9 protein that is chosen. Exemplary PAM sequences are known to those of skill in the art and include, without limitation, NNG, NGN, NAG, and NGG, wherein N represents any nucleotide. In some embodiments, the allele targeted by a gRNA comprises a mutation that creates a PAM within the allele, wherein the PAM promotes binding of the Cas9- gRNA complex to the allele. [00614] In some embodiments, the gRNA is 5-50 nucleotides, 10-30 nucleotides, 15- 25 nucleotides, 18-22 nucleotides, or 19-21 nucleotides in length, or any length between the stated ranges, including, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. The guide RNA may be a single guide RNA comprising crRNA and tracrRNA sequences in a single RNA molecule, or the guide RNA may comprise two RNA molecules with crRNA and tracrRNA sequences residing in separate RNA molecules. [00615] In another embodiment, the CRISPR nuclease from Prevotella and Francisella 1 (Cpfl, or Cas12a) is used. Cpfl is another class II CRISPR/Cas system RNA-guided nuclease with similarities to Cas9 and may be used analogously. Unlike Cas9, Cpfl does not require a tracrRNA and only depends on a crRNA in its guide RNA, which provides the advantage that shorter guide RNAs can be used with Cpfl for targeting than Cas9. Cpfl is capable of cleaving either DNA or RNA. The PAM sites recognized by Cpfl have the sequences 5ʹ-YTN-3ʹ (where “Y” is a pyrimidine and “N” is any nucleobase) or 5ʹ-TTN-3ʹ, in contrast to the G-rich PAM site recognized by Cas9. Cpfl cleavage of DNA produces double-stranded breaks with a sticky-ends having a 4 or 5 nucleotide overhang. For a discussion of Cpfl, see, e.g., Ledford et al. (2015) Nature.526 (7571):17-17, Zetsche et al. (2015) Cell.163 (3):759-771, Murovec et al. (2017) Plant Biotechnol. J.15(8):917-926, Zhang et al. (2017) Front. Plant Sci.8:177, Fernandes et al. (2016) Postepy Biochem.62(3):315-326; herein incorporated by reference. [00616] C2c1 (Cas12b) is another class II CRISPR/Cas system RNA-guided nuclease that may be used. C2cl, similarly to Cas9, depends on both a crRNA and tracrRNA for guidance to target sites. See, e.g., Shmakov et al. (2015) Mol Cell.60(3):385-397, Zhang et al. (2017) Front Plant Sci. 8:177; herein incorporated by reference. [00617] In yet another embodiment, an engineered RNA-guided Fokl nuclease may be used. RNA-guided Fokl nucleases comprise fusions of inactive Cas9 (dCas9) and the Fokl endonuclease (FokI-dCas9), wherein the dCas9 portion confers guide RNA-dependent targeting on Fokl. For a description of engineered RNA-guided Fold nucleases, see, e.g., Havlicek et al. (2017) Mol. Ther. 25(2):342-355, Pan et al. (2016) Sci Rep.6:35794, Tsai et al. (2014) Nat Biotechnol.32(6):569-576; herein incorporated by reference. [00618] In other embodiments, any other Cas enzymes and variants described in other sections of the application (all incorporated herein) can be used similarly. [00619] In some embodiments, the RNA-guided nuclease is provided in the form of a protein, optionally where the nuclease is complexed with a gRNA to form a ribonucleoprotein (RNP) complex. In some embodiments, the RNA-guided nuclease is provided by a nucleic acid encoding the RNA-guided nuclease, such as an RNA (e.g., messenger RNA) or DNA (expression vector). In some embodiments, the RNA-guided nuclease and the gRNA are both provided by vectors, such as the vectors and the vector system described in other parts of the application (all incorporated herein by reference). Both can be expressed by a single vector or separately on different vectors. The vectors encoding the RNA-guided nuclease and gRNA may be included in the vector system comprising the engineered retron msr gene, msd gene and ret gene sequences. In some embodiments, the RNA- guided nuclease is fused to the RT and/or the msDNA. [00620] The RNP complex may be administered to a subject or delivered into a cell by methods known in the art, such as those described in U.S. Pat. No.11,390,884, which is incorporated by reference herein in its entirety. In some embodiments, the endonuclease/gRNA ribonucleoprotein (RNP) complexes are delivered to cells by electroporation. Direct delivery of the RNP complex to a subject or cell eliminates the need for expression from nucleic acids (e.g., transfection of plasmids encoding Cas9 and gRNA). It also eliminates unwanted integration of DNA segments derived from nucleic acid delivery (e.g., transfection of plasmids encoding Cas9 and gRNA). An endonuclease/gRNA ribonucleoprotein (RNP) complex usually is formed prior to administration. [00621] Codon usage may be optimized to further improve production of an RNA-guided nuclease and/or reverse transcriptase (RT) in a particular cell or organism. For example, a nucleic acid encoding an RNA-guided nuclease or reverse transcriptase can be modified to substitute codons having a higher frequency of usage in a yeast cell, a bacterial cell, a human cell, a non-human cell, a mammalian cell, a rodent cell, a mouse cell, a rat cell, or any other host cell of interest, as compared to the naturally occurring polynucleotide sequence. When a nucleic acid encoding the RNA-guided nuclease or reverse transcriptase is introduced into cells, the protein can be transiently, conditionally, or constitutively expressed in the cell. [00622] In some embodiments, the engineered retron used for genome editing with nuclease genome editing systems can further include accessory or enhancer proteins for recombination. Examples of recombination enhancers can include nonhomologous end joining (NHEJ) inhibitors (e.g., inhibitor of DNA ligase IV, a KU inhibitor (e.g., KU70 or KU80), a DNA-PKc inhibitor, or an artemis inhibitor) and homologous directed repair (HDR) promoters, or both, that can enhance or improve more precise genome editing and/or the efficiency of homologous recombination. In some embodiments, the recombination accessory or enhancers can comprise C-terminal binding protein interacting protein (CtIP), cyclinB2, Rad family members (e.g. Rad50, Rad51, Rad52, etc). [00623] CtIP is a transcription factor containing C2H2 zinc fingers that are involved in early steps of homologous recombination. Mammalian CtIP and its orthologs in other eukaryotes promote the resection of DNA double-strand breaks and are essential for meiotic recombination. HDR may be enhanced by using Cas9 nuclease associated (e.g. fused) to an N-terminal domain of CtIP, an approach that forces CtIP to the cleavage site and increases transgene integration by HDR. In some embodiments, an N-terminal fragment of CtIP, called HE for HDR enhancer, may be sufficient for HDR stimulation and requires the CtIP multimerization domain and CDK phosphorylation sites to be active. HDR stimulation by the Cas9-HE fusion depends on the guide RNA used, and therefore the guide RNA will be designed accordingly. [00624] Using the gene editing system described herein, any target gene or sequence in a host cell can be edited or modified for a desired trait, including but not limited to: Myostatin (e.g., GDF8) to increase muscle growth; Pc POLLED to induce hairlessness; KISS1R to induce bore taint; Dead end protein (dnd) to induce sterility; Nano2 and DDX to induce sterility; CD163 to induce PRRSV resistance; RELA to induce ASFV resilience; CD18 to induce Mannheimia (Pasteurella) haemolytica resilience; NRAMPl to induce tuberculosis resilience; Negative regulators of muscle mass (e.g., Myostatin) to increase muscle mass. [00625] Any of the above retron editor embodiments or variants, modifications, or derivatives thereof are contemplated herein to be delivered by the LNP systems disclosed in this specification for gene editing in cells, tissues, and/or organs under in vitro, ex vivo, or in vivo conditions. The various components described herein may be configured and delivered in any suitable manner. Any of the descriptions presented in this section are not intended to be strictly limiting. TnpB editors [00626] In other embodiments, the herein disclosed LNPs may be used to encapsulate and deliver a TnpB editing system and/or components thereof. A TnpB editing system in various embodiments may comprise (a) a TnpB protein, or a nucleic acid molecule encoding a TnpB protein, (b) a TnpB guide RNA known as an “reRNA” or “right end RNA”, and optionally one or more additional components, including (c) an effector domain or otherwise accessory protein, and (d) a DNA template (e.g., a DNA donor for HDR-dependent repair at the TnpB-cut target site. [00627] In various embodiments, the TnpB protein can be naturally occurring or the TnpB can be an engineered variant thereof and can be used in various applications, including precision gene editing in cells, tissues, organs, or organisms. The TnpB-based gene editing systems comprise a TnpB polypeptide and a nucleic acid component capable of forming a complex with the TnpB polypeptide which directs the complex to a target nucleotide sequence (e.g., a genomic target sequence such as a disease-associated gene). The TnpB gene editing systems contemplated herein may also be modified with one or more additional effector or accessory functions, such as a nuclease, recombinase, ligase, reverse transcriptase, polymerase, deaminase, etc. to provide additional genome editing functionality. In addition, the TnpB gene editing systems contemplated herein can utilize a nuclease-limited or nuclease-deficienty TnpB variant. Normal TnpB nuclease activity cuts both strands of a target DNA, however, TnpB nickases (having only the ability to cut one of the two strands but not both strands) and nuclease-inactive or “dead” TnpB (which does not cut either strand) may also be used into the TnpB systems described herein, particularly when combined with at least another genome editing functionality, such as a deaminase (for base editing functionality) or a reverse transcriptase (for prime editing functionality). Thus, disclosed herein are TnpB systems that may function as nuclease, nickases, or catalytically inactive polynucleotide binding proteins that can be coupled with other functional domains, such as deaminases, recombinase, ligases, polymerases (e.g., reverse transcriptase), nucleases, or reverse transcriptases. [00628] In one embodiment, the TnpB systems and related compositions may specifically target single-strand or double-strand DNA. In one embodiment, the TnpB system may bind and cleave double-strand DNA. In one embodiment, the TnpB system may bind to double-stranded DNA without introducing a break to either of the strands. In one embodiment, the TnpB polypeptides or nuclease/nucleic acid component complexes may open, disrupting the continuity of one of the two DNA strands, thereby introducing a nick of the double stranded DNA. In an embodiment, and without being bound by theory, the size and configuration of the TnpB systems allows exposure to the non- targeting strand, which may be in single-stranded form, to allow for for the ability to modify, edit, delete or insert polynucleotides on the non-target strand. In an embodiment, this accessibility further allows for enhanced editing outcomes on the target and/or non-target strand, e.g., increased specificity, enhanced editing efficiency. [00629] In one aspect, embodiments disclosed herein are directed to compositions comprising a TnpB and a reRNA capable of forming a complex with the TnpB and directing site-specific binding of the TnpB to a target sequence on a target polynucleotide. TnpB polypeptides [00630] Any TnpB polypeptide may be utilized with the compositions described herein. The below description of various TnpBs which can be used in connection with the presently disclose TnpB editing systems is not meant to be limiting in any way. The TnpB editing systems disclosed herein may comprise a canonical or naturally-occurring TnpB, or any ortholog TnpB protein, or any variant TnpB protein—including any naturally occurring variant, mutant, or otherwise engineered version of TnpB—that is known or which can be made or evolved through a directed evolutionary or otherwise mutagenic process. In various embodiments, the TnpB or TnpB variants can have a nickase activity, i.e., only cleave of strand of the target DNA sequence. In other embodiments, the TnpB or TnpB variants have inactive nucleases, i.e., are “dead” TnpB proteins. Other variant TnpB proteins that may be used are those having a smaller molecular weight than the canonical TnpB (e.g., for easier delivery) or having modified amino acid sequences or substitutions. [00631] Examples of TnpB proteins are provided as follows; however, these specific examples are not meant to be limiting. The TnpB editing systems of the present disclosure may use any suitable TnpB protein. [00632] In various embodiments, the TnpB editing systems of the present disclosure may include one or more TnpB polypeptides selected from those disclosed in WO 2023/240261A1, or a polypeptide having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with one or more of the TnpB polypeptides of WO 2023/240261A1, which is incorporated by reference herein, in its entirety. [00633] In various other embodiments, the TnpB editing systems of the present disclosure may include one or more TnpB polypeptides and reRNAs disclosed in any of the following published applications, or a polypeptide (or reRNA as the case may be) having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with one or more of the TnpB polypeptides or reRNAs disclosed therein: US2023/0056577; US2023/0051396 A1; US11578313 B2; US2023/0040216 A1; WO2023/015259 A2; US2023/0032369 A1; US2023/0033866 A1; WO2023/004430 A1; US11560555 B2; WO2023/275601 A1; WO2022/253903 A1; WO2022/248607 A2; US2022/0372525 A1; US2022/0348929 A1; US2022/0348925 A1; US11453866 B2; WO2022/173830 A1; WO2022/174144 A1; WO2022/159892 A1; WO2022/150651 A1; US11384344 B2; WO2022/140572 A1; US2022/0195503 A1; WO2022/098923 A1; WO2022/087494 A1; WO2022/086846 A2; WO2022/076425 A1; WO2022/076890 A1; WO2021/257997 A2; WO2021/247924 A1; US2021/0380956 A1; US11180751 B2; WO2021/188729 A1; WO2021/188286 A2; WO2021/183807 A1; WO2021/159020 A2; US2021/0214697 A1; US2021/0166783 A1; WO2021/050601 A1; EP3009511 B2; US2020/0291395 A1; US2020/0239896 A1; WO2019/178428 A1; US2012/0178668 A1; US7608450 B2; US2004/0091856 A1; US2004/0009477 A1; US2003/0134302 A1; US6562958 B1; and WO1999/051766 A1, each of which are incorporated in their entireties by reference. [00634] In certain example embodiments, the TnpB polypeptides are between 175 and 800 amino acids in size, between 200 and 790 amino acids in size, between 200 and 780 amino acids in size, between 200 and 770 amino acids in size, between 200 and 760 amino acids in size, between 200 and 750 amino acids in size, between 200 and 740 amino acids in size, between 200 and 730 amino acids in size, between 200 and 720 amino acids in size, between 200 and 720 amino acids in size, between 200 and 710 amino acids in size, between 200 and 700 amino acids in size, between 200 and 690 amino acids in size, between 200 and 680 amino acids in size, between 200 and 670 amino acids in size, between 200 and 660 amino acids in size, between 200 and 650 amino acids in size, between 200 and 640 amino acids in size, between 200 and 630 amino acids in size, between 200 and 620 amino acids in size, between 200 and 610 amino acids in size, between 200 and 600 amino acids in size, between 200 and 590 amino acids in size, between 200 and 580 amino acids in size, between 200 and 570 amino acids in size, between 200 and 560 amino acid, between 200 between 550 amino acids, between 200 and 540 amino acids, between 200 and 530 amino acids, between 200 and 520 amino acids, between 200 and 510 amino acids, between 200 and 500 amino acids, between 200 and 490 amino acids, between 200 and 480 amino acids, between 200 and 470 amino acids, between 200 and 460 amino acids, between 200 and 450 amino acids, between 200 and 440 amino acids, between 200 and 430 amino acids, between 200 and 420 amino acids, between 200 and 410 amino acids, between 210 and 500 amino acids, between 220 and 500 amino acids. Between 230 and 500 amino acids, between 240 and 500 amino acids, between 250 and 500 amino acids, between 260 and 500 amino acids, between 270 and 500 amino acids, between 280 and 500 amino acids, between 290 and 500 amino acids, between 300 and 500 amino acids, between 250 and 490 amino acids, between 250 and 480 amino acids, between 250 and 490 amino acids, or between 250 and 600 amino acids. In one embodiment, the TnpB polypeptide is between 300 and 500 amino acids, or between 350 and 450 amino acids. [00635] In one embodiment, the TnpB polypeptides may comprise a modified naturally occurring protein, functional fragment or truncated version thereof, or a non-naturally occurring protein. In one embodiment, the TnpB polypeptide comprises one or more domains originating from other TnpB polypeptides, more particularly originating from different organisms. In one embodiment, the TnpB polypeptides may be designed by in silico approaches. Examples of in silico protein design have been described in the art and are therefore known to a skilled person. [00636] The TnpB polypeptides also encompass homologs or orthologs of TnpB polypeptides whose sequences are specifically described herein (such as the sequences of Table A). The terms “ortholog” and “homolog” are well known in the art. By means of further guidance, a “homolog” of a protein as used herein is a protein of the same species which performs the same or a similar function as the protein it is a homolog of. Homologous proteins may but need not be structurally related, or are only partially structurally related. An “ortholog” of a protein as used herein is a protein of a different species which performs the same or a similar function as the protein it is an orthologue of. Orthologous proteins may be, but may not always be, structurally related or are only partially structurally related. In particular embodiments, the homolog or ortholog of a TnpB polypeptide such as referred to herein has a sequence homology or identity of at least 80%, at least 81%, at least 82%, at least 83%, at least 84% at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% with a TnpB polypeptide, more specifically with a TnpB sequence identified in Table A. In particular embodiments, a homolog or ortholog is identified according to its domain structure and/or function. Sequence alignments conducted as described herein, as well as folding studies and domain predictions can aid in the identification of a homolog or ortholog with the structural and functional characteristics identifying TnpB polypeptides, particularly those with conserved residues, including catalytic residues, and domains of TnpB polypeptides. [00637] In one embodiment, the TnpB polypeptide comprises at least at least one RuvC-like nuclease domain. The RuvC domain may comprise conserved catalytic amino acids indicative of the RuvC catalytic residue. In an example embodiment, the RuvC catalytic residue may be referenced relative to D191, E278, and D361 of the TnpB of D. radiodurans or a corresponding amino acid in an aligned sequence. In an aspect, the RuvC domain may comprise multiple subdomains, e.g., RuvC-I, RuvC-II and RuvC-III. The subdomains may be separated by intervening amino acid sequence of the protein. [00638] In one embodiment, examples of the RuvC domain include any polypeptides a structural similarity and/or sequence similarity to a RuvC domain described in the art. In some examples, the RuvC domain may have an amino acid sequence that share at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% sequence identity with RuvC domains known in the art. One of ordinary skill in the art can modify, substitute, or otherwise alter the activity of the RuvC domain to alter the nuclease activity, such as whether and/or where the nuclease cuts the DNA. [00639] In embodiments, the TnpB polypeptide has a nuclease activity. In one embodiment, the TnpB and the targeting RNA (e.g., the reRNA) can direct sequence-specific nuclease activity. The cleavage may result in a 5’ overhang. The cleavage may occur distal to a target-adjacent motif (TAM), and may occur at the site of the spacer (i.e., the spacer of the reRNA which is complementary to the target sequences) annealing site or 3’ of the target sequence. In an aspect, the TnpB cleaves at multiple positions within and beyond the nucleic acid component annealing site. In an aspect, DNA cleavage occurs 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more base pairs distal to the TAM and results in a 5’ overhang. In various embodiments, the TnpB has a nuclease activity against single- stranded DNA. In other embodiments, the TnpB has a nuclease activity against double-stranded DNA. TnpB modifications [00640] In various aspects, the present disclosure provides one or more modifications of TnpB comprising TnpB fusions, TnpB mutations to increase sufficiency and/or efficiency and modification of TnpB reRNA. In some embodiments, one or more domains of the TnpB are modified, e.g., wedge domain, corresponding to the β-barrel, REC – helical bundle, RuvC – RuvC domain with the inserted helical hairpin (HH) and the zinc-finger domain (ZnF). [00641] Without intending to be limited to any particular theory, TnpB operates as a homodimer with one DNA molecule and for some orthologs, its ability to form this conformation may be efficacy limiting. Takeda, Satoru N et al. “Structure of the miniature type V-F CRISPR-Cas effector enzyme.” Molecular cell vol.81,3 (2021): 558-570.e3. [00642] Karvelis et al. demonstrated Deinococcus radiodurans ISDra2 TnpB to be an RNA-directed nuclease guided by RE-derived RNA (reRNA) to cleave DNA next to the 5' TTGAT transposon associated motif (TAM). Karvelis, T., Druteika, G., Bigelyte, G. et al. Transposon-associated TnpB is a programmable RNA-guided DNA endonuclease. Nature 599, 692–696 (2021). [00643] Without being bound by theory, it is contemplated that TnpB likely operates as a homodimer. Recent studies show that Cas9-Cas9 fusions displayed higher levels of genome modification and a higher proportion of these editing events were precise deletions than are observed for two independent Cas9 nucleases. Bolukbasi, M.F., Liu, P., Luk, K. et al. Orthogonal Cas9–Cas9 chimeras provide a versatile platform for genome editing. Nat Commun 9, 4856 (2018). [00644] Accordingly, in one embodiment, a TnpB is fused to a second TnpB or the like, for example TnpB-TnpB or TnpB-Cas9. Such dual-nuclease formats comprise one TnpB component displaying expanded targeting and/or enhanced specificity and the second TnpB component having nuclease activity. In other preferred embodiments, a TnpB is fused to two or more nuclease proteins. [00645] The TnpB polypeptide may comprise one or more modifications. As used herein, the term “modified” with regard to a TnpB polypeptide generally refers to a TnpB polypeptide having one or more modifications or mutations (including point mutations, truncations, insertions, deletions, chimeras, fusion proteins, etc.) compared to the wild type counterpart from which it is derived (e.g., from a TnpB sequence from Tables B or C). By derived is meant that the derived enzyme is largely based, in the sense of having a high degree of sequence or structural homology with, a wildtype enzyme, but that it has been mutated (modified) in some way as known in the art or as described herein. [00646] The modified proteins, e.g., modified TnpB polypeptide may be catalytically inactive (dead). As used herein, a catalytically inactive or dead nuclease may have reduced, or no nuclease activity compared to a wildtype counterpart nuclease. In some cases, a catalytically inactive or dead nuclease may have nickase activity. In some cases, a catalytically inactive or dead nuclease may not have nickase activity. Such a catalytically inactive or dead nuclease may not make either double- strand or single-strand break on a target polynucleotide but may still bind or otherwise form complex with the target polynucleotide. [00647] In an embodiment, eukaryotic homologues of bacterial TnpB may be utilized in the present disclosure. These TnpB-like proteins, Fanzor 1 and Fanzor 2, while having a shared amino acid motif in their C-terminal half regions, are variable in their N terminal regions. [00648] In one embodiment, the modifications of the TnpB polypeptide may or may not cause an altered functionality. By means of example, modifications which do not result in an altered functionality include for instance codon optimization for expression into a particular host, or providing the nuclease with a particular marker (e.g. for visualization). Modifications with may result in altered functionality may also include mutations, including point mutations, insertions, deletions, truncations (including split nucleases), etc., as well as chimeric nucleases (e.g., comprising domains from different orthologues or homologues) or fusion proteins. Fusion proteins may without limitation include, for instance, fusions with heterologous domains or functional accessory domains (e.g., localization signals, catalytic domains, etc.). In one embodiment, various different modifications may be combined (e.g., a mutated nuclease which is catalytically inactive and which further is fused to a functional domain, such as for instance to induce DNA methylation or another nucleic acid modification, such as including without limitation, a break (e.g. by a different nuclease (domain)), a mutation, a deletion, an insertion, a replacement, a ligation, a digestion, a break or a recombination). As used herein, “altered functionality” includes without limitation an altered specificity (e.g., altered target recognition, increased (e.g., “enhanced” TnpB polypeptide) or decreased specificity, or altered TAM recognition), altered activity (e.g., increased or decreased catalytic activity, including catalytically inactive nucleases or nickases), and/or altered stability (e.g., fusions with destabilization domains). [00649] Examples of all these modifications are known in the art. It will be understood that a “modified” nuclease as referred to herein, and in particular a “modified” TnpB polypeptide or system or complex preferably still has the capacity to interact with or bind to the polynucleic acid (e.g., in complex with the nucleic acid component molecule). Such modified TnpB polypeptide can be combined with the deaminase protein or active domain thereof as described herein. [00650] In one embodiment, an unmodified TnpB polypeptides may have cleavage activity. In one embodiment, the TnpB polypeptides may direct cleavage of one or both nucleic acid (DNA or RNA) strands at the location of or near a target sequence, such as within the target sequence and/or within the complement of the target sequence or at sequences associated with the target sequence. In one embodiment, the TnpB polypeptides may direct cleavage of one or both DNA or RNA strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs or nucleotides from the first or last nucleotide of a target sequence. In one embodiment, the cleavage may be staggered, i.e., generating sticky ends. In one embodiment, the cleavage is a staggered cut with a 5’ overhang. In one embodiment, the cleavage is a staggered cut with a 5’ overhang of 1 to 5 or up to 10 nucleotides. In particular embodiments, the TnpB polypeptides cleave DNA strands. [00651] In one embodiment, a TnpB polypeptide may be mutated with respect to a corresponding wild-type enzyme (e.g., the TnpB polypeptides of Tables B and C) such that the mutated TnpB lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence. As a further example, two or more catalytic domains of a TnpB polypeptide (e.g., RuvC) may be mutated to produce a mutated TnpB polypeptide substantially lacking all DNA cleavage activity. In one embodiment, a TnpB polypeptide may be considered to substantially lack all polynucleotide cleavage activity when the polynucleotide cleavage activity of the mutated enzyme is no more than 25%, no more than 10%, no more than 5%, no more than 1%, no more than 0.1%, no more than 0.01% of the nucleic acid cleavage activity of the non-mutated form of the enzyme; an example can be when the nucleic acid cleavage activity of the mutated form is nil or negligible as compared with the non-mutated form. [00652] In one embodiment, the TnpB polypeptide may comprise one or more modifications resulting in enhanced activity and/or specificity, such as including mutating residues that stabilize the targeted or non-targeted strand. In one embodiment, the altered or modified activity of the engineered TnpB polypeptide comprises increased targeting efficiency or decreased off-target binding. In one embodiment, the altered activity of the engineered TnpB polypeptide comprises modified cleavage activity. In one embodiment, the altered activity comprises increased cleavage activity as to the target polynucleotide loci. In one embodiment, the altered activity comprises decreased cleavage activity as to the target polynucleotide loci. In one embodiment, the altered activity comprises decreased cleavage activity as to off-target polynucleotide loci. In one embodiment, the modified nuclease comprises a modification that alters association of the protein with the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. [00653] In an aspect of the disclosure, the engineered TnpB polypeptide comprises a modification that alters formation of the TnpB polypeptide and related complex. In one embodiment, the altered activity comprises increased cleavage activity as to off-target polynucleotide loci. Accordingly, in one embodiment, there is increased specificity for target polynucleotide loci as compared to off-target polynucleotide loci. In other embodiments, there is reduced specificity for target polynucleotide loci as compared to off-target polynucleotide loci. In one embodiment, the mutations result in decreased off-target effects (e.g. cleavage or binding properties, activity, or kinetics), such as in case for TnpB polypeptide for instance resulting in a lower tolerance for mismatches between target and the reRNA. Other mutations may lead to increased off-target effects (e.g., cleavage or binding properties, activity, or kinetics). Other mutations may lead to increased or decreased on-target effects (e.g., cleavage or binding properties, activity, or kinetics). In one embodiment, the mutations result in altered (e.g., increased or decreased) activity, association or formation of the functional nuclease complex. Examples mutations include mutation of negative or neutral residues to positively charged residues, or positively charged residues to neutral or neutral residues to negative residues and/or (evolutionary) conserved residues, such as conserved positively charged residues, in order to enhance specificity. In one embodiment, such residues may be mutated to uncharged residues, such as alanine. Because the TnpB polypeptide interacts with guide or bound DNA over the length of the TnpB polypeptide, mutation of residues across the TnpB polypeptide may be utilized for altered activity. In an aspect, the TnpB polypeptide residues for mutation are altered based on amino acid sequence positions of Deinococcus radiodurans ISDra2, see, e.g. Karvelis et al., Nature 599, 692-696 (2021). [0001] Preferably, one or more TnpB comprises one or more mutated residues in the Rec domain and optionally these mutated residues are hydrophobic. Alternatively, one or more TnpB comprises mutated residues in the RuvC domain. Preferably, one or more of the mutated residues typically form a hydrogen bond with another TnpB monomer. More preferably, a combination of the two sets of mutations as described above. [0002] In yet other embodiments, the TnpB-nuclease fusions are linked using a polypeptide comprising glycine and serine residues or unstructured XTEN protein polymer. [0003] In other exemplary embodiments, the TnpB-nuclease fusions are linked using an RNA wherein the RNA comprises a guide RNA or a reRNA. [0004] In further embodiments, the TnpB-nuclease fusions comprise one or more nuclear localization signals selected from but not limited to SV40, c-Myc, NLP-1. [0005] Also described herein are methods and compositions for increasing the TnpB-mediated editing efficiency. In some aspects, the editing effiency is greater than 70%, at least 70.5%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. [00654] Additionally described herein are methods and compositions for increasing the TnpB- mediated editing specificity. In some aspects, the editing specificity is greater than 70%, at least 70.5%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. TnpB accessory domains/proteins [00655] In other aspect, the TnpB-based genome perturbation systems may comprise one or more additional accessory proteins having genome modifying functions, including recombinases, invertases, nucleases, polymerases, ligases, deaminases, or reverse transcriptases. In various embodiments, the accessory proteins may be provided separately. In other embodiments, the accessory proteins may be fused to TnpB, optionally with a linker. [0006] Liu et al. has recently developed base editing as a technology that edits target nucleotides without creating DSBs or relying on HDR. Direct modification of DNA bases by Cas-fused deaminase enzymes allows for C•G to T•A, or A•T to G•C, base pair conversions in a short target window (~5-7 bases) with very high efficiency. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016). Nishida, K. et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science 353, aaf8729 (2016). 6. Gaudelli, N. M. et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464– 471 (2017). Kim, Y. B. et al. Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nat. Biotechnol.35, 371–376 (2017).25. Li, X. et al. Base editing with a Cpf1–cytidine deaminase fusion. Nat. Biotechnol.36, 324–327 (2018). Gehrke, J. M. et al. An APOBEC3A-Cas9 base editor with minimized bystander and off-target activities. Nat. Biotechnol. (2018). doi:10.1038/nbt.4199. Rees, H. A. & Liu, D. R. Base editing: precision chemistry on the genome and transcriptome of living cells. Nat. Rev. Genet.1 (2018). doi:10.1038/s41576-018- 0059-1. [0007] Accordingly, in various aspects of the disclosure, the TnpB is fused to a deaminase suitable for base editing. In some embodiments, the deaminase is selected from an adenosine deaminase, E. coli tRNA adenosine, or TadA deaminase wherein TadA is engineered for higher efficiency in human cells in comparison to pWT TadA base editor. In certain embodiments, TadA is engineered through directed evolution. [0008] In certain other embodiments, the deaminase comprises a cytidine deaminase. Preferably, the cytidine deaminase is engineered for higher efficiency in human cells in comparison to wild type cytidine deaminase base editor. In further embodiments, the TnpB genome editing system contains one or more uracil glycosylase inhibitor. [0009] In yet other embodiments, the TnpB-deaminase fusions are linked using a polypeptide comprising glycine and serine residues or unstructured XTEN protein polymer. [0010] In further embodiments, the TnpB RuvC domain is mutated wherein the mutation slows cleavage of the target strand or slows the cleavage of the non-target strand. In other embodiments, the TnpB is mutated to be catalytically inactive. [0011] In certain preferred embodiments one or more deaminase is fused to a TnpB dimer. In certain embodiments, the deaminase is fused to the N-terminus of TnpB. In other embodiments, the deaminase is fused to the C-terminus of TnpB. In further embodiments, the deaminase is placed in various locations of the TnpB including without limitations: inside the Rec-domain of the TnpB, after the Rec- domain of the TnpB, in the Wedge domain of TnpB, after the Wedge domain of TnpB, in the RuvC domain of TnpB, after the RuvC domain of TnpB, in the Helical hairpin domain of TnpB, after the Helical hairpin domain of TnpB, in the ZnF domain of TnpB, after the Znf domain of TnpB. The present disclosure contemplates placement of the deaminase in and around or near or adjacent to the aforementioned domains. [0012] In certain alternative embodiments, the TnpB fusion protein is co-expressed with one or more TnpB not fused to a deaminase. In other embodiments, the unfused TnpB is mutated to be catalytically inactive. In other examples, the TnpB fusion contains one or more nuclear localization signals selected or derived from SV40, c-Myc or NLP-1. [0013] In other exemplary embodiments, the TnpB-deaminase fusions bind to a guide RNA or a reRNA. In instances where the TnpB system is fused to a polypeptide that modulates host-repair. In some examples, the polypeptide is a uracil glycosylase inhibitor. In other examples, the polypeptide inhibits mismatch repair wherein the MMR inhibiting polypeptide is a dominant negative MLH1. [0014] In various other aspects, one or more TnpB is fused to a reverse transcriptase suitable for prime editing. In some embodiments, the reverse transcriptase comprises M-MLV. In certain embodiments, the M-MLV is an engineered reverse transcriptase variant designed to improve processivity, efficiency, and/or fidelity. In various embodiments, the reverse transcriptase is derived from the human genome or derived from a human endogenous retrovirus. [00656] In one embodiment, the accessory function that is added or otherwise coupled or attached to a TnpB polypeptide (e.g., deaminase or reverse transcriptase) provides for a TnpB-based system that is capable of performing a specialized function or activity (e.g., base editing or prime editing). For example, the TnpB protein may be fused, operably coupled to, or otherwise associated with one or more heterologous functionals domains. In certain example embodiments, the TnpB protein may be a catalytically dead TnpB protein and/or have nickase activity. A nickase is an TnpB protein that cuts only one strand of a double stranded target. In such embodiments, the catalytically inactive TnpB or nickase provide a sequence specific targeting functionality via the coRNA that delivers the functional domain to or proximate a target sequence. [00657] It is also contemplated that the TnpB complex as a whole may be associated with two or more functional domains. For example, there may be two or more functional domains associated with the TnpB polypeptide, or there may be two or more functional domains associated with the reRNA component (via one or more adaptor proteins or aptamers), or there may be one or more functional domains associated with the TnpB polypeptide and one or more functional domains associated with the reRNA component. [00658] In one embodiment, one or more functional domains are associated with a TnpB polypeptide via an adaptor protein, for example as used with the modified guides of Konnerman et al. (Nature 517, 583-588, 29 January 2015). In one embodiment, the one or more functional domains is attached to the adaptor protein so that upon binding of the TnpB polypeptide to reRNA and target, the functional domain is in a spatial orientation allowing for the functional domain to function in its attributed function. [00659] Exemplary functional accessory domains that may be fused to, operably coupled to, or otherwise associated with an TnpB protein can be or include, but are not limited to a nuclear localization signal (NLS) domain, a nuclear export signal (NES) domain, a translational activation domain, a transcriptional activation domain (e.g. VP64, p65, MyoDl, HSF1, RTA, and SET7/9), a translation initiation domain, a transcriptional repression domain (e.g., a KRAB domain, NuE domain, NcoR domain, and a SID domain such as a SID4X domain), a nuclease domain (e.g., FokI), a histone modification domain (e.g., a histone acetyltransferase), a light inducible/controllable domain, a chemically inducible/controllable domain, a transposase domain, a homologous recombination machinery domain, a recombinase domain, a ligase domain, a topoisomerase domain, a deaminase domain, a polymerase domain (e.g., reverse transcriptase), an integrase domain, and combinations thereof. In an embodiment, the functional domain is an HNH domain, and may be used with a naturally catalytically inactive TnpB protein to engineer a nickase. Methods for generating catalytically dead TnpB or a nickase TnpB can be adapted from approaches in Cas9 proteins, see, for example, WO 2014/204725, Ran et al. Cell.2013 Sept 12; 154(6): 1380-1389, known in the art and incorporated herein by reference. Briefly, one or more mutations in the catalytic domain of the RuvC domain and/or the HNH domain of the TnpB protein can be introduced that may reduce or abolish NHEJ activity. In an aspect, at least one mutation in the RuvC domain and at least one mutation in the HNH domain is provided. In an embodiment, the TnpB polypeptide comprises a mutation at D191 and/or E278 based on amino acid sequence positions of Deinococcus radiodurans ISDra2. In an aspect, the amino acid mutations comprise D191A and/or E278A based on amino acid sequence positions of Deinococcus radiodurans ISDra2. [00660] In one embodiment, the functional domains can have one or more of the following activities: nucleobase deaminse activity, reverse transcriptase activity, retrotransposase activity, transposase activity, integrase activity, recombinase activity, topoisomerase activity, ligase activity, polymerase activity, helicase activity, methylase activity, demethylase activity, translation activation activity, translation initiation activity, translation repression activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, nuclease activity (e.g. VirD2), single-strand RNA cleavage activity, double-strand RNA cleavage activity, single-strand DNA cleavage activity, double-strand DNA cleavage activity, molecular switch activity, chemical inducibility, light inducibility, and nucleic acid binding activity. In one embodiment, the one or more functional domains may comprise epitope tags or reporters. Non- limiting examples of epitope tags include histidine (His) tags, V5 tags, FLAG tags, influenza hemagglutinin (HA) tags, Myc tags, VSV-G tags, and thioredoxin (Trx) tags. Examples of reporters include, but are not limited to, glutathione- S-transferase (GST), horseradish peroxidase (HRP), chloramphenicol acetyltransferase (CAT) betagalactosidase, beta-glucuronidase, luciferase, green fluorescent protein (GFP), HcRed, DsRed, cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and auto-fluorescent proteins including blue fluorescent protein (BFP). [00661] The one or more functional domain(s) may be positioned at, near, and/or in proximity to a terminus of the TnpB protein. In embodiments having two or more functional domains, each of the two can be positioned at or near or in proximity to a terminus of the TnpB protein. In one embodiment, such as those where the functional domain is operably coupled to the effector protein, the one or more functional domains can be tethered or linked via a suitable linker (including, but not limited to, GlySer linkers) to the TnpB protein. When there is more than one functional domain, the functional domains can be same or different. In one embodiment, all the functional domains are the same. In one embodiment, all of the functional domains are different from each other. In one embodiment, at least two of the functional domains are different from each other. In one embodiment, at least two of the functional domains are the same as each other. [00662] In additional embodiments, the TnpB-deaminase fusion protein is co-expressed with a TnpB not fused to a reverse transcriptase. Preferably, the unfused TnpB is mutated to be catalytically inactive, however, fused TnpB may also be mutated to be catalytically inactive, either or both. Various TnpB-RT fusion protein binds to a truncated reRNA or to a truncated guide RNA. In some embodiments, this maintains DNA binding activity but slows cleavage kinetics or deactivates DNA cleavage partially or entirely. Additional embodiments, include the reverse transcriptase fused to the N-terminus of TnpB or to the C-terminus of TnpB. In further embodiments, the reverse transcriptase is placed inside the Rec-domain of the TnpB, after the Rec-domain of the TnpB, in the Wedge domain of TnpB, after the Wedge domain of TnpB, in the RuvC domain of TnpB, after the RuvC domain of TnpB, in the Helical hairpin domain of TnpBafter the Helical hairpin domain of TnpB, in the ZnF domain of TnpB, after the Znf domain of TnpB. [00663] Preferably, the TnpB-RT fusion protein is bound to an engineered reRNA wherein the engineered reRNA contains a 5’ extension, the engineered reRNA contains a 3’ extension, the extensions contain a template for a desired edit, the extension contains homology to the target site, the extension contains homology to the human genome, the extension contains sequence encoding a landing-pad for a homing integrase and/or recombinase. In preferred embodiments, the TnpB-RT fusion protein is fused or cleaved. In certain embodiments, the TnpB-RT system is fused to a polypeptide that modulates host-repair, wherein the polypeptide is a uracil glycosylase inhibitor, wherein the polypeptide inhibits mismatch repair, wherein the MMR inhibiting polypeptide is a dominant negative MLH1. [00664] In various aspects of the disclosure, the TnpB fused to a transcriptional modulating polypeptide suitable for transcriptional interference, activation or epigenetic editing. [00665] In some embodiments, the TnpB-transcriptional modulating polypeptide fusions comprise one or more nuclear localization signals selected or derived from SV40, c-Myc or NLP-1. [00666] In other embodiments, the TnpB-transcriptional modulating polypeptide fusion proteins bind to a truncated guide RNA. In further embodiments, the TnpB-transcriptional modulating polypeptide comprises glycine and serine residues. In yet other embodiments, the TnpB- transcriptional modulating polypeptide are linked to one or more unstructured XTEN protein polymers. [00667] In various embodiments, the transcriptional modulating polypeptide of the TnpB- transcriptional modulating polypeptide fusion performs histone acetylation or comprises histone acetyltransferase (HAT) p300 activity. [00668] In other embodiments, the transcriptional modulating polypeptide of the TnpB- transcriptional modulating polypeptide fusion performs histone demethylation or comprises lysine- specific demethylase (LSD1) activity. [00669] In further embodiments, the transcriptional modulating polypeptide of the TnpB- transcriptional modulating polypeptide fusion performs cystine methylation or comprises one or more activities selected from DNA (cytosine-5)-methyltransferase (DNMT3A), DNA-methyltransferase 3- like (DNMT3L) and MQ1. [00670] In other embodiments, the transcriptional modulating polypeptide of the TnpB- transcriptional modulating polypeptide fusion performs cystine demethylation or comprises TET1 activity. [00671] In additional embodiments, the transcriptional modulating peptide of the TnpB- transcriptional modulating polypeptide fusion is a transcriptional repressor or comprises a KRAB domain. Alternatively, the transcriptional modulating peptide of the TnpB-transcriptional modulating polypeptide fusion is a transcriptional activator or comprises one or more activators including without limitation, for example, HS1, VP64 and p65. [00672] In other embodiments, Where the the transcriptional modulating peptide of the TnpB- transcriptional modulating polypeptide fusion is a repressor or comprises multiple transcriptional modulating peptides. In yet other embodiments, the TnpB of the TnpB-transcriptional modulating polypeptide fusion is mutated to be catalytically inactive. [00673] In further embodiments, the transcriptional modulating peptides of the TnpB- transcriptional modulating polypeptide fusion are physically coupled through an engineered reRNA wherein the reRNA comprises one or more aptamers. [00674] In additional embodiments, the transcriptional modulating peptides of the TnpB- transcriptional modulating polypeptide fusion are physically coupled through an engineered guide RNA, wherein the guide RNA contains one or more aptamers. reRNA [00675] The TnpB systems herein may further comprise one or more nucleic acid components, which are also referred to herein as reRNA. As reported in Karvelis et al., “Transposon- associated TnpB is a programmable RNA-guided DNA endonuclease,” Nature, November 25, 2021, Vol.599, pp.692-700 (incorporated herein by reference), TnpB is an RNA-guided dsDNA nuclease that forms a complex with a non-coding RNA called “reRNA.” The reRNA is a transcript that is generated from the transcription of the IS DNA sequence beginning at a transcription initiation site located within the 3’ end of the TnpB coding region and ending at a transcription termination site located in the flanking genomic DNA region that is immediately downstream of the RE of the Insertion Sequence. Thus, the reRNA comprises three regions: (a) a region corresponding to the 3’ end of the TnpB coding region, (b) a region corresponding to the RE, and (c) a region corresponding to the flanking genomic DNA immediately downstream of the 3’ end of the RE. Regions (a) and (b) generally form a folded scaffold that appears to bind to the TnpB protein. Region (c) functions as a spacer or targeting sequence which allows for the targeting of a TnpB-reRNA complex to a target site to which the region (c) has complementarity to and anneals. Region (c), in various embodiments, can be engineered to be any desired target sequence such that the TnpB-reRNA complex is targeted to a desired target sequence. [00676] Thus, the reRNA sequence may be predicted from the sequence of the region spanning the 3’ end of the TnpB coding region through a flanking region downstream of the RE. [00677] Computational methods can be used to predict the reRNA sequences for identified TnpB and TnpB-like proteins. As reported in Karvelis et al., “Transposon-associated TnpB is a programmable RNA-guided DNA endonuclease,” Nature, November 25, 2021, Vol.599, pp.692- 700, the TnpB protein co-purified with an RNA molecule of about 150 nucleotides long which had a sequence that was derived from the IS and a sequence downstream of the IS. [00678] In various embodiments, reRNA may be engineered to include RNA, DNA, or combinations of both and include modified and non-canonical nucleotides as described further below. The reRNA can comprise a reprogrammable spacer sequence and a scaffold that interacts with the TnpB polypeptide. reRNA may form a complex with a TnpB polypeptide, and direct sequence- specific binding of the complex to a target sequence of a target polynucleotide. In one example embodiment, the reRNA is a single molecule comprising a scaffold sequence and a spacer sequence. In certain example embodiments, the spacer is 5’ of the scaffold sequence. In one example embodiment, the reRNA may further comprise a conserved nucleic acid sequence between the scaffold and spacer portions. [00679] In embodiments, the reRNA comprises a spacer sequence and a scaffold sequence, e.g. a conserved nucleotide sequence. In embodiments, the reRNA comprises about 45 to about 350 nucleotides, or about 45, 46, 4748, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 17, 138, 19, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 11, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180.181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 2340, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 272, 273, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, or 350 nucleotides. [00680] In embodiments, the reRNA comprises a scaffold sequence, e.g. a conserved nucleotide sequence that binds to the TnpB protein. The scaffold sequence therefore typically comprises conserved regions, with the scaffold comprising about 30 to 200 nucleotides, about 50 to 180, about 80 to 175 nucleotides, or about 30, 31, 32, 33, 34, 35, 36, 37, 38, 3940, 41, 42, 43, 44, 45, 46, 4748, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180 or more nucleotides. [00681] The reRNA may further comprise a spacer, which can be re-programmed to direct site specific binding to a target sequence of a target polynucleotide. The spacer may also be referred to herein as part of the reRNA scaffold or reRNA, and may comprise an engineered heterologous sequence. [00682] In one embodiment, the spacer length or targeting sequence length of the reRNA is from 10 to 50 nt. In one embodiment, the spacer length of the oRNA is at least 10, 11, 12, 13, 14, or 15 nucleotides. In one embodiment, the spacer length is from 10 to 40 nuecleotides, from 15 to 30 nt, 15 to 17 nt, e.g., 15, 16, or 17 nt, from 17 to 20 nt, e.g., 17, 18, 19, or 20 nt, from 20 to 24 nt, e.g., 20, 21, 22, 23, or 24 nt, from 23 to 25 nt, e.g., 23, 24, or 25 nt, from 24 to 27 nt, e.g., 24, 25, 26, or 27 nt, from 27 to 30 nt, e.g., 27, 28, 29, or 30 nt, from 30 to 35 nt, e.g., 30, 31, 32, 33, 34, or 35 nt, or 35 nt or longer. In example embodiments, the spacer sequence is 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 3940, 41, 42, 43, 44, 45, 46, 4748, 49, or 50 nt. [00683] As used herein, the term “spacer” may also be referred to as a “guide sequence” or “targeting sequence” which has complementarity to a target sequence (e.g., a desired target gene in a genome which is desired to be edited). In one embodiment, the degree of complementarity of the spacer sequence to a given target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. In certain example embodiments, the reRNA molecule comprises a spacer sequence that may be designed to have at least one mismatch with the target sequence, such that a RNA duplex formed between the sequence and the target sequence. Accordingly, the degree of complementarity is less than 99%. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman- Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g., the Burrows Wheeler Aligner), ClustalW, Clustal X, BLAT, Novoalign (Novocraft Technologies), ELAND (Illumina, San Diego, CA), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). [00684] The ability of a sequence (within a nucleic acid-targeting reRNA molecule) to direct sequence-specific binding of a nucleic acid-targeting complex to a target nucleic acid sequence may be assessed by any suitable assay. For example, the components of a reRNA system sufficient to form a TnpB-targeting complex, including the reRNA molecule sequence to be tested, may be provided to a host cell having the corresponding target nucleic acid sequence, such as by transfection with vectors encoding the components of the TnpB-targeting complex, followed by an assessment of preferential targeting (e.g., cleavage) within the target nucleic acid sequence. Similarly, cleavage of a target nucleic acid sequence (or a sequence in the vicinity thereof) may be evaluated in a test tube by providing the target nucleic acid sequence, components of a TnpB-targeting complex, including the sequence to be tested and a control sequence different from the test coRNA, and comparing binding or rate of cleavage at or in the vicinity of the target sequence between the test and control reRNA molecule sequence reactions. Other assays are possible, and will occur to those skilled in the art. A spacer sequence, and hence a nucleic acid targeting reRNA may be selected to target any target nucleic acid sequence. reRNA modifications [00685] In one embodiment, the reRNA comprises non-naturally occurring nucleic acids and/or non-naturally occurring nucleotides and/or nucleotide analogs, and/or chemical modifications. Preferably, these non-naturally occurring nucleic acids and non-naturally occurring nucleotides are located outside the reRNA sequence. Non-naturally occurring nucleic acids can include, for example, mixtures of naturally and non-naturally occurring nucleotides. Non-naturally occurring nucleotides and/or nucleotide analogs may be modified at the ribose, phosphate, and/or base moiety. In an embodiment of the disclosure, a reRNA component nucleic acid comprises ribonucleotides and non- ribonucleotides. In one such embodiment, a reRNA component comprises one or more ribonucleotides and one or more deoxyribonucleotides. In an embodiment of the disclosure, the reRNA component comprises one or more non-naturally occurring nucleotide or nucleotide analog such as a nucleotide with phosphorothioate linkage, a locked nucleic acid (LNA) nucleotides comprising a methylene bridge between the 2' and 4' carbons of the ribose ring, or bridged nucleic acids (BNA). [00686] Other examples of modified nucleotides include 2'-O-methyl analogs, 2'-deoxy analogs, or 2'-fluoro analogs. Further examples of modified bases include, but are not limited to, 2- aminopurine, 5-bromo-uridine, pseudouridine, inosine, 7-methylguanosine. Examples of coRNA chemical modifications include, without limitation, incorporation of 2'-O-methyl (M), 2'-O-methyl 3 'phosphorothioate (MS), S-constrained ethyl(cEt), or 2'-O-methyl 3 'thioPACE (MSP) at one or more terminal nucleotides. Such chemically modified oRNA components can comprise increased stability and increased activity as compared to unmodified oRNA components, though on-target vs. off-target specificity is not predictable. (See, Hendel, 2015, Nat Biotechnol.33(9):985-9, doi: 10.1038/nbt.3290, published online 29 June 2015 Ragdarm et al., 0215, PNAS, E7110-E7111; Allerson et al., J. Med. Chem.2005, 48:901-904; Bramsen et al., Front. Genet., 2012, 3:154; Deng et al., PNAS, 2015, 112: 11870-11875; Sharma et al., MedChemComm., 2014, 5: 1454-1471; Hendel et al., Nat. Biotechnol. (2015) 33(9): 985-989; Li et al., Nature Biomedical Engineering, 2017, 1, 0066 D01: 10.1038/s41551- 017-0066). In one embodiment, the 5’ and/or 3’ end of a reRNA component is modified by a variety of functional moieties including fluorescent dyes, polyethylene glycol, cholesterol, proteins, or detection tags. (See Kelly et al., 2016, J. Biotech.233:74-83). In one embodiment, a reRNA component comprises ribonucleotides in a region that binds to a target sequence and one or more deoxyribonucletides and/or nucleotide analogs in a region that binds to the TnpB polypeptide. [00687] In an embodiment, deoxyribonucleotides and/or nucleotide analogs are incorporated in engineered reRNA component structures. In one embodiment, 3-5 nucleotides at either the 3’ or the 5’ end of a reRNA component is chemically modified. In one embodiment, only minor modifications are introduced in the seed region, such as 2’-F modifications. In one embodiment, 2’-F modification is introduced at the 3’ end of a reRNA component. In one embodiment, three to five nucleotides at the 5’ and/or the 3’ end of the reRNA component are chemically modified with 2’ -O-methyl (M), 2’-O- methyl 3’ phosphorothioate (MS), S-constrained ethyl(cEt), or 2’ -O-methyl 3’ thioPACE (MSP). Such modification can enhance genome editing efficiency (see Hendel et al., Nat. Biotechnol. (2015) 33(9): 985-989). In one embodiment, all of the phosphodiester bonds of a reRNA component are substituted with phosphorothioates (PS) for enhancing levels of gene disruption. In one embodiment, more than five nucleotides at the 5’ and/or the 3’ end of the reRNA component are chemically modified with 2’-0-Me, 2’-F or S-constrained ethyl(cEt). Such chemically modified reRNA component can mediate enhanced levels of gene disruption (see Ragdarm et al., 0215, PNAS, E7110- E7111). In an embodiment of the disclosure, a reRNA component is modified to comprise a chemical moiety at its 3’ and/or 5’ end. Such moieties include, but are not limited to amine, azide, alkyne, thio, dibenzocyclooctyne (DBCO), or Rhodamine. In certain embodiment, the chemical moiety is conjugated to the reRNA component by a linker, such as an alkyl chain. In one embodiment, the chemical moiety of the modified nucleic acid component can be used to attach the reRNA component to another molecule, such as DNA, RNA, protein, or nanoparticles. Such chemically modified reRNA component can be used to identify or enrich cells generically edited by a TnpB polypeptide and related systems (see Lee et al., eLife, 2017, 6:e25312, DOI: 10.7554). [00688] Other reRNA modifications are described in Kim, D.Y., Lee, J.M., Moon, S.B. et al. Efficient CRISPR editing with a hypercompact Cas12f1 and engineered guide RNAs delivered by adeno-associated virus. Nat Biotechnol 40, 94–102 (2022). [0015] Accordingly, in various aspects of the disclosure, the reRNA are modified in one or more TnpB reRNA. MS1, an internal penta(uridinylate) (UUUUU) sequence in the tracrRNA; MS2, the 3′ terminus of the crRNA; MS3, the ‘stem 1’ region of the tracrRNA; MS4, the tracrRNA–crRNA complementary region; and MS5, the ‘stem 2’ region of the tracrRNA. [00689] Various aspects of the disclosure provide methods and compositions for improved reRNA stability via chemical modifications. Braasch, D. A., Jensen, S., Liu, Y., Kaur, K., Arar, K., White, M. A., et al. (2003). RNA interference in mammalian cells by chemically-modified RNA. Biochemistry 42, 7967–7975. Chiu, Y. L., and Rana, T. M. (2003). siRNA function in RNAi: a chemical modification analysis. RNA 9, 1034–1048. Behlke, M. A. (2008). Chemical modification of siRNAs for in vivo use. Oligonucleotides18, 305–319. Bennett, C. F., and Swayze, E. E. (2010). RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol.50, 259–293. Deleavey, G. F., and Damha, M. J. (2012). Designing chemically modified oligonucleotides for targeted gene silencing. Chem. Biol.19, 937– 954. Lennox, K. A., and Behlke, M. A. (2020). Chemical modifications in RNA interference and CRISPR/Cas genome editing reagents. Methods Mol. Biol.2115, 23–55. [00690] For instance, Hendel et al. improved guideRNA stability by chemically modifying gRNA ends to reduce degradation by exonucleases, RNA nuclease. Hendel, A., Bak, R. O., Clark, J. T., Kennedy, A. B., Ryan, D. E., Roy, S., et al. (2015a). Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat. Biotechnol.33, 985–989. Chemical modifications of gRNAs may enable more efficient and safer gene-editing in primary cells suitable for clinical applications. [00691] A review of types of chemical modifications are provided in the table below. Allen, Daniel et al. “Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells.” Frontiers in genome editing vol.2617910.28 Jan.2021. * additionally validated in vivo; # additionally validated in human primary cells 2’-O-methyl (M or 2’-O-Me); 2’-O-methyl 3’phosphorothioate (MS); 2’-O-methyl-3’-thioPACE (MSP); S-constrained ethyl (cET); 2’-fluoro (2’-F); phosphorothioate (PS) [00692] Accordingly, in various embodiments of the present disclosure, the genome editing system comprising TnpB and further comprises one or more chemical modifications selected from, but not limited to the modifications in the above table. [00693] In exemplary embodiments, chemical modifications to the reRNA include modifications on the ribose rings and phosphate backbone of reRNAs and modifications at the 2′OH include 2′-O-Me, 2′-F, and 2′F-ANA. More extensive ribose modifications include 2′F-4′-Cα-OMe and 2′,4′-di-Cα-OMe combine modification at both the 2′ and 4′ carbons. Phosphodiester modifications include sulfide-based Phosphorothioate (PS) or acetate-based phosphonoacetate alterations. Combinations of the ribose and phosphodiester modifications have given way to formulations such as 2′-O-methyl 3′phosphorothioate (MS), or 2′-O-methyl-3′-thioPACE (MSP), and 2′-O-methyl-3′-phosphonoacetate (MP) RNAs. Locked and unlocked nucleotides such as locked nucleic acid (LNA), bridged nucleic acids (BNA), S-constrained ethyl (cEt), and unlocked nucleic acid (UNA) are examples of sterically hindered nucleotide modifications. Modifications to make a phosphodiester bond between the 2′ and 5′ carbons (2′,5′-RNA) of adjacent RNAs as well as a butane 4-carbon chain link between adjacent RNAs have been described. [00694] Any of the above TnpB editor embodiments or variants, modifications, or derivatives thereof are contemplated herein to be delivered by the LNP systems disclosed in this specification for gene editing in cells, tissues, and/or organs under in vitro, ex vivo, or in vivo conditions. The various components described herein may be configured and delivered in any suitable manner. Any of the descriptions presented in this section are not intended to be strictly limiting. Integrase editors (e.g., PASTE) [00695] In some embodiments, the gene editing system comprises one or more integrase editors. In certain embodiments, the gene editing system comprises a construct enabling programmable addition via site-specific targeting elements (PASTE). In certain embodiments, the gene editing system comprises one or more integrase editors and/or gene editing systems described and disclosed in PCT Publications WO2022087235A1, WO2020191245A1, WO2022060749A1, WO2021188840A1, WO2021138469A1, US Patent Application Publications US20140349400A1, US20210222164A1 or US20150071898A1, each of which is incorporated by reference herein in their entirety. In certain embodiments, the one or more integrase editors comprise CRISPR directed integrases disclosed in Yarnall, M.T.N., Ioannidi, E.I., Schmitt-Ulms, C. et al. Drag-and-drop genome insertion of large sequences without double-strand DNA cleavage using CRISPR-directed integrases. Nat Biotechnol (2022). Epigenetic editors In still other embodiments, the LNPs may be used to deliver an epigenetic editing system. Epigenetic editors are generally composed of an epigenetic enzyme or their catalytic domain fused with a user- programmable DNA-binding protein, such as a CRISPR-Cas enzyme or TnpB enzyme. The user- programmable DNA-binding protein (plus a guide RNA in the case of a nucleic acid programmable DNA binding protein) guides the epigenetic enzyme (e.g., a DNA methyltransferase or DNMT) to a specific site (e.g., a CpG island in a promoter region of a gene) in order to induce a change in promoter activity. [00696] Epigenetic modifications of DNA and histones are known for their multifaceted contributions to transcriptional regulation. As these modifications are faithfully propagated throughout DNA replication, they are considered central players in cellular memory of transcriptional states. Many efforts in the last decade have generated a vast understanding of individual epigenetic modifications and their contribution to transcriptional regulation. Epigenetic editing offers powerful tools to selectively induce epigenetic changes in a genome without altering the sequence of a nucleotide sequence as a means to regulate gene activity. The foundation of epigenetic editing is formed by the ability to generate fusion proteins of epigenetic enzymes or their catalytic domains with programmable DNA-binding platforms such as the clustered regularly interspaced short palindromic repeat (e.g., CRISPR Cas9 or Cas12a) to target these to an endogenous locus of choice. The enzymatic fusion protein then dictates the initial deposited modification while subsequent cross-talk within the local chromatin environment likely influences epigenetic and transcriptional output. [00697] The following published literature discussing epigenetic editing is incorporated herein by reference each in their entireties. Gjaltema RAF, Rots MG. Advances of epigenetic editing. Curr Opin Chem Biol.2020 Aug;57:75-81. Epub 2020 Jun 30. PMID: 32619853. Kleinstiver BP, Sousa AA, Walton RT, Tak YE, Hsu JY, Clement K, Welch MM, Horng JE, Malagon-Lopez J, Scarfò I, Maus MV, Pinello L, Aryee MJ, Joung JK. Engineered CRISPR-Cas12a variants with increased activities and improved targeting ranges for gene, epigenetic and base editing. Nat Biotechnol.2019 Mar;37(3):276-282. Epub 2019 Feb 11. Erratum in: Nat Biotechnol.2020 Jul;38(7):901. PMID: 30742127; PMCID: PMC6401248. Rots MG, Jeltsch A. Editing the Epigenome: Overview, Open Questions, and Directions of Future Development. Methods Mol Biol.2018;1767:3-18. PMID: 29524127. Liu XS, Jaenisch R. Editing the Epigenome to Tackle Brain Disorders. Trends Neurosci.2019 Dec;42(12):861-870. Epub 2019 Nov 7. PMID: 31706628. Waryah CB, Moses C, Arooj M, Blancafort P. Zinc Fingers, TALEs, and CRISPR Systems: A Comparison of Tools for Epigenome Editing. Methods Mol Biol.2018;1767:19-63. PMID: 29524128. Xu X, Hulshoff MS, Tan X, Zeisberg M, Zeisberg EM. CRISPR/Cas Derivatives as Novel Gene Modulating Tools: Possibilities and In Vivo Applications. Int J Mol Sci.2020 Apr 25;21(9):3038. PMID: 32344896; PMCID: PMC7246536. [00698] In addition, the following published patent literature relating to epigenetic editing is incorporated herein by reference each in their entireties.

Gene writing [00699] In some embodiments, the gene editing system is a gene writing system. In certain embodiments, the gene editing system is one described and disclosed in US Patent Application Publications US2022039681A1 or US20200109398A1, each of which is incorporated by reference herein in their entirety. [00700] In certain embodiments, the gene editing system is a system for modifying DNA comprising a polypeptide or a nucleic acid encoding a polypeptide capable of target primed reverse transcription, wherein the polypeptide comprises (a) a reverse transcriptase domain and (b) an endonuclease domain, wherein at least one of (a) or (b) is heterologous; and a template RNA comprising (i) a sequence that binds the polypeptide and (ii) a heterologous object sequence. In certain embodiments, the gene editing system is a system for modifying DNA comprising a polypeptide or a nucleic acid encoding a polypeptide capable of target primed reverse transcription, wherein the polypeptide comprises (a) a target DNA binding domain, (b) a reverse transcriptase domain and (c) an endonuclease domain, wherein at least one of (a), (b) or (c) is heterologous, and a template RNA comprising (i) a sequence that binds the polypeptide and (ii) a heterologous object sequence. In certain embodiments, the polypeptide comprises a sequence of at least 50 amino acids having at least 80% identity to a reverse transcriptase domain of a sequence of a polypeptide listed in TABLE 1, TABLE 2, or TABLE 3 of US Patent Application Publication US20200109398A1, which is incorporated by reference in its entirety, including the aforementioned sequence tables. [00701] In certain embodiments, the reverse transcriptase domain is from a retrovirus or a retrotransposon, such as a LTR-retrotransposon, or a non-LTR retrotransposon. In certain embodiments, the reverse transcriptase is from a non-LTR retrotransposon, wherein the non-LTR retrotransposon is a RLE-type non-LTR retrotransposon from the R2, NeSL, HERO, R4, or CRE clade, or an APE-type non-LTR retrotransposon from the R1, or Tx1 clade. In certain embodiments, the reverse transcriptase domain is from an avian retrotransposase of column 8 of Table 3 of US20200109398A1, or a sequence having at least 70%, identity thereto. In certain embodiments, the reverse transcriptase domain does not comprise an RNA binding domain and the polypeptide comprises an RNA binding domain heterologous to the reverse transcriptase domain, wherein the RNA binding domain is a B-box protein, a MS2 coat protein, a dCas protein, or a UTR binding protein, or a fragment or variant of any of the foregoing. [00702] In certain embodiments, the endonuclease domain is heterologous to the reverse transcriptase domain, and wherein the endonuclease is a Fok1 nuclease (or a functional fragment thereof), a type-II restriction 1-like endonuclease (RLE-type nuclease), another RLE-type endonuclease, or a Prp8 nuclease. In certain embodiments, the endonuclease domain is heterologous to the reverse transcriptase domain, wherein endonuclease domain contains DNA binding functionality. In certain embodiments, the endonuclease domain is heterologous to the reverse transcriptase domain, and wherein the endonuclease has nickase activity and does not form double stranded breaks. [00703] In certain embodiments, the polypeptide comprises a DNA binding domain heterologous to the reverse transcriptase domain, and wherein the DNA binding domain is: a zinc- finger element, or a functional fragment thereof; or a TAL effector element, or a functional fragment thereof; a Myb domain; or a sequence-guided DNA binding element. In certain embodiments, the polypeptide comprises a DNA binding domain heterologous to the reverse transcriptase domain, and wherein the DNA binding element is a sequence-guided DNA binding element, further wherein the sequence-guided DNA binding element is Cas9, Cpf1, or other CRISPR-related protein. In certain embodiments, the polypeptide comprises a DNA binding domain heterologous to the reverse transcriptase domain, and wherein the DNA binding domain is a transcription factor. [00704] In certain embodiments, the sequence-guided DNA binding element has been altered to have no endonuclease activity. In certain embodiments, the sequence-guided DNA binding element replaces the endonuclease element of the polypeptide. In certain embodiments, the editing system is capable of modifying DNA using reverse transcriptase activity, optionally in the absence of homologous recombination activity. [00705] In certain embodiments, the gene editing system is a system for modifying DNA comprising: a) a recombinase polypeptide selected from Rec27 (WP_021170377.1, SEQ ID NO: 1241 of US20220396813A1), Rec35 (WP_134161939.1, SEQ ID NO: 1249 of US20220396813A1), or comprising an amino acid sequence of Table 1 or 2 of US20220396813A1, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a nucleic acid encoding the recombinase polypeptide; and b) a double-stranded insert DNA comprising: (i) a DNA recognition sequence that binds to the recombinase polypeptide of (a), said DNA recognition sequence having a first parapalindromic sequence and a second parapalindromic sequence, wherein each parapalindromic sequence is about 10-30, 12-27, or 10-15 nucleotides, e.g., about 13 nucleotides, and the first and second parapalindromic sequences together comprise the parapalindromic region of a nucleotide sequence of Table 1 of US20220396813A1, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, or having no more than 1, 2, 3, 4, 5, 6, 7, 8 sequence alterations (e.g., substitutions, insertions, or deletions) relative thereto, and said DNA recognition sequence further comprises a core sequence of about 5-10 nucleotides, e.g., about 8 nucleotides, wherein the core sequence is situated between the first and second parapalindromic sequences, and (ii) a heterologous object sequence. Gene inactivating systems [00706] In some embodiments, the gene editing system comprises a polypeptide or an RNA encoding a polypeptide capable of inducing a double-stranded or single-stranded break in a desired gene, thereby inactivating said gene. In certain embodiments, the gene editing system is one described and disclosed in PCT Publications WO2020028327A1, WO2020069296A1 or WO2020118041A1, each of which is incorporated by reference herein in their entirety. In certain embodiments, the gene editing system is one described and disclosed in a patent application publication disclosed below, each of which is incorporated by reference herein in their entirety: Compositions that increase gene editing efficiency [00707] In some embodiments, the gene editing system comprises a polypeptide, or a nucleic acid that encodes a polypeptide, that increases gene editing efficiency. In some embodiments, the gene editing system comprises a composition described and disclosed in US Application Publication US20220090064A1, which is incorporated by reference herein in its entirety. In some embodiments, the composition comprises a guide nucleic acid, a Cas9 nickase, and/or a reverse transcriptase. The reverse transcriptase may be fused to the Cas9 nickase. The reverse transcriptase may heterodimerize with the Cas9 nickase. The reverse transcriptase may bind to a guide nucleic acid. The reverse transcriptase may be engineered to increase processivity. The guide nucleic acid may be engineered to facilitate synthesis or editing of a sequence. The guide nucleic acid may comprise a region that binds to another region on the guide nucleic acid to improve gene editing. [00708] In some embodiments, the composition comprises a Cas 9 nickase and a reverse transcriptase, or one or two polynucleotides encoding the Cas 9 nickase and reverse transcriptase, wherein: (i) the composition comprises a first polypeptide chain comprising the Cas nickase or a segment of the Cas nickase, and a second polypeptide chain comprising the reverse transcriptase, or the one or two polynucleotides encoding the polypeptide chains, wherein the polypeptide chains comprise leucine zippers that bind one another, or (ii) the composition comprises a first polypeptide chain comprising a first segment of the Cas nickase, and a second polypeptide chain comprising a second segment of the Cas nickase and the reverse transcriptase, or the one or two polynucleotides encoding the polypeptide chains, wherein the polypeptide chains comprise inteins that bind one another, the Cas nickase comprises an amino acid sequence at least 80% identical to SEQ ID NO: 32 of US20220090064A1, the first and second polypeptide chains respectively comprise amino acids 1-1124 and 1125-1368 of the Cas nickase, 1- 1129 and 1130-1368 of the Cas nickase, 1-1139 and 1140-1368 of the Cas nickase, 1-1167 and 1168- 1368 of the Cas nickase, 1-1172 and 1173-1368 of the Cas nickase, or 1-1202 and 1203-1368 of the Cas nickase, and the Cas nickase comprises a mutation at amino acid position 1030 or after amino acid position 1030 with regard to SEQ ID NO: 32 of US20220090064A1, the mutation comprising a point mutation to a cysteine, threonine, alanine, or serine, or an insertion of a cysteine, threonine, alanine, or serine at the C-terminal half of the Cas9 nickase or (iii) the reverse transcriptase comprises a Moloney leukemia virus reverse transcriptase (mlvRT) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 13 of US20220090064A1 or at least 80% identical to a functional fragment thereof comprising at least 400 amino acids, and a point mutation at amino acid position Q84, L139, Q221, V223, T664, or L671 with regard to SEQ ID NO: 13 of US20220090064A1; wherein the respective SEQ ID NOs are those disclosed in US Application Publication US20220090064A1. [00709] In certain embodiments, the composition comprises a guide nucleic acid comprising: optionally, a spacer reverse complementary to a first region of a target nucleic acid, wherein the spacer is included in the guide nucleic acid, or the spacer is included in a second, different guide nucleic acid when not included in the guide nucleic acid; a scaffold configured to bind to a Cas nuclease; a reverse transcriptase template encoding a sequence to be reverse transcribed into a first synthesized strand to be inserted into the target nucleic acid; a first strand primer binding site reverse complementary to a second region of the target nucleic acid; and at least one of: (i) a guide nucleic acid positioning system (GPS) region and a GPS binding site that hybridizes to the GPS region, wherein the GPS region and the GPS binding site are at least 10 nucleotides in length and are at least 60% reverse complementary to each other, and wherein hybridization of the GPS region and the GPS binding site positions the first strand primer binding site closer to the second region of the target nucleic acid, (ii) a GPS region that hybridizes to a GPS binding site on the second guide nucleic acid, wherein the GPS region and the GPS binding site are at least 10 nucleotides in length and are at least 60% reverse complementary to each other, wherein the second region of the target nucleic acid does not include any part of the first region of the target nucleic acid, and wherein the second region of the target nucleic acid does not include any part of a reverse complement of the first region of the target nucleic acid, and wherein hybridization of the GPS region and the GPS binding site positions the first strand primer binding site closer to the second region of the target nucleic acid, or (iii) a modification in the reverse transcriptase template that disrupts a track of at least 4 consecutive nucleotides of the same base in the target nucleic acid. Zinc finger nucleases, TALENS, and meganucleases [00710] In some embodiments, the gene editing systems contemplated herein may comprise user-programmable DNA binding proteins that bind DNA through a specific amino acid sequence (i.e., are not reliant upon a guide RNA or nucleic acid programmability). Such enzymes include zinc finger nucleases and TALENS. [00711] In some embodiments, the user-programmable nuclease is or comprises a TALE Nuclease, a TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, meganuclease, or a combination thereof. In some embodiments, the non-CRISPR/Cas sequence-specific nuclease is or includes two, three, four, or more of an independently selected TALE Nuclease, TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, Meganuclease, restriction enzymes or a combination thereof. In some embodiments, the combination is or comprises a TALE Nuclease/a ZF Nuclease; a TALE Nickase/a ZF nickase. TALENs [00712] In some embodiments, the non-CRISPR/Cas sequence-specific nuclease is or comprises a TALE Nuclease (Transcription Activator-Like Effector Nucleases (TALEN)). TALENs are restriction enzymes engineered to cut specific target DNA sequences. TALENs comprise a TAL effector (TALE) DNA-binding domain (which binds at or close to the target DNA), fused to a DNA cleavage domain which cuts target DNA. TALEs are engineered to bind to practically any desired DNA sequence. Thus in some embodiments, the TALEN comprises an N-terminal capping region, a DNA binding domain which may comprise at least one or more TALE monomers or half-monomers specifically ordered to target the genomic locus of interest, and a C-terminal capping region, wherein these three parts are arranged in a predetermined N-terminus to C-terminus orientation. Optionally, the TALEN includes at least one or more regulatory or functional protein domains. [00713] In some embodiments, the TALE monomers or half monomers may be variant TALE monomers derived from natural or wild type TALE monomers but with altered amino acids at positions usually highly conserved in nature, and in particular have a combination of amino acids as RVDs that do not occur in nature, and which may recognize a nucleotide with a higher activity, specificity, and/or affinity than a naturally occurring RVD. The variants may include deletions, insertions and substitutions at the amino acid level, and transversions, transitions and inversions at the nucleic acid level at one or more locations. The variants may also include truncations. [00714] In some embodiments, the TALE monomer / half monomer variants include homologous and functional derivatives of the parent molecules. In some embodiments, the variants are encoded by polynucleotides capable of hybridizing under high stringency conditions to the parent molecule-encoding wild-type nucleotide sequences. [00715] In some embodiments, the DNA binding domain of the TALE has at least 5 of more TALE monomers and at least one or more half-monomers specifically ordered or arranged to target a genomic locus of interest. The construction and generation of TALEs or polypeptides of the disclosure may involve any of the methods known in the art. [00716] Naturally occurring TALEs or “wild type TALEs” are nucleic acid binding proteins secreted by numerous species of proteobacteria. TALEs contain a nucleic acid binding domain composed of tandem repeats of highly conserved monomer polypeptides that are predominantly 33, 34 or 35 amino acids in length and that differ from each other mainly in amino acid positions 12 and 13. A general representation of a TALE monomer which is comprised within the DNA binding domain is Xl-11-(X12X13)-X14-33 or 34 or 35, where the subscript indicates the amino acid position and X represents any amino acid. X12X13 indicate the RVDs. In some polypeptide monomers, the variable amino acid at position 13 is missing or absent and in such monomers, the RVD consists of a single amino acid. In such cases the RVD may be alternatively represented as X*, where X represents X12 and (*) indicates that X13 is absent. The DNA binding domain may comprise several repeats of TALE monomers and this may be represented as (Xl-11-(X12X13)-X14-33 or 34 or 35)z, where z is optionally at least 5-40, such as 10-26. [00717] The TALE monomers have a nucleotide binding affinity that is determined by the identity of the amino acids in its RVD. Polypeptide monomers with an RVD of NI preferentially bind to adenine (A), monomers with an RVD of NG preferentially bind to thymine (T), monomers with an RVD of HD preferentially bind to cytosine (C), monomers with an RVD of NN preferentially bind to both adenine (A) and guanine (G), monomers with an RVD of IG preferentially bind to T, monomers with an RVD of NS recognize all four base pairs and may bind to A, T, G or C. Thus, the number and order of the polypeptide monomer repeats in the nucleic acid binding domain of a TALE determines its nucleic acid target specificity. The structure and function of TALEs is further described in, for example, Moscou et al., Science 326:1501 (2009); Boch et al., Science 326:1509-1512 (2009); and Zhang et al., Nature Biotechnology 29:149-153 (2011), each of which is incorporated by reference in its entirety. [00718] In some embodiments, the TALE is a dTALE (or designerTALE), see Zhang et al., Nature Biotechnology 29:149-153 (2011), incorporated herein by reference. [00719] In some embodiments, the TALE monomer comprises an RVD of HN or NH that preferentially binds to guanine, and the TALEs have high binding specificity for guanine containing target nucleic acid sequences. In come embodiments, polypeptide monomers having RVDs RN, NN, NK, SN, NH, KN, HN, NQ, HH, RG, KH, RH and SS preferentially bind to guanine. In some embodiments, polypeptide monomers having RVDs RN, NK, NQ, HH, KH, RH, SS and SN preferentially bind to guanine. In some embodiments, polypeptide monomers having RVDs HH, KH, NH, NK, NQ, RH, RN and SS preferentially bind to guanine. In some embodiments, the RVDs that have high binding specificity for guanine are RN, NH RH and KH. In some embodiments, polypeptide monomers having an RVD of NV preferentially bind to adenine and guanine as do monomers having the RVD HN. Monomers having an RVD of NC preferentially bind to adenine, guanine and cytosine, and monomers having an RVD of S (or S*), bind to adenine, guanine, cytosine and thymine with comparable affinity. In more embodiments, monomers having RVDs of H*, HA, KA, N*, NA, NC, NS, RA, and S* bind to adenine, guanine, cytosine and thymine with comparable affinity. Such polypeptide monomers allow for the generation of degenerative TALEs able to bind to a repertoire of related, but not identical, target nucleic acid sequences. [00720] In certain embodiments, the TALE polypeptide has a nucleic acid binding domain containing polypeptide monomers arranged in a predetermined N-terminus to C-terminus order such that each polypeptide monomer binds to a nucleotide of a predetermined target nucleic acid sequence, and where at least one of the polypeptide monomers has an RVD of HN or NH and preferentially binds to guanine, an RVD of NV and preferentially binds to adenine and guanine, an RVD of NC and preferentially binds to adenine, guanine and cytosine or an RVD of S and binds to adenine, guanine, cytosine and thymine. [00721] In some embodiments, each polypeptide monomer of the nucleic acid binding domain that binds to adenine has an RVD of NI, NN, NV, NC or S. [00722] In certain embodiments, each polypeptide monomer of the nucleic acid binding domain that binds to guanine has an RVD of HN, NH, NN, NV, NC or S. [00723] In certain embodiments, each polypeptide monomer of the nucleic acid binding domain that binds to cytosine has an RVD of HD, NC or S. [00724] In some embodiments, each polypeptide monomer that binds to thymine has an RVD of NG or S. [00725] In some embodiments, each polypeptide monomer of the nucleic acid binding domain that binds to adenine has an RVD of NI. [00726] In certain embodiments, each polypeptide monomer of the nucleic acid binding domain that binds to guanine has an RVD of HN or NH. [00727] In certain embodiments, each polypeptide monomer of the nucleic acid binding domain that binds to cytosine has an RVD of HD. [00728] In some embodiments, each polypeptide monomer that binds to thymine has an RVD of NG. [00729] In certain embodiments, the RVDs that have a specificity for adenine are NI, RI, KI, HI, and SI. [00730] In certain embodiments, the RVDs that have a specificity for adenine are HN, SI and RI, most preferably the RVD for adenine specificity is SI. [00731] In certain embodiments, the RVDs that have a specificity for thymine are NG, HG, RG and KG. [00732] In certain embodiments, the RVDs that have a specificity for thymine are KG, HG and RG, most preferably the RVD for thymine specificity is KG or RG. [00733] In certain embodiments, the RVDs that have a specificity for cytosine are HD, ND, KD, RD, HH, YG and SD. [00734] In certain embodiments, the RVDs that have a specificity for cytosine are SD and RD. [00735] FIG.4B of WO 2012/067428 provides representative RVDs and the nucleotides they target, the entire content of which is hereby incorporated herein by reference. [00736] In certain embodiments, the variant TALE monomers may comprise any of the RVDs that exhibit specificity for a nucleotide as depicted in FIG.4A of WO2012/067428. All such TALE monomers allow for the generation of degenerative TALEs able to bind to a repertoire of related, but not identical, target nucleic acid sequences. [00737] In certain embodiments, the RVD SH may have a specificity for G, the RVD IS may have a specificity for A, and the RVD IG may have a specificity for T. [00738] In certain embodiments, the RVD NT may bind to G and A. In certain embodiments, the RVD NP may bind to A, T and C. In certain embodiments, at least one selected RVD may be NI, HD, NG, NN, KN, RN, NH, NQ, SS, SN, NK, KH, RH, HH, KI, HI, RI, SI, KG, HG, RG, SD, ND, KD, RD, YG, HN, NV, NS, HA, S*, N*, KA, H*, RA, NA or NC. [00739] The predetermined N-terminal to C-terminal order of the one or more polypeptide monomers of the nucleic acid or DNA binding domain determines the corresponding predetermined target nucleic acid sequence to which the TALE or polypeptides of the disclosure may bind. [00740] As used herein the monomers and at least one or more half monomers are “specifically ordered to target” the genomic locus or gene of interest. In plant genomes, the natural TALE-binding sites always begin with a thymine (T), which may be specified by a cryptic signal within the non-repetitive N-terminus of the TALE polypeptide; in some cases this region may be referred to as repeat 0. In animal genomes, TALE binding sites do not necessarily have to begin with a thymine (T) and polypeptides of the disclosure may target DNA sequences that begin with T, A, G or C. The tandem repeat of TALE monomers always ends with a half-length repeat or a stretch of sequence that may share identity with only the first 20 amino acids of a repetitive full length TALE monomer and this half repeat may be referred to as a half-monomer (FIG.8 of WO 2012/067428). Therefore, it follows that the length of the nucleic acid or DNA being targeted is equal to the number of full monomers plus two (see FIG.44 of WO 2012/067428). [00741] In certain embodiments, nucleic acid binding domains are engineered to contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more polypeptide monomers arranged in a N-terminal to C-terminal direction to bind to a predetermined 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 nucleotide length nucleic acid sequence. [00742] In certain embodiments, nucleic acid binding domains are engineered to contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or more full length polypeptide monomers that are specifically ordered or arranged to target nucleic acid sequences of length 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 nucleotides, respectively. In certain embodiments, the polypeptide monomers are contiguous. In some embodiments, half- monomers may be used in the place of one or more monomers, particularly if they are present at the C-terminus of the TALE. [00743] Polypeptide monomers are generally 33, 34 or 35 amino acids in length. With the exception of the RVD, the amino acid sequences of polypeptide monomers are highly conserved or as described herein, the amino acids in a polypeptide monomer, with the exception of the RVD, exhibit patterns that effect TALE activity, the identification of which may be used in preferred embodiments of the disclosure. [00744] In certain embodiments, when the DNA binding domain may comprise (Xl-11- X12X13-X14-33 or 34 or 35)z, wherein Xl-11 is a chain of 11 contiguous amino acids, wherein X12X13 is a repeat variable di-residue (RVD), wherein X14-33 or 34 or 35 is a chain of 21, 22 or 23 contiguous amino acids, wherein z is at least 5 to 26, then the preferred combinations of amino acids are LTLD or LTLA or LTQV at Xl-4, or EQHG or RDHG at positions X30-33 or X31-34 or X32-35. Furthermore, other amino acid combinations of interest in the monomers are LTPD at Xl-4 and NQALE at XI 6-20 and DHG at X32-34 when the monomer is 34 amino acids in length. When the monomer is 33 or 35 amino acids long, then the corresponding shift occurs in the positions of the contiguous amino acids NQALE and DHG. In certain embodiments, NQALE is at X15-19 or X17-21 and DHG is at X31-33 or X33-35. [00745] In certain embodiments, amino acid combinations of interest in the monomers, are LTPD at Xl-4 and KRALE at X16-20 and AHG at X32-34 or LTPE at Xl-4 and KRALE at XI 6-20 and DHG at X32-34 when the monomer is 34 amino acids in length. When the monomer is 33 or 35 amino acids long, the corresponding shift occurs in the positions of the contiguous amino acids KRALE, AHG and DHG. In certain embodiments, the positions of the contiguous amino acids may be (LTPD at Xl-4 and KRALE at X15-19 and AHG at X31-33) or (LTPE at Xl-4 and KRALE at X15- 19 and DHG at X31-33) or (LTPD at Xl-4 and KRALE at X17-21 and AHG at X33-35) or (LTPE at Xl-4 and KRALE at X17-21 and DHG at X33-35). [00746] In certain embodiments, contiguous amino acids [NGKQALE] are present at positions X14-20 or X13-19 or X15-21. These representative positions put forward various embodiments of the disclosure and provide guidance to identify additional amino acids of interest or combinations of amino acids of interest in all the TALE monomers (see FIGs.24A-24F, and 25 of WO 2012/067428). [00747] As used herein the predetermined “N-terminus” to “C terminus” orientation of the N- terminal capping region, the DNA binding domain comprising the repeat TALE monomers and the C- terminal capping region provide structural basis for the organization of different domains in the d- TALEs or polypeptides of the disclosure. [00748] The entire N-terminal and/or C-terminal capping regions are not necessary to enhance the binding activity of the DNA binding region. Therefore, in certain embodiments, fragments of the N-terminal and/or C-terminal capping regions are included in the TALE polypeptides described herein. [00749] In certain embodiments, the TALE (including TALEs) polypeptides described herein contain a N-terminal capping region fragment that included at least 10, 20, 30, 40, 50, 54, 60, 70, 80, 87, 90, 94, 100, 102, 110, 117, 120, 130, 140, 147, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260 or 270 amino acids of an N-terminal capping region. In certain embodiments, the N-terminal capping region fragment amino acids are of the C-terminus (the DNA-binding region proximal end) of an N-terminal capping region. N-terminal capping region fragments that include the C-terminal 240 amino acids enhance binding activity equal to the full length capping region, while fragments that include the C-terminal 147 amino acids retain greater than 80% of the efficacy of the full length capping region, and fragments that include the C-terminal 117 amino acids retain greater than 50% of the activity of the full-length capping region. [00750] In some embodiments, the TALE polypeptides described herein contain a C-terminal capping region fragment that included at least 6, 10, 20, 30, 37, 40, 50, 60, 68, 70, 80, 90, 100, 110, 120, 127, 130, 140, 150, 155, 160, 170, 180 amino acids of a C-terminal capping region. In certain embodiments, the C-terminal capping region fragment amino acids are of the N-terminus (the DNA- binding region proximal end) of a C-terminal capping region. In certain embodiments, C-terminal capping region fragments that include the C-terminal 68 amino acids enhance binding activity equal to the full length capping region, while fragments that include the C-terminal 20 amino acids retain greater than 50% of the efficacy of the full length capping region. [00751] In certain embodiments, the capping regions of the TALE polypeptides described herein do not need to have identical sequences to the capping region sequences provided herein. Thus, in some embodiments, the capping region of the TALE polypeptides described herein have sequences that are at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or share identity to the capping region amino acid sequences provided herein. Sequence identity is related to sequence homology. Homology comparisons may be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs may calculate percent (%) homology between two or more sequences and may also calculate the sequence identity shared by two or more amino acid or nucleic acid sequences. In some preferred embodiments, the capping region of the TALE polypeptides described herein have sequences that are at least 95% identical or share identity to the capping region amino acid sequences provided herein. [00752] Sequence homologies may be generated by any of a number of computer programs known in the art, which include but are not limited to BLAST or FASTA. Suitable computer program for carrying out alignments like the GCG Wisconsin Bestfit package may also be used. Once the software has produced an optimal alignment, it is possible to calculate % homology, preferably % sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result. % homology may be calculated over contiguous sequences, i.e., one sequence is aligned with the other sequence and each amino acid or nucleotide in one sequence is directly compared with the corresponding amino acid or nucleotide in the other sequence, one residue at a time. This is called an “ungapped” alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues. [00753] Additional sequences for the conserved portions of polypeptide monomers and for N- terminal and C-terminal capping regions are included in the sequences with the following gene accession numbers: AAW59491.1, AAQ79773.2, YP_450163.1, YP_001912778.1, ZP_02242672.1, AAW59493.1, AAY54170.1, ZP_02245314.1, ZP_02243372.1, AAT46123.1, AAW59492.1, YP_451030.1, YP_001915105.1, ZP_02242534.1, AAW77510.1, ACD11364.1, ZP_02245056.1, ZP_02245055.1, ZP_02242539.1, ZP_02241531.1, ZP_02243779.1, AAN01357.1, ZP_02245177.1, ZP_02243366.1, ZP_02241530.1, AAS58130.3, ZP_02242537.1, YP_200918.1, YP_200770.1, YP_451187.1, YP_451156.1, AAS58127.2, YP_451027.1, UR_451025.1, AAA92974.1, UR_001913755.1, ABB70183.1, UR_451893.1, UR_450167.1, ABY60855.1, UR_200767.1, ZR_02245186.1, ZR_02242931.1, ZR_02242535.1, AAU54169.1, UR_450165.1, UR_001913452.1, AAS58129.3, ACM44927.1, ZR_02244836.1, AAT46125.1, UR_450161.1, ZR_02242546.1, AAT46122.1, UR_451897.1, AAF98343.1, UR_001913484.1, AAY54166.1, UR_001915093.1, UR_001913457.1, ZR_02242538.1, UR_200766.1, UR_453043.1, UR_001915089.1, UR_001912981.1, ZR_02242929.1, UR_001911730.1, UR_201654.1, UR_199877.1, ABB70129.1, UR_451696.1, UR_199876.1, AAS75145.1, AAT46124.1, UR_200914.1, UR 001915101.1, ZR_02242540.1, AAG02079.2, UR_451895.1, YP 451189.1, UR_200915.1, AAS46027.1, UR_001913759.1, UR_001912987.1, AAS58128.2, AAS46026.1, UR_201653.1, UR_202894.1, UR_001913480.1, ZR_02242666.1, R_001912775.1, ZR_02242662.1, AAS46025.1, AAC43587.1, BAA37119.1, NPJ544725.1, AB077779.1, BAA37120.1, ACZ62652.1, BAF46271.1, ACZ62653.1, NPJ544793.1, ABO77780.1, ZR_02243740.1, ZR_02242930.1, AAB69865.1, AAY54168.1, ZR_02245191.1, UR_001915097.1, ZR_02241539.1, UR_451158.1, BAA37121.1, UR_001913182.1, UR_200903.1, ZR_02242528.1, ZR_06705357.1, ZR_06706392.1, ADI48328.1, ZR_06731493.1, ADI48327.1, AB077782.1, ZR 06731656.1, NR_942641.1, AAY43360.1, ZR_06730254.1, ACN39605.1, UR_451894.1, UR_201652.1, UR_001965982.1, BAF46269.1, NPJ544708.1, ACN82432.1, AB077781.1, P14727.2, BAF46272.1, AAY43359.1, BAF46270.1, NR_644743.1, ABG37631.1, AAB00675.1, YP 199878.1, ZR_02242536.1, CAA48680.1, ADM80412.1, AAA27592.1, ABG37632.1, ABP97430.1, ZR_06733167.1, AAY43358.1, 2KQ5_A, BAD42396.1, ABO27075.1, UR_002253357.1, UR_002252977.1, ABO27074.1, ABO27067.1, ABO27072.1, ABO27068.1, UR_003750492.1, ABO27073.1, NR_519936.1, ABO27071.1, AB027070.1, and ABO27069.1, each of which is hereby incorporated by reference. [00754] In some embodiments, the TALEs described herein also include a nuclear localization signal and/or cellular uptake signal. Such signals are known in the art and may target a TALE to the nucleus and/or intracellular compartment of a cell. Such cellular uptake signals include, but are not limited to, the minimal Tat protein transduction domain which spans residues 47-57 of the human immunodeficiency virus Tat protein. [00755] In some embodiments, the TALEs described herein include a nucleic acid or DNA binding domain that is a non-TALE nucleic acid or a non-TALE DNA binding domain. [00756] As used herein the term “non-TALE DNA binding domain” refers to a DNA binding domain that has a nucleic acid sequence corresponding to a nucleic acid sequence which is not substantially homologous to a nucleic acid that encodes for a TALE protein or fragment thereof, e.g., a nucleic acid sequence which is different from a nucleic acid that encodes for a TALE protein and which is derived from the same or a different organism. [00757] In certain embodiments, the TALEs described herein include a nucleic acid or DNA binding domain that is linked to a non-TALE polypeptide. [00758] A “non-TALE polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a protein which is not substantially homologous to a TALE protein or fragment thereof, e.g., a protein which is different from a TALE protein and which is derived from the same or a different organism. In this context, the term “linked” is intended include any manner by which the nucleic acid binding domain and the non-TALE polypeptide could be connected to each other, including, for example, through peptide bonds by being part of the same polypeptide chain or through other covalent interactions, such as a chemical linker. The non-TALE polypeptide may be linked, for example to the N-terminus and/or C-terminus of the nucleic acid binding domain, may be linked to a C-terminal or N-terminal cap region, or may be connected to the nucleic acid binding domain indirectly. [00759] In certain embodiments, the TALEs or polypeptides of the disclosure comprise chimeric DNA binding domains. Chimeric DNA binding domains may be generated by fusing a full TALE (including the N- and C- terminal capping regions) with another TALE or non-TALE DNA binding domain such as zinc finger (ZF), helix-loop-helix, or catalytically-inactivated DNA endonucleases (e.g., EcoRI, meganucleases, etc.), or parts of TALE may be fused to other DNA binding domains. The chimeric domain may have novel DNA binding specificity that combines the specificity of both domains. [00760] In certain embodiments, the TALE polypeptides of the disclosure include a nucleic acid binding domain linked to the one or more effector domains. In certain embodiments, the effector domain is a nickase or nuclease. ZFNs [00761] In certain embodiments, the sequence-specific nuclease is a zinc finger nuclease (ZFN), such as an artificial zinc-finger nuclease having arrays of zinc-finger (ZF) modules to target new DNA-binding sites in a target sequence (e.g., target sequence or target site in the genome). Each zinc finger module in a ZF array targets three DNA bases. A customized array of individual zinc finger domains is assembled into a ZF protein (ZFP). The resulting ZFP can be linked to a functional domain such as a nuclease. [00762] ZF nucleases (ZFN) may be used as alternative programmable nucleases for use in retron-based editing in place of RNA-guide nucleases. ZFN proteins have been extensively described in the art, for example, in Carroll et al.,“Genome Engineering with Zinc-Finger Nucleases,” Genetics, Aug 2011, Vol.188: 773-782; Durai et al.,“Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells,” Nucleic Acids Res, 2005, Vol.33: 5978-90; and Gaj et al., “ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering,” Trends Biotechnol.2013, Vol.31: 397-405, each of which are incorporated herein by reference in their entireties. [00763] In certain embodiments, the ZF-linked nuclease is a catalytic domain of the Type IIS restriction enzyme FokI (see Kim et al., PNAS U.S.A.91:883-887, 1994; Kim et al., PNAS U.S.A. 93:1156-1160, 1996, both incorporated herein by reference). [00764] In certain embodiments, the ZFN comprises paired ZFN heterodimers, resulting in increased cleavage specificity and/or decreased off-target activity. In this embodiment, each ZFN in the heterodimer targets different nucleotide sequences separated by a short spacer (see Doyon et al., Nat. Methods 8:74-79, 2011, incorporated herein by reference). [00765] In certain embodiments, the ZFN comprises a polynucleotide-binding domain (comprising multiple sequence-specific ZF modules) and a polynucleotide cleavage nickase domain. [00766] In certain embodiments, the ZFs are engineered using libraries of two finger modules. [00767] In certain embodiments, strings of two-finger units are used in ZFNs to improve DNA binding specificity from polyzinc finger peptides (see PNAS USA 98: 1437-1441, incorporated herein by reference). [00768] In certain embodiments, the ZFN has more than 3 fingers. In certain embodiments, the ZFN has 4, 5, or 6 fingers. In certain embodiments, the ZF modules in the ZFN are separated by one or more linkers to improve specificity. [00769] In certain embodiments, the ZF of the ZFN includes substitutions in the dimer interface of the cleavage domain that prevent homodimerization between ZFs, but allow heterodimers to form. [00770] In certain embodiments, the ZF of the ZFN has a design that retains activity while suppressing homodimerization. [00771] In certain embodiments, the ZFN is any one of the ZF nucleases in Table 1 of Carroll et al., Genetics 188(4):773-782, 2011, incorporated herein by reference. [00772] General principles and guidance for generating ZF, ZF arrays, and ZFN can be found in the art, such as the modular design (where the different modules can be rearranged and assembled into new combinations for new targets) of the ZF or ZF arrays in the ZFN as taught in Carroll et al., Nat. Protoc.1: 1329-1341, 2006 (incorporated herein by reference); the new three-finger sets for engineered ZFs generated by using partially randomized libraries; profiling the DNA-binding specificities of engineered Cys2His2 zinc finger domains using a rapid cell-based method (see Nucleic Acids Res.35: e81, incorporated by reference). ZFs for certain DNA triplets that work well in neighbor combination are described in Sander et al., 2011. Selection-free zinc-finger-nuclease engineering by context-dependent assembly (CoDA) is taught in Nat. Methods 8: 67-69). ToolGen describes the individual fingers in their collection that are best behaved in modular assembly (Kim et al., 2011). Preassembled zinc-finger arrays for rapid construction of ZFNs are taught in Nat. Methods 8:7. [00773] Additional, non-limiting ZFs and AFNz that can be adapted for use in the instant disclosure include those described in WO2010/065123, WO2000/041566, WO2003/080809, WO2015/143046, WO2016/183298, WO2013/044008, WO2015/031619, WO2017/136049, WO2016/014794, WO2017/091512, WO1995/009233, WO2000/023464, WO2000/042219, WO2002/026960, WO2001/083793; US9428756, US9145565, US8846578, US8524874, US6777185, US6599692, US7235354, US6503717, US7491531, US7943553, US7262054, US8680021, US7705139, US7273923, US6780590, US6785613, US7788044, US7177766, US6453242, US6794136, US7358085, US8383766, US7030215, US7013219, US7361635, US7939327, US8772453, US9163245, US7045304, US8313925, US9260726, US6689558, US8466267, US7253273, US7947873, US9388426, US8153399, US8569253, US8524221, US7951925, US9115409, US8772008, US9121072, US9624498, US6979539, US9491934, US6933113, US9567609, US7070934, US9624509, US8735153, US9567573, US6919204, US2002- 0081614, US2004-0203064, US2006-0166263, US2006-0292621, US2003-0134318, US2006- 0294617, US2007-0287189, US2007-0065931, US2003-0105593, US2003-0108880, US2009- 0305402, US2008-0209587, US2013-0123484, US2004-0091991, US2009-0305977, US2008- 0233641, US2014-0287500, US2011-0287512, US2009-0258363, US2013-0244332, US2007- 0134796, US2010-0256221, US2005-0267061, US2012-0204282, US2012-0252122, US2010- 0311124, US2016-0215298, US2008-0031109, US2014-0017214, US2015-0267205, US2004- 0235002, US2004-0204345, US2015-0064789, US2006-0063231, US2011-0265198, US2017- 0218349, all incorporated herein by reference. [00774] Polynucleotides and vectors capable of expressing one or more of the ZFNs are also provided herein, which can be part of the vector system of the disclosure. The polynucleotides and vectors can be expressed in a cell, such as a eukaryotic cell, a mammalian cell, or a human cell. Suitable vectors, cells and expression systems are described in greater detail elsewhere herein, and can be suitable for use with the TALEs, the meganucleases, and the CRISPR-Cas nucleases. Meganucleases [00775] In some embodiments, the gene editing system comprises meganucleases. Meganucleases are homing endonucleases discovered in yeast that recognize fairly long DNA sequences, and create double-strand breaks that are mended via stimulation of homologous recombination. Meganucleases are sequence-specific endonucleases that use large (recognition sites to generate accurate double-strand breaks (DSBs), promoting efficient gene targeting through homologous recombination (HR). Meganuclease enzymes and editing systems comprising meganucleases have been described in the literature, including the following references, each of which are incorporated herein in their entireties by reference. Khalil AM. The genome editing revolution: review. J Genet Eng Biotechnol.2020 Oct 29;18(1):68. doi: 10.1186/s43141-020-00078-y. PMID: 33123803; PMCID: PMC7596157. Lanigan TM, Kopera HC, Saunders TL. Principles of Genetic Engineering. Genes (Basel).2020 Mar 10;11(3):291. doi: 10.3390/genes11030291. PMID: 32164255; PMCID: PMC7140808. Arnould S, Delenda C, Grizot S, Desseaux C, Pâques F, Silva GH, Smith J. The I-CreI meganuclease and its engineered derivatives: applications from cell modification to gene therapy. Protein Eng Des Sel. 2011 Jan;24(1-2):27-31. doi: 10.1093/protein/gzq083. Epub 2010 Nov 3. PMID: 21047873. Pâques F, Duchateau P. Meganucleases and DNA double-strand break-induced recombination: perspectives for gene therapy. Curr Gene Ther.2007 Feb;7(1):49-66. doi: 10.2174/156652307779940216. PMID: 17305528. Zekonyte U, Bacman SR, Smith J, Shoop W, Pereira CV, Tomberlin G, Stewart J, Jantz D, Moraes CT. Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo. Nat Commun.2021 May 28;12(1):3210. doi: 10.1038/s41467-021-23561-7. PMID: 34050192; PMCID: PMC8163834. [00776] Meganuclease enzymes and editing systems comprising meganucleases have also been described in the patent literature, including the following references, each of which are incorporated herein in their entireties by reference.

Gene editor accessory proteins [00777] In other aspects, the gene editing systems described herein may comprise one or more additional accessory proteins having genome modifying functions, including recombinases, invertases, nucleases, polymerases (e.g., reverse transcriptases), ligases, deaminases, transposases, or DNA binding domains. In various embodiments, the accessory proteins may be provided separately. In other embodiments, the accessory proteins may be fused to another component of a given gene editing system, such as a CRISPR-Cas9, through a linker. Guide RNA components Guide RNAs [00778] The present disclosure further provides guide RNAs for use in accordance with the disclosed nucleic acid programmable DNA binding proteins (e.g., Cas9) for use in methods of editing. The disclosure provides guide RNAs that are designed to recognize target sequences. Such gRNAs may be designed to have guide sequences (or “spacers”) having complementarity to a target sequence. Such gRNAs may be designed to have not only a guide sequences having complementarity to a target sequence to be edited, but also to have a backbone sequence that interacts specifically with the nucleic acid programmable DNA binding protein. [00779] In some embodiments, the guide RNA may be 15-100 nucleotides in length and comprise a sequence of at least 10, at least 15, or at least 20 contiguous nucleotides that is complementary to a target nucleotide sequence. The guide RNA may comprise a spacer sequence of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous nucleotides that is complementary to a target nucleotide sequence. In some cases, the guide sequence has a length in a range of from 17-30 nucleotides (nt) (e.g., from 17-25, 17-22, 17-20, 19-30, 19-25, 19-22, 19-20, 20-30, 20-25, or 20-22 nt). In some cases, the guide sequence has a length in a range of from 17-25 nucleotides (nt) (e.g., from 17-22, 17-20, 19-25, 19-22, 19-20, 20-25, or 20- 22 nt). In some cases, the guide sequence has a length of 17 or more nt (e.g., 18 or more, 19 or more, 20 or more, 21 or more, or 22 or more nt; 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, etc.). In some cases, the guide sequence has a length of 19 or more nt (e.g., 20 or more, 21 or more, or 22 or more nt; 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, etc.). In some cases, the guide sequence has a length of 17 nt. In some cases, the guide sequence has a length of 18 nt. In some cases, the guide sequence has a length of 19 nt. In some cases, the guide sequence has a length of 20 nt. In some cases, the guide sequence has a length of 21 nt. In some cases, the guide sequence has a length of 22 nt. In some cases, the guide sequence has a length of 23 nt. [00780] In some cases, the spacer sequence has a length of from 15 to 50 nucleotides (e.g., from 15 nucleotides (nt) to 20 nt, from 20 nt to 25 nt, from 25 nt to 30 nt, from 30 nt to 35 nt, from 35 nt to 40 nt, from 40 nt to 45 nt, or from 45 nt to 50 nt). [00781] A subject guide RNA can interact with a target nucleic acid (e.g., double stranded DNA (dsDNA), single stranded DNA (ssDNA), single stranded RNA (ssRNA), or double stranded RNA (dsRNA)) in a sequence-specific manner via hybridization (i.e., base pairing). [00782] The guide RNA can be modified to hybridize to any desired target sequence (e.g., while taking the PAM into account, e.g., when targeting a dsDNA target) within a target nucleic acid (e.g., a eukaryotic target nucleic acid such as genomic DNA). In some cases, the percent complementarity between the spacer sequence of the guide and the target site of the target nucleic acid is 60% or more (e.g., 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the spacer and the target site of the target nucleic acid is 80% or more (e.g., 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the spacer and the target site of the target nucleic acid is 90% or more (e.g., 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the spacer and the target site of the target nucleic acid is 100%. [00783] In some cases, the percent complementarity between the spacer sequence and the target site of the target nucleic acid is 100% over an at least 5-nucleotide contiguous region of the spacer. In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 6-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 7-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 8-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 9-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 10-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 11-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 12-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 13-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 14-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 15-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 16-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 17-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 18-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 19-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 20-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 21-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 22-nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). [00784] In some cases, the percent complementarity between the spacer sequence and the target site of the target nucleic acid is 100% over an at least 5-10 nucleotide contiguous region of the spacer. In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 6-11 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 7-12 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 8-13 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 9-14 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 10-15 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 11-16 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 12-17 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 13-18 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 14-19 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 15-20 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 16-21 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 17-22 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 18-23 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 19-24 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 20-25 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 21-26 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). In some cases, the percent complementarity between the guide sequence and the target site of the target nucleic acid over an at least 22-27 nucleotide contiguous region of the spacer is 60% or more (e.g., 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100%). [00785] In various embodiments, the guide RNAs may have a scaffold or core region that complexes with a cognate nucleic acid programmable DNA binding protein (e.g., CRISPR Cas9 or Cas12a). In some cases, a guide scaffold can have two stretches of nucleotides that are complementary to one another and hybridize to form a double stranded RNA duplex (dsRNA duplex). Thus, in some cases, the protein binding segment of a guide RNA includes a dsRNA duplex. In some embodiments, the dsRNA duplex region includes a range of from 5-25 base pairs (bp) (e.g., from 5- 22, 5-20, 5-18, 5-15, 5-12, 5-10, 5-8, 8-25, 8-22, 8-18, 8-15, 8-12, 12-25, 12-22, 12-18, 12- 15, 13-25, 13-22, 13-18, 13-15, 14-25, 14-22, 14-18, 14-15, 15-25, 15-22, 15-18, 17-25, 17-22, or 17-18 bp, e.g., 5 bp, 6 bp, 7 bp, 8 bp, 9 bp, 10 bp, etc.). In some cases, the dsRNA duplex region includes a range of from 6-15 base pairs (bp) (e.g., from 6-12, 6-10, or 6-8 bp, e.g., 6 bp, 7 bp, 8 bp, 9 bp, 10 bp, etc.). In some cases, the duplex region includes 5 or more bp (e.g., 6 or more, 7 or more, or 8 or more bp). In some cases, the duplex region includes 6 or more bp (e.g., 7 or more, or 8 or more bp). In some cases, not all nucleotides of the duplex region are paired, and therefore the duplex forming region can include a bulge. The term “bulge” herein is used to mean a stretch of nucleotides (which can be one nucleotide) that do not contribute to a double stranded duplex, but which are surround 5’ and 3’ by nucleotides that do contribute, and as such a bulge is considered part of the duplex region. In some cases, the dsRNA includes 1 or more bulges (e.g., 2 or more, 3 or more, 4 or more bulges). In some cases, the dsRNA duplex includes 2 or more bulges (e.g., 3 or more, 4 or more bulges). In some cases, the dsRNA duplex includes 1-5 bulges (e.g., 1-4, 1-3, 2-5, 2-4, or 2-3 bulges). [00786] Thus, in some cases, the stretches of nucleotides that hybridize to one another to form the dsRNA duplex in a guide scaffold region have 70%-100% complementarity (e.g., 75%-100%, 80%-10%, 85%-100%, 90%- 100%, 95%-100% complementarity) with one another. In some cases, the stretches of nucleotides that hybridize to one another to form the dsRNA duplex have 70%-100% complementarity (e.g., 75%-100%, 80%-10%, 85%-100%, 90%-100%, 95%-100% complementarity) with one another. In some cases, the stretches of nucleotides that hybridize to one another to form the dsRNA duplex have 85%-100% complementarity (e.g., 90%-100%, 95%-100% complementarity) with one another. In some cases, the stretches of nucleotides that hybridize to one another to form the dsRNA duplex have 70%-95% complementarity (e.g., 75%-95%, 80%-95%, 85%-95%, 90%-95% complementarity) with one another. In other words, in some cases, the dsRNA duplex includes two stretches of nucleotides that have 70%-100% complementarity (e.g., 75%-100%, 80%-10%, 85%- 100%, 90%-100%, 95%-100% complementarity) with one another. In some cases, the dsRNA duplex includes two stretches of nucleotides that have 85%-100% complementarity (e.g., 90%-100%, 95%- 100% complementarity) with one another. In some cases, the dsRNA duplex includes two stretches of nucleotides that have 70%-95% complementarity (e.g., 75%-95%, 80%-95%, 85%-95%, 90%-95% complementarity) with one another. [00787] In various embodiments, the scaffold region of a guide RNA can also include one or more (1, 2, 3, 4, 5, etc.) mutations relative to a naturally occurring scaffold region. For example, in some cases a base pair can be maintained while the nucleotides contributing to the base pair from each segment can be different. In some cases, the duplex region of a subject guide RNA includes more paired bases, less paired bases, a smaller bulge, a larger bulge, fewer bulges, more bulges, or any convenient combination thereof, as compared to a naturally occurring duplex region (of a naturally occurring guide RNA). [00788] Examples of various guide RNAs can be found in the art, and in some cases variations similar to those introduced into Cas9 guide RNAs can also be introduced into guide RNAs of the present disclosure (e.g., mutations to the dsRNA duplex region, extension of the 5’ or 3’ end for added stability for to provide for interaction with another protein, and the like). For example, see Jinek et al., Science.2012 Aug 17;337(6096):816-21; Chylinski et al., RNA Biol.2013 May;10(5):726- 37; Ma et al., Biomed Res Int.2013;2013:270805; Hou et al., Proc Natl Acad Sci U S A.2013 Sep 24;110(39):15644-9; Jinek et al., Elife.2013;2:e00471; Pattanayak et al., Nat Biotechnol. 2013 Sep;31(9):839-43; Qi et al, Cell.2013 Feb 28 ; 152(5): 1173-83 ; Wang et al., Cell.2013 May 9;153(4):910-8; Auer et al., Genome Res.2013 Oct 31; Chen et al., Nucleic Acids Res.2013 Nov 1 ;41(20):el9; Cheng et al., Cell Res.2013 Oct;23(10):1163-71; Cho et al., Genetics.2013 Nov;195(3):1177-80; DiCarlo et al., Nucleic Acids Res.2013 Apr;41(7):4336-43; Dickinson et al., Nat Methods.2013 Oct;10(10):1028-34; Ebina et al., Sci Rep.2013;3:2510; Fujii et. al, Nucleic Acids Res.2013 Nov l;41(20):el87; Hu et al., Cell Res.2013 Nov;23(ll):1322-5; Jiang et al., Nucleic Acids Res.2013 Nov l;41(20):el88; Larson et al., Nat Protoc.2013 Nov;8(l l):2180-96; Mali et. at., Nat Methods.2013 Oct;10(10):957-63; Nakayama et al., Genesis.2013 Dec;51(12):835-43; Ran et al., Nat Protoc.2013 Nov;8(l l):2281-308; Ran et al., Cell.2013 Sep 12;154(6):1380-9; Upadhyay et al., G3 (Bethesda).2013 Dec 9;3(12):2233-8; Walsh et al., Proc Natl Acad Sci U S A.2013 Sep 24;110(39):15514-5; Xie et al., Mol Plant.2013 Oct 9; Yang et al., Cell.2013 Sep 12;154(6):1370-9; Briner et al., Mol Cell.2014 Oct 23;56(2):333-9; and U.S. patents and patent applications: 8,906,616; 8,895,308; 8,889,418; 8,889,356; 8,871,445; 8,865,406; 8,795,965; 8,771,945; 8,697,359; 20140068797; 20140170753; 20140179006; 20140179770; 20140186843; 20140186919; 20140186958; 20140189896; 20140227787; 20140234972; 20140242664; 20140242699; 20140242700; 20140242702; 20140248702; 20140256046; 20140273037; 20140273226; 20140273230; 20140273231; 20140273232; 20140273233; 20140273234; 20140273235; 20140287938; 20140295556; 20140295557; 20140298547; 20140304853; 20140309487; 20140310828; 20140310830; 20140315985; 20140335063; 20140335620; 20140342456; 20140342457; 20140342458; 20140349400; 20140349405; 20140356867; 20140356956; 20140356958; 20140356959; 20140357523; 20140357530; 20140364333; and 20140377868; all of which are hereby incorporated by reference in their entirety. Guide RNA modifications [00789] In one embodiment, the guide RNAs (including pegRNAs) contemplated herein comprise non-naturally occurring nucleic acids and/or non-naturally occurring nucleotides and/or nucleotide analogs, and/or chemical modifications. Non-naturally occurring nucleic acids can include, for example, mixtures of naturally and non-naturally occurring nucleotides. Non-naturally occurring nucleotides and/or nucleotide analogs may be modified at the ribose, phosphate, and/or base moiety. In an embodiment of the disclosure, a guide RNA (including pegRNA) component nucleic acid comprises ribonucleotides and non-ribonucleotides. In one such embodiment, a guide RNA (including pegRNA) component comprises one or more ribonucleotides and one or more deoxyribonucleotides. In an embodiment of the disclosure, the guide RNA (including pegRNA) component comprises one or more non-naturally occurring nucleotide or nucleotide analog such as a nucleotide with phosphorothioate linkage, a locked nucleic acid (LNA) nucleotides comprising a methylene bridge between the 2' and 4' carbons of the ribose ring, or bridged nucleic acids (BNA). [00790] Other examples of modified nucleotides include 2'-O-methyl analogs, 2'-deoxy analogs, or 2'-fluoro analogs. Further examples of modified bases include, but are not limited to, 2- aminopurine, 5-bromo-uridine, pseudouridine, inosine, 7-methylguanosine. Examples of coRNA chemical modifications include, without limitation, incorporation of 2'-O-methyl (M), 2'-O-methyl 3 'phosphorothioate (MS), S-constrained ethyl(cEt), or 2'-O-methyl 3 'thioPACE (MSP) at one or more terminal nucleotides. Such chemically modified oRNA components can comprise increased stability and increased activity as compared to unmodified oRNA components, though on-target vs. off-target specificity is not predictable. (See, Hendel, 2015, Nat Biotechnol.33(9):985-9, doi: 10.1038/nbt.3290, published online 29 June 2015 Ragdarm et al., 0215, PNAS, E7110-E7111; Allerson et al., J. Med. Chem.2005, 48:901-904; Bramsen et al., Front. Genet., 2012, 3:154; Deng et al., PNAS, 2015, 112: 11870-11875; Sharma et al., MedChemComm., 2014, 5: 1454-1471; Hendel et al., Nat. Biotechnol. (2015) 33(9): 985-989; Li et al., Nature Biomedical Engineering, 2017, 1, 0066 D01: 10.1038/s41551- 017-0066). In one embodiment, the 5’ and/or 3’ end of a guide RNA (including pegRNA) component is modified by a variety of functional moieties including fluorescent dyes, polyethylene glycol, cholesterol, proteins, or detection tags. (See Kelly et al., 2016, J. Biotech.233:74-83). In one embodiment, a guide RNA (including pegRNA) component comprises ribonucleotides in a region that binds to a target sequence and one or more deoxyribonucletides and/or nucleotide analogs in a region that binds to a nucleic acid programmable DNA binding protein (e.g., Cas9 nickase). [00791] In an embodiment, deoxyribonucleotides and/or nucleotide analogs are incorporated in engineered guide RNA (including pegRNA) component structures. In one embodiment, 3-5 nucleotides at either the 3’ or the 5’ end of a guide RNA (including pegRNA) component is chemically modified. In one embodiment, only minor modifications are introduced in the seed region, such as 2’-F modifications. In one embodiment, 2’-F modification is introduced at the 3’ end of a guide RNA (including pegRNA) component. In one embodiment, three to five nucleotides at the 5’ and/or the 3’ end of the reRNA component are chemically modified with 2’ -O-methyl (M), 2’-O- methyl 3’ phosphorothioate (MS), S-constrained ethyl(cEt), or 2’ -O-methyl 3’ thioPACE (MSP). Such modification can enhance genome editing efficiency (see Hendel et al., Nat. Biotechnol. (2015) 33(9): 985-989). In one embodiment, all of the phosphodiester bonds of a guide RNA (including pegRNA) component are substituted with phosphorothioates (PS) for enhancing levels of gene disruption. In one embodiment, more than five nucleotides at the 5’ and/or the 3’ end of the guide RNA (including pegRNA) component are chemically modified with 2’-0-Me, 2’-F or S-constrained ethyl(cEt). Such chemically modified guide RNA (including pegRNA) component can mediate enhanced levels of gene disruption (see Ragdarm et al., 0215, PNAS, E7110-E7111). In an embodiment of the disclosure, a guide RNA (including pegRNA) component is modified to comprise a chemical moiety at its 3’ and/or 5’ end. Such moieties include, but are not limited to amine, azide, alkyne, thio, dibenzocyclooctyne (DBCO), or Rhodamine. In certain embodiment, the chemical moiety is conjugated to the guide RNA (including pegRNA) component by a linker, such as an alkyl chain. In one embodiment, the chemical moiety of the modified nucleic acid component can be used to attach the guide RNA (including pegRNA) component to another molecule, such as DNA, RNA, protein, or nanoparticles. Such chemically modified guide RNA (including pegRNA) component can be used to identify or enrich cells generically edited by a gene editing system described herein. [00792] Other guide RNA (including pegRNA) modifications are described in Kim, D.Y., Lee, J.M., Moon, S.B. et al. Efficient CRISPR editing with a hypercompact Cas12f1 and engineered guide RNAs delivered by adeno-associated virus. Nat Biotechnol 40, 94–102 (2022). [0016] Accordingly, in various aspects of the disclosure, the guide RNA (including pegRNA) are modified in one or more locations within the molecule. MS1, an internal penta(uridinylate) (UUUUU) sequence in the tracrRNA; MS2, the 3′ terminus of the crRNA; MS3, the ‘stem 1’ region of the tracrRNA; MS4, the tracrRNA–crRNA complementary region; and MS5, the ‘stem 2’ region of the tracrRNA. [00793] Various aspects of the disclosure provide methods and compositions for improved guide RNA (including pegRNA) stability via chemical modifications. Braasch, D. A., Jensen, S., Liu, Y., Kaur, K., Arar, K., White, M. A., et al. (2003). RNA interference in mammalian cells by chemically-modified RNA. Biochemistry 42, 7967–7975. doi: 10.1021/bi0343774. Chiu, Y. L., and Rana, T. M. (2003). siRNA function in RNAi: a chemical modification analysis. RNA 9, 1034–1048. doi: 10.1261/rna.5103703. Behlke, M. A. (2008). Chemical modification of siRNAs for in vivo use. Oligonucleotides18, 305–319. doi: 10.1089/oli.2008.0164. Bennett, C. F., and Swayze, E. E. (2010). RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol.50, 259–293. doi: 10.1146/annurev.pharmtox.010909.105654. Deleavey, G. F., and Damha, M. J. (2012). Designing chemically modified oligonucleotides for targeted gene silencing. Chem. Biol.19, 937–954. doi: 10.1016/j.chembiol.2012.07.011. Lennox, K. A., and Behlke, M. A. (2020). Chemical modifications in RNA interference and CRISPR/Cas genome editing reagents. Methods Mol. Biol.2115, 23–55. doi: 10.1007/978-1-0716-0290-4_2. [00794] For instance, Hendel et al. improved guide RNA stability by chemically modifying gRNA ends to reduce degradation by exonucleases, RNA nuclease. Hendel, A., Bak, R. O., Clark, J. T., Kennedy, A. B., Ryan, D. E., Roy, S., et al. (2015a). Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat. Biotechnol.33, 985–989. doi: 10.1038/nbt.3290. Chemical modifications of gRNAs may enable more efficient and safer gene- editing in primary cells suitable for clinical applications. [00795] A review of types of chemical modifications are provided in Allen, Daniel et al. “Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells.” Frontiers in genome editing vol.2617910.28 Jan.2021, doi:10.3389/fgeed.2020.617910. [00796] Accordingly, in various embodiments of the present disclosure, the genome editing system comprising a guide RNA (including pegRNA) and further comprises one or more chemical modifications selected from, but not limited to the modifications in the above table. [00797] In exemplary embodiments, chemical modifications to the guide RNA (including pegRNA) include modifications on the ribose rings and phosphate backbone of guide RNA (including pegRNA) and modifications at the 2′OH include 2′-O-Me, 2′-F, and 2′F-ANA. More extensive ribose modifications include 2′F-4′-Cα-OMe and 2′,4′-di-Cα-OMe combine modification at both the 2′ and 4′ carbons. Phosphodiester modifications include sulfide-based Phosphorothioate (PS) or acetate- based phosphonoacetate alterations. Combinations of the ribose and phosphodiester modifications have given way to formulations such as 2′-O-methyl 3′phosphorothioate (MS), or 2′-O-methyl-3′- thioPACE (MSP), and 2′-O-methyl-3′-phosphonoacetate (MP) RNAs. Locked and unlocked nucleotides such as locked nucleic acid (LNA), bridged nucleic acids (BNA), S-constrained ethyl (cEt), and unlocked nucleic acid (UNA) are examples of sterically hindered nucleotide modifications. Modifications to make a phosphodiester bond between the 2′ and 5′ carbons (2′,5′-RNA) of adjacent RNAs as well as a butane 4-carbon chain link between adjacent RNAs have been described. E. Additional components and aspects [00798] In addition to the above LNPs and cargoes, including (A) nucleic acid payloads, (B) linear mRNA payloads, circular mRNA payloads, and (D) gene editing systems, the present disclosure provides additional optional LNP cargo components and tools that may be included as appropriate in the LNP gene editing systems described herein. The following optional components and tools may be combined in any combination as appropriate depending upon the particular gene editing system being delivered by the herein disclosed LNP-based gene editing systems. IV. Encoded products of payload mRNA (e.g., antigens and therapeutic proteins) A. Polypeptides, peptides, and proteins [00799] The LNP-based RNA vaccines and therapeutics described herein comprise one or more RNA payloads (e.g., linear or circular mRNA) which may comprise one or more coding regions that encode one or more products of interest. The one or more coding regions may encode a polypeptide, peptide and/or protein. As used herein, the term “polypeptide” generally refers to polymers of amino acids linked by peptide bonds and embraces “protein” and “peptides.” Polypeptides for the present disclosure include all polypeptides, proteins and/or peptides known in the art. Non-limiting categories of polypeptides include antigens, antibodies, antibody fragments, cytokines, peptides, hormones, enzymes, oxidants, antioxidants, synthetic polypeptides, and chimeric polypeptides, receptor, enzymes, hormones, transcription factors, ligands, membrane transporters, structural proteins, nucleases, or a component, variant or fragment (e.g., a biologically active fragment) thereof. [00800] As used herein, the term “peptide” generally refers to shorter polypeptides of about 50 amino acids or less. Peptides with only two amino acids may be referred to as “dipeptides.” Peptides with only three amino acids may be referred to as “tripeptides.” Polypeptides generally refer to polypeptides with from about 4 to about 50 amino acids. Peptides may be obtained via any method known to those skilled in the art. In some embodiments, peptides may be expressed in culture. In some embodiments, peptides may be obtained via chemical synthesis (e.g., solid phase peptide synthesis). [00801] In some embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest), e.g., the originator constructs and benchmark constructs described herein, may encode a simple protein which upon hydrolysis yields the amino acids and occasionally small carbohydrate compounds. Non-limiting examples of simple proteins include albumins, albuminoids, globulins, glutelins, histones and protamines. [00802] In some embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest), e.g., the originator constructs and benchmark constructs described herein, may encode a simple protein associated with a non-protein. Non-limiting examples of conjugated proteins include, glycoproteins, hemoglobins, lecithoproteins, nucleoproteins, and phosphoproteins. [00803] In some embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest), e.g., the originator constructs and benchmark constructs described herein, may encode a protein that is derived from a simple or conjugated protein by chemical or physical means. Non-limiting examples of derived proteins include denatured proteins and peptides. [00804] In some embodiments, the polypeptide, protein or peptide may be unmodified. [00805] In some embodiments, the polypeptide, protein or peptide may be modified. Types of modifications include, but are not limited to, phosphorylation, glycosylation, acetylation, ubiquitylation/sumoylation, methylation, palmitoylation, quinone, amidation, myristoylation, pyrrolidone carboxylic acid, hydroxylation, phosphopantetheine, prenylation, GPI anchoring, oxidation, ADP-ribosylation, sulfation, S-nitrosylation, citrullination, nitration, gamma- carboxyglutamic acid, formylation, hypusine, topaquinone (TPQ), bromination, lysine topaquinone (LTQ), tryptophan tryptophylquinone (TTQ), iodination, and cysteine tryptophylquinone (CTQ). In some aspects, the polypeptide, protein or peptide may be modified by a post-transcriptional modification which can affect its structure, subcellular localization, and/or function. [00806] In some embodiments, the polypeptide, protein or peptide may be modified using phosphorylation. Phosphorylation, or the addition of a phosphate group to serine, threonine, or tyrosine residues, is one of most common forms of protein modification. Protein phosphorylation plays an important role in fine tuning the signal in the intracellular signaling cascades. [00807] In some embodiments, the polypeptide, protein or peptide may be modified using ubiquitination which is the covalent attachment of ubiquitin to target proteins. Ubiquitination- mediated protein turnover has been shown to play a role in driving the cell cycle as well as in protein- degradation-independent intracellular signaling pathways. [00808] In some embodiments, the polypeptide, protein or peptide may be modified using acetylation and methylation which can play a role in regulating gene expression. As a non-limiting example, the acetylation and methylation could mediate the formation of chromatin domains (e.g., euchromatin and heterochromatin) which could have an impact on mediating gene silencing. [00809] In some embodiments, the polypeptide, protein or peptide may be modified using glycosylation. Glycosylation is the attachment of one of a large number of glycan groups and is a modification that occurs in about half of all proteins and plays a role in biological processes including, but not limited to, embryonic development, cell division, and regulation of protein structure. The two main types of protein glycosylation are N-glycosylation and O-glycosylation. For N-glycosylation the glycan is attached to an asparagine and for O-glycosylation the glycan is attached to a serine or threonine. [00810] In some embodiments, the polypeptide, protein or peptide may be modified using sumoylation. Sumoylation is the addition of SUMOs (small ubiquitin-like modifiers) to proteins and is a post-translational modification similar to ubiquitination. [00811] In other embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest), e.g., the originator constructs and benchmark constructs described herein, may encode a therapeutic protein, such as those exemplified below. [00812] In other embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest), e.g., the originator constructs and benchmark constructs described herein, may encode vaccine antigen, such as those exemplified below. As used herein, a “vaccine antigen” is a biological preparation that improves immunity to a particular disease or infectious agent. According to the present disclosure, one or more vaccine antigens currently being marketed or in development may be encoded by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) described herein of the present disclosure. B. Therapeutic proteins [00813] In various embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) may encode a therapeutic protein. Therapeutic proteins mediate a variety of effects in a host cell or a subject in order to treat a disease or ameliorate the signs and symptoms of a disease. For example, a therapeutic protein can replace a protein that is deficient or abnormal, augment the function of an endogenous protein, provide a novel function to a cell (e.g., inhibit or activate an endogenous cellular activity, or act as a delivery agent for another therapeutic compound (e.g., an antibody-drug conjugate). Therapeutic proteins may be useful for the treatment of the following diseases and conditions: bacterial infections, viral infections, parasitic infections, cell proliferation disorders, cancer, genetic disorders, and autoimmune disorders, among others, or utilized to treat conditions or diseases in many therapeutic areas such as, but not limited to, blood, cardiovascular, CNS, poisoning (including antivenoms), dermatology, endocrinology, genetic, genitourinary, gastrointestinal, musculoskeletal, oncology, and immunology, respiratory, sensory and anti-infective. As used herein, a “therapeutic protein” refers to a protein that, when administered to a cell has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect. [00814] The RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) may encode a therapeutic protein selected from any of several categories including, but not limited to, biologics, antibodies, vaccines, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease, targeting moieties or those proteins encoded by the human genome for which no therapeutic indication has been identified but which nonetheless have utility in areas of research and discovery. As used herein, a “biologic” is a polypeptide-based molecule produced by the methods provided herein and which may be used to treat, cure, mitigate, prevent, or diagnose a serious or life-threatening disease or medical condition. Biologics, according to the present disclosure include, but are not limited to, allergenic extracts (e.g., for allergy shots and tests), blood components, gene therapy products, human tissue or cellular products used in transplantation, vaccines, monoclonal antibodies, cytokines, growth factors, enzymes, thrombolytics, and immunomodulators, among others. [00815] In various embodiments, the therapeutic proteins produced by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) may be a cell-penetrating polypeptide. As used herein, a “cell-penetrating polypeptide” refers to a polypeptide which may facilitate the cellular uptake of molecules. A cell-penetrating polypeptide of the present disclosure may contain one or more detectable labels. The polypeptides may be partially labeled or completely labeled throughout. The mRNA may encode the detectable label completely, partially or not at all. The cell-penetrating peptide may also include a signal sequence. As used herein, a “signal sequence” refers to a sequence of amino acid residues bound at the amino terminus of a nascent protein during protein translation. The signal sequence may be used to signal the secretion of the cell-penetrating polypeptide. [00816] The cell-penetrating polypeptide encoded by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) described herein may form a complex after being translated. The complex may comprise a charged protein linked, e.g., covalently linked, to the cell-penetrating polypeptide. [00817] In one embodiment, the cell-penetrating polypeptide encoded by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) described herein may comprise a first domain and a second domain. The first domain may comprise a supercharged polypeptide. The second domain may comprise a protein-binding partner. As used herein, “protein-binding partner” includes, but is not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides. The cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner. The cell-penetrating polypeptide may be capable of being secreted from a cell where the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more encoded products of interest) described herein may be introduced. The cell-penetrating polypeptide may also be capable of penetrating the first cell. [00818] In one embodiment, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein may encode a cell-penetrating polypeptide which may comprise a protein-binding partner. The protein binding partner may include, but is not limited to, an antibody, a supercharged antibody or a functional fragment. The RNA payloads may be introduced into the cell where a cell-penetrating polypeptide comprising the protein- binding partner is introduced. [00819] In another embodiment, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein may encode therapeutic proteins have organelle-sorting sequences. Human and other eukaryotic cells are subdivided by membranes into many functionally distinct compartments. Each membrane-bound compartment, or organelle, contains different proteins essential for the function of the organelle. The cell uses “sorting signals” which are amino acid motifs located within the protein, to target proteins to particular cellular organelles. One type of sorting signal, called a signal sequence, a signal peptide, or a leader sequence, directs a class of proteins to an organelle called the endoplasmic reticulum (ER). Proteins targeted to the ER by a signal sequence can be released into the extracellular space as a secreted protein. Similarly, proteins residing on the cell membrane can also be secreted into the extracellular space by proteolytic cleavage of a "linker" holding the protein to the membrane. While not wishing to be bound by theory, the molecules of the present disclosure may be used to exploit the cellular trafficking described above. As such, in some embodiments of the disclosure, therapeutic proteins are expressed as secreted proteins. In one embodiment, these may be used in the manufacture of large quantities of valuable human gene products. [00820] In some embodiments of the disclosure, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein may encode a protein of the plasma membrane. [00821] In some embodiments of the disclosure, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein may encode a cytoplasmic or cytoskeletal protein. [00822] In some embodiments of the disclosure, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein may encode an intracellular membrane bound protein. [00823] In some embodiments of the disclosure, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein may encode a nuclear protein. [00824] Examples of therapeutic proteins that may be encoded by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein can include hormones and growth and differentiation factors including, without limitation, insulin, glucagon, growth hormone (GH), parathyroid hormone (PTH), growth hormone releasing factor (GRF), follicle stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), vascular endothelial growth factor (VEGF), angiopoietins, angiostatin, granulocyte colony stimulating factor (GCSF), erythropoietin (EPO), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin growth factors I and II (IGF-I and IGF-II), any one of the transforming growth factor alpha superfamily, including TGFα, activins, inhibins, or any of the bone morphogenic proteins (BMP) BMPs 1-15, any one of the heregluin/neuregulin/ARIA/neu differentiation factor (NDF) family of growth factors, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophies NT-3 and NT-4/5, ciliary neurotrophic factor (CNTF), glial cell line derived neurotrophic factor (GDNF), neurturin, agrin, any one of the family of semaphorins/collapsins, netrin-1 and netrin-2, hepatocyte growth factor (HGF), ephrins, noggin, sonic hedgehog and tyrosine hydroxylase. [00825] Examples of additional therapeutic proteins that may be encoded by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein can include, but are not limited to proteins that regulate the immune system including, without limitation, cytokines and lymphokines such as thrombopoietin (TPO), interleukins (IL) IL-1 through IL-25 (including IL-2, IL-4, IL-12 and IL-18), monocyte chemoattractant protein, leukemia inhibitory factor, granulocyte-macrophage colony stimulating factor, Fas ligand, tumor necrosis factors alpha and beta., interferons (alpha, beta, and gamma), stem cell factor, flk-2/flt3 ligand. Gene products produced by the immune system are also useful in the present disclosure. These include, without limitations, immunoglobulins IgG, IgM, IgA, IgD and IgE, chimeric immunoglobulins, humanized antibodies, single chain antibodies, T cell receptors, chimeric T cell receptors, single chain T cell receptors, class I and class II MHC molecules, as well as engineered immunoglobulins and MHC molecules. Useful gene products also include complement regulatory proteins such as complement regulatory proteins, membrane cofactor protein (MCP), decay accelerating factor (DAF), CR1, CF2 and CD59. [00826] Examples of still further therapeutic proteins that may be encoded by the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) described herein can include, in some embodiments; receptors for the hormones, growth factors, cytokines, lymphokines, regulatory proteins and immune system proteins; receptors for cholesterol regulation and/or lipid modulation, including the low density lipoprotein (LDL) receptor, high density lipoprotein (HDL) receptor, the very low density lipoprotein (VLDL) receptor, and scavenger receptors. The disclosure also encompasses the use of gene products such as members of the steroid hormone receptor superfamily including glucocorticoid receptors and estrogen receptors, Vitamin D receptors and other nuclear receptors. In addition, useful gene products include transcription factors such as jun, fos, max, mad, serum response factor (SRF), AP-1, AP-2, myb, MyoD and myogenin, ETS-box containing proteins, TFE3, E2F, ATFL, ATF2, ATF3, ATF4, ZF5, NFAT, CREB, HNF-4, C/EBP, SP1, CCAAT-box binding proteins, interferon regulation factor (IRF-1), Wilms tumor protein, ETS-binding protein, STAT, GATA-box binding proteins, e.g., GATA-3, and the forkhead family of winged helix proteins. [00827] In some embodiments, useful heterologous nucleic acid sequence products include, carbamoyl synthetase I, ornithine transcarbamylase, arginosuccinate synthetase, arginosuccinate lyase, arginase, fumarylacetacetate hydrolase, phenylalanine hydroxylase, alpha-1 antitrypsin, glucose-6-phosphatase, porphobilinogen deaminase, cystathione beta-synthase, branched chain ketoacid decarboxylase, albumin, isovaleryl-coA dehydrogenase, propionyl CoA carboxylase, methyl malonyl CoA mutase, glutaryl CoA dehydrogenase, insulin, beta-glucosidase, pyruvate carboxylate, hepatic phosphorylase, phosphorylase kinase, glycine decarboxylase, H-protein, T-protein, a cystic fibrosis transmembrane regulator (CFTR) sequence, and a dystrophin cDNA sequence. Still other useful gene products include enzymes useful in enzyme replacement therapy, and which are useful in a variety of conditions resulting from deficient activity of enzyme. For example, enzymes containing mannose-6-phosphate may be utilized in therapies for lysosomal storage diseases (e.g., a suitable gene includes that encoding β-glucuronidase (GUSB)). Exemplary therapeutic proteins [00828] In some embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) and associated compositions and methods described herein provide for the delivery of one or more therapeutic proteins chosen from the proteins listed in Table (IV), or the delivery of one or more homologs of the therapeutic proteins of Table (IV). Table (IV) – Exemplary therapeutic proteins encoded by RNA payloads

A1E959, Odontogenic ameloblast associated A6NI73 Leukocyte immunoglobulin-like protein, ODAM receptor subfamily A member 5, LILRA5 A1KZ92, Peroxidasin like protein, PXDN L A6NIT4 Chorionic somatomammotropin A1L453, Serine protease 38, PRSS38 hormone 2 isoform 2, CSH2 A1L4H1, Soluble scavenger receptor cysteine- A6NJ69 IgA-inducing protein homolog, IGIP rich domain-containing protein, SSC5D A6NKQ9 Choriogonadotropin subunit beta A2RUU4, Colipase-like protein 1, CLPSL1 variant 1 CGB1 A2VDF0, Fucose mutarotase, FUOM A6NMZ7 Collagen alpha-6(VI) chain COL6A6 A2VEC9, SCO-spondin, SSPO A6NNS2 Dehydrogenase/reductase SDR A3KMH 1, von Willebrand factor A domain- family DHRS7C member 7C containing protein 8, VWA8 A6XGL2 Insulin A chain INS A4D0S4, Laminin subunit beta-4, LAMB A8K0G1 Protein Wnt WNT7B A4D1T9, Probable inactive serine protease 37, A8K2U0 Alpha-2-macroglobulin-like protein 1 PRSS37 A2ML1 A5D8T8, C-type lectin domain family 18 A8K7I4 Calcium-activated chloride channel member A, CLEC18A CLCA1 regulator 1 A6NC86, phospholipase A2 inhibitor and A8MTL9 Serpin-like protein HMSD HMSD Ly6/PLAUR domain-containing protein, A8MV23 Serpin E3, SERPINE3 PINLYP A8MZH6 Oocyte-secreted protein 1 homolog, A6NCI4, von Willebrand factor A domain OOSP1 containing protein 3A, VWA3A A8TX70 Collagen alpha-5(VI) chain, COL6A5 A6ND01, Probable folate receptor delta, B0ZBE8 Natriuretic peptide, NPPA FOLR4 B1A4G9 Somatotropin, GH1 A6NE02, BTB/POZ domain-containing protein B1A4H2 HCG 1749481, isoform CRA_d, 17, BTBD17 CSH1 A6NEF6, Growth hormone 1, GH1 B1A4H9 Chorionic somatomammotropin A6NF02, NPIP-like protein, LOC730153 hormone, CSH2 A6NFB4, HCG 1749481, isoform CRA_k, B1AJZ6 Protein Wnt, WNT4 CSH1 B1AKI9 lsthmin-1, ISM1 A6NFZ4, Protein FAM24A, FAM24A B2RN N3 Complement Clq and tumor necrosis A6NG13, Glycosyltransferase 54 domain- F9B factor-related protein 9B, C1QTN containing Protein B2RUY7 von Willebrand factor C domain- A6NGN9, IgLON family member 5, IGLON5 containing protein 2-like, VWC2L A6NHN0, Otolin-1, OTOL1 B3GLJ2 Prostate and testis expressed protein 3, A6NHN6, Nuclear pore complex-interacting PATE3 protein-like 2, NPIPL2 B4DI03 SECll-like 3 (S. cerevisiae), SEC11L3 B4DJF9 Protein Wn,t WNT4 B4DUL4 SECll-like 1 (S. cerevisiae), isoform H0YK83 Signal peptidase complex catalytic CRA_d, SEC11L1 subunit, SEC11A B5MCC8 Protein Wnt, WNT10B H0YM39 Chorionic somatomammotropin B8A595 Protein Wnt,WNT7B hormone, CSH2 B8A597 Protein Wnt, WNT7B H0YMT7 Chorionic somatomammotropin B8A598 Protein Wnt, WNT7B hormone, CSH1 B9A064 Immunoglobulin lambda-like H0YN 17 Chorionic somatomammotropin polypeptide5, IGLL5 hormone, CSH2 C9J3H3 Protein Wnt, WNT10B H0YNA5 Signal peptidase complex catalytic C9J8I8 Protein Wnt, WNT5A subunit SEC11A C9JAF2 Insulin-like growth factor II Ala-25 H0YNG3 Signal peptidase complex catalytic Del, IGF2 subunit SEC11A C9JCI2 Protein Wnt, WNT10B H0YNX5 Signal peptidase complex catalytic C9JL84 HERV-H LTR-associating protein 1, subunit SEC11A HHLA1 H7BZB8 Protein Wnt. WNT10A C9JN R5 Insulin A chain, INS H9KV56 Choriogonadotropin subunit beta C9JU I2 Protein Wnt, WNT2 variant 2, CGB2 D6RF47 Protein Wnt, WNT8A I3L0L8 Protein Wnt. WNT9B D6RF94 Protein Wnt, WNT8A J3KNZ1 Choriogonadotropin subunit beta E2RYF7 Protein PBMUCL2, HCG22 variant 1, CGB1 E5RFR1 PEN K(114-133), PENK J3KP00 Choriogonadotropin subunit beta. E7EM L9 Serine protease 44, PRSS44 CGB7 E7EPC3 Protein Wnt, WNT9B J3QT02 Choriogonadotropin subunit beta E7EVP0 Nociceptin, PNOC variant 1, CGB1 E9PD02 Insulin-like growth factor 1, IGF1 000175 C-C motif chemokine 24, CCL24 E9PH60 Protein Wnt, WNT16 000182 Galectin-9, LGALS9 E9PJ L6 Protein Wnt, WNT11 000187 Mannan-binding lectin serine protease F5GYM2 Protein Wnt, WNT5B 2, MASP2 F5H034 Protein Wnt, WNT5B 000230 Cortistatin, CORT F5H364 Protein Wnt, WNT5B 000253 Agouti-related protein, AGRP F5H7Q6 Protein Wnt, WNT5B 00027012-(S)-hydroxy-5,8,10,14- F8WCM5 Protein INS-IGF2, INS-IGF2 eicosatetraenoic acid receptor, GPR31 F8WDR1 Protein Wnt, WNT2 000292 Left-right determination factor 2, H0Y663 Protein Wnt, WNT4 LEFTY2 H0YK72 Signal peptidase complex catalytic 000294 Tubby-related protein 1, TULP1 subunit, SEC11A 000295 Tubby-related protein 2, TULP2 000300 Tumor necrosis factor receptor 014960 Leukocyte cell-derived chemotaxin-2, superfamily member 11B, TNFRSF11B LECT2 000339 Matrilin-2, MATN2 015018 Processed PDZ domain-containing 000391 Sulfhydryl oxidase 1, QSOX1 protein 2, PDZD2 000468 Agrin, AGRN 015041 Semaphorin-3E, SEMA3E 000515 Ladinin-1, LAD1 015072 A disintegrin and metalloproteinase 000533 Processed neural cell adhesion with thrombospondin motifs 3, ADAMTS3 molecule Ll-like protein, CHL1 015123 Angiopoietin-2, ANGPT2 000584 Ribonuclease T2, RNASET2 015130 Neuropeptide FF, NPFF 000585 C-C motif chemokine 21, CCL21 015197 Ephrin type-B receptor 6, EPHB6 000602 Ficolin-1, FCN1 015230 Laminin subunit alpha-5, LAMA5 000622 Protein CYR61, CYR61 015232 Matrilin-3, MATN3 000626 MDC(5-69), CCL22 015240 Neuroendocrine regulatory peptide-1, 000634 Netrin-3, NTN3 VGF 000744 Protein Wnt-10b, WNT10B 015263 Beta-defensin 4A, DEFB4A 000755 Protein Wnt-7a, WNT7A 015335 Chondroadherin, CHAD 014498 Immunoglobulin superfamily 015393 Transmembrane protease serine 2 containing leucine-rich repeat protein, ISLR catalytic chain, TMPRSS2 014511 Pro-neuregulin-2, membrane-bound 015444 C-C motif chemokine 25, CCL25 isoform, NRG2 015467 C-C motif chemokine 16, CCL16 014594 Neurocan core protein, NCAN 015496 Group 10 secretory phospholipase A2, 014625 C-X-C motif chemokine 11, CXCL11 PLA2G10 014638 Ectonucleotide 015520 Fibroblast growth factor 10, FGF10 pyrophosphatase/phosphodiesterase family 015537 Retinoschisin, RSI member 3, ENPP3 043157 Plexin-Bl, PLXN B1 014656 Torsin-IA, TOR1A 043184 Disintegrin and metalloproteinase 014657 Torsin-IB, TOR1B domain-containing protein 12, ADAM12 014786 Neuropilin-1, NRP1 043240 Kallikrein-10, KLK10 014788 Tumor necrosis factor ligand 043278 Kunitz-type protease inhibitor 1, superfamily member 11, membrane form, SPINT1 TNFSF11 043320 Fibroblast growth factor 16, FGF16 014791 Apolipoprotein LI, APOL1 043323 Desert hedgehog protein C-product, 014793 Growth/differentiation factor 8, MSTN DHH 014904 Protein Wnt-9a, WNT9A 043405 Cochlin, COCH 014905 Protein Wnt-9b, WNT9B 043508 Tumor necrosis factor ligand 014944 Proepiregulin, EREG superfamily member 12, membrane form, TNFSF12 043555 Progonadoliberin-2, GN RH2 060938 Keratocan, KERA 043557 Tumor necrosis factor ligand 075015 Low affinity immunoglobulin gamma superfamily member 14, soluble form, Fc region receptor lll-B, FCGR3B TNFSF14 075077 Disintegrin and metalloproteinase 043692 Peptidase inhibitor 15, PI15 domain-containing protein 23, ADAM23 043699 Sialic acid-binding Ig-like lectin 6, 075093 Slit homolog 1 protein, SLIT1 SIGLEC6 075094 Slit homolog 3 protein, SLIT3 043820 Hyaluronidase-3, HYAL3 075095 Multiple epidermal growth factor-like 043827 Angiopoietin-related protein 7, domains protein 6, MEGF6 ANGPTL7 075173 A disintegrin and metalloproteinase 043852 Calumenin, CALU with thrombospondin motifs 4, ADAMTS4 043854 EGF-like repeat and discoidin l-like 075200 Nuclear pore complex-interacting domain-containing protein 3, EDIL3 protein-like 1, NPIPL1 043866 CD5 antigen-like, CD5L 075339 Cartilage intermediate layer protein 1, 043897 Tolloid-like protein 1, TLL1 CI CILP 043915 Vascular endothelial growth factor D, 075354 Ectonucleoside triphosphate FIGF diphosphohydrolase 6, ENTPD6 043927 C-X-C motif chemokine 13, CXCL13 075386 Tubby-related protein 3, TULP3 060218 Aldo-keto reductase family 1 member, 075398 Deformed epidermal autoregulatory AKR1B10 factor 1 homolog, DEAF1 060235 Transmembrane protease serine 11D, 075443 Alpha-tectorin, TECTA TMPRSS11D 075445 Usherin, USH2A 060258 Fibroblast growth factor 17, FGF17 075462 Cytokine receptor-like factor 1, CRLF1 060259 Kallikrein-8, KLK8 075487 Glypican-4, GPC4 060383 Growth/differentiation factor 9, GDF9 075493 Carbonic anhydrase-related protein 11, 060469 Down syndrome cell adhesion CA11 molecule, DSCAM 075594 Peptidoglycan recognition protein 1, 060542 Persephin, PSPN PGLYRP1 060565 Gremlin-1, GREM1 075596 C-type lectin domain family 3 member 060575 Serine protease inhibitor Kazal-type 4, A, CLEC3A SPIN K4 075610 Left-right determination factor 1, 060676 Cystatin-8, CST8 LEFTY1 060687 Sushi repeat-containing protein, 075629 Protein CREG1, CREG1 SRPX2 075636 Ficolin-3, FCN3 060844 Zymogen granule membrane protein 075711 Scrapie-responsive protein 1, SCRG1 16, ZG16 075715 Epididymal secretory glutathione 060882 Matrix metalloproteinase-20, MMP20 peroxidase, GPX5 075718 Cartilage-associated protein, CRTAP 095399 Urotensin-2, UTS2 075829 Chondrosurfactant protein, LECT1 095407 Tumor necrosis factor receptor 075830 Serpin 12, SERPINI2 superfamily member 6B, TNFRSF6B 075882 Attractin, ATRN 095428 Papilin, PAPLN 075888 Tumor necrosis factor ligand 095445 Apolipoprotein M, APOM superfamily member 13, TNFSF13 095450 A disintegrin and metalloproteinase 075900 Matrix metalloproteinase-23, MMP23A with thrombospondin motifs 2, ADAMTS2 075951 Lysozyme-like protein 6, LYZL6 095460 Matrilin-4, MATN4 075973 Clq-related factor, C1QL1 095467 LHAL tetrapeptide, GNAS 076038 Secretagogin, SCGN 095631 Netrin-1, NTN1 076061 Stanniocalcin-2, STC2 095633 Follistatin-related protein 3, FSTL3 076076 WNTl-inducible-signaling pathway 095711 Lymphocyte antigen 86, LY86 protein 2, WISP2 095715 C-X-C motif chemokine 14, CXCL14 076093 Fibroblast growth factor 18, FGF18 095750 Fibroblast growth factor 19, FGF19 076096 Cystatin-F, CST7 095760 lnterleukin-33, IL33 094769 Extracellular matrix protein 2, ECM2 095813 Cerberus, CER1 094813 Slit homolog 2 protein C-product, 095841 Angiopoietin-related protein 1, SLIT2 ANGPTL1 094907 Dickkopf-related protein 1, DKK1 095897 Noelin-2, OLFM2 094919 Endonuclease domain-containing 1 095925 Eppin, EPPIN protein, ENDOD1 095965 Integrin beta-like protein 1, ITGBL1 094964 N-terminal form, SOGA1 095967 EGF-containing fibulin-like 095025 Semaphorin-3D, SEMA3D extracellular matrix protein 2, EFEMP2 095084 Serine protease 23, PRSS23 095968 Secretoglobin family ID member 1, 095150 Tumor necrosis factor ligand SCGB1D1 superfamily member 15, TNFSF15 095969 Secretoglobin family ID member 2, 095156 Neurexophilin-2, NXPH2 SCGB1D2 095157 Neurexophilin-3, NXPH3 095970 Leucine-rich glioma-inactivated protein 095158 Neurexophilin-4 ,NXPH4 1, LGI1 095388 WNTl-inducible-signaling pathway 095972 Bone morphogenetic protein 15, protein 1, WISP1 BMP15 095389 WNTl-inducible-signaling pathway 095994 Anterior gradient protein 2 homolog, protein 3, WISP3 AGR2 095390 Growth/differentiation factor 11, 095998 lnterleukin-18-binding protein, IL18BP GDF11 096009 Napsin-A, NAPSA 095393 Bone morphogenetic protein 10, 096014 Protein Wnt-11, WNT11 BMP10 P00450 Ceruloplasmin CP P00451 Factor Villa light chain F8 P01042 Kininogen-1 light chain, KNG1 P00488 Coagulation factor XIII A chain, P01127 Platelet-derived growth factor subunit F13A1 B, PDGFB P00533 Epidermal growth factor receptor, P01135 Transforming growth factor alpha, EGFR TGFA P00709 Alpha-lactalbumin LA LB A P01137 Transforming growth factor beta-1, P00734 Prothrombin F2 TGFB1 P00738 Haptoglobin beta chain HP P01138 Beta-nerve growth factor, NGF P00739 Haptoglobin-related protein HPR P01148 Gonadoliberin-1, GN RH 1 P00740 Coagulation factor IXa heavy chain F9 P01160 Atrial natriuretic factor, NPPA P00742 Factor X heavy chain F10 P01178 Oxytocin, OXT P00746 Complement factor D CFD P01185 Vasopressin-neurophysin 2-copeptin, P00747 Plasmin light chain B PLG AVP P00748 Coagulation factor XI la light chain P01189 Corticotropin, POMC F12 P01210 PEN K(237-258), PENK P00749 Urokinase-type plasminogen activator P01213 Alpha-neoendorphin, PDYN long chain A, PLAU P01215 Glycoprotein hormones alpha chain, P00750 Tissue-type plasminogen activator, CGA PLAT P01222 Thyrotropin subunit beta, TSHB P00751 Complement factor B Ba fragment, P01225 Follitropin subunit beta, FSHB CFB P01229 Lutropin subunit beta, LHB P00797 Renin, REN P01233 Choriogonadotropin subunit beta, P009732'-5'-oligoadenylate synthase 1, OAS1 CGB8 P00995 Pancreatic secretory trypsin inhibitor, P01236 Prolactin, PRL SPIN K1 P01241 Somatotropin, GH1 P01008 Antithrombin-lll, SERPINC1 P01242 Growth hormone variant, GH2 P01009 Alpha-l-antitrypsin, SERPINA1 P01243 Chorionic somatomammotropin P01011 Alpha-l-antichymotrypsin His-Pro-less, hormone, CSH2 SERPINA3 P01258 Katacalcin, CALCA P01019 Angiotensin-1, AGT P01266 Thyroglobulin, TG P01023 Alpha-2-macroglobulin, A2M P01270 Parathyroid hormone, PTH P01024 Acylation stimulating protein, C3 P01275 Glucagon, GCG P01031 Complement C5 beta chain, C5 P01282 Intestinal peptide, PHM-27 VIP P01033 Metalloproteinase inhibitor 1, TIM P1 P01286 Somatoliberin, GH RH P01034 Cystatin-C, CST3 P01298 Pancreatic prohormone, PPY P01036 Cystatin-S, CST4 P01303 C-flanking peptide of N PY, NPY P01037 Cystatin-SN, CST1 P01308 Insulin, INS P01344 Insulin-like growth factor, II IGF2 P02656 Apolipoprotein C-lll APOC3 P01350 Big gastrin, GAST P02671 Fibrinogen alpha chain FGA P01374 Lymphotoxin-alpha, LTA P02675 Fibrinopeptide B FGB P01375 C-domain 1, TNF P02679 Fibrinogen gamma chain FGG P01562 Interferon alpha-1/13 IFNA1 P02741 C-reactive protein CRP P01563 Interferon alpha-2 IFNA2 P02743 Serum amyloid P-component(l-203) P01566 Interferon alpha-10 IFNA10 APCS P01567 Interferon alpha-7 IFNA7 P02745 Complement Clq subcomponent P01568 Interferon alpha-21 IFNA21 subunit A, C1QA P01569 Interferon alpha-5 IFNA5 P02746 Complement Clq subcomponent P01570 Interferon alpha-14 IFNA14 subunit B, C1QB P01571 Interferon alpha-17 IFNA17 P02747 Complement Clq subcomponent P01574 Interferon beta IFNB1 subunit C, C1QC P01579 Interferon gamma IFNG P02748 Complement component C9b C9 P01583 lnterleukin-1 alpha ILIA P02749 Beta-2-glycoprotein 1 APOH P01584 lnterleukin-1 beta IL1B P02750 Leucine-rich alpha-2-glycoprotein P01588 Erythropoietin EPO LRG1 P01591 Immunoglobulin J chain IGJ P02751 Ugl-Y2 FN 1 P01732 T-cell surface glycoprotein CD8 alpha P02753 Retinol-binding protein 4 RBP4 CD8A chain P02760 Trypstatin AMBP P01833 Polymeric immunoglobulin receptor P02763 Alpha-l-acid glycoprotein 1 ORM1 PIGR P02765 Alpha-2-HS-glycoprotein chain A P01857 Ig gamma-l chain C region IGHG1 AHSG P01859 Ig gamma-2 chain C region IGHG2 P02766 Transthyretin TTR P01860 Ig gamma-3 chain C region IGHG3 P02768 Serum albumin ALB P01861 Ig gamma-4 chain C region IGHG4 P02771 Alpha-fetoprotein AFP P01871 Ig mu chain C region IGHM P02774 Vitamin D-binding protein GC P01880 Ig delta chain C region IGHD P02775 Connective tissue-activating peptide III P02452 Collagen alpha-l(l) chain COL1A1 PPBP P02458 Chondrocalcin COL2A1 P02776 Platelet factor 4 PF4 P02461 Collagen alpha-l(lll) chain COL3A1 P02778 CXCL10(l-73) CXCL10 P02462 Collagen alpha-l(IV) chain COL4A1 P02786 Transferrin receptor protein 1 TFRC P02647 Apolipoprotein A-l APOA1 P02787 Serotransferrin TF P02649 Apolipoprotein E APOE P02788 Lactoferroxin-C LTF P02652 Apolipoprotein A-ll APOA2 P02790 Hemopexin HPX P02654 Apolipoprotein C-l APOC1 P02808 Statherin STATH P02655 Apolipoprotein C-ll APOC2 P02810 Salivary acidic proline-rich PRH2 P05000 Interferon omega-1 IFNW1 phosphoprotein 1/2 P05013 Interferon alpha-6 IFNA6 P02812 Basic salivary proline-rich protein 2 P05014 Interferon alpha-4 IFNA4 PRB2 P05015 Interferon alpha-16 IFNA16 P02814 Peptide D1A SMR3B P05019 Insulin-like growth factor 1 IGF1 P02818 Osteocalcin BGLAP P05060 GAWK peptide CHGB P03950 Angiogenin ANG P05090 Apolipoprotein D APOD P03951 Coagulation factor Xla heavy chain Fll P05109 Protein S100-A8 S100A8 P03952 Plasma kallikrein KLKB1 P05111 Inhibin alpha chain INHA P0395627 kDa interstitial collagenase MMP1 P05112 lnterleukin-4 IL4 P03971 Muellerian-inhibiting factor AMH P05113 lnterleukin-5 IL5 P03973 Antileukoproteinase SLPI P05120 Plasminogen activator inhibitor 2 P04003 C4b-binding protein alpha chain SERPINB2 C4BPA P05121 Plasminogen activator inhibitor 1 P04004 Somatomedin-B VTN SERPINE1 P04054 Phospholipase A2 PLA2G1B P05154 Plasma serine protease inhibitor P04085 Platelet-derived growth factor subunit SERPINA5 A PDGFA P05155 Plasma protease CI inhibitor P04090 Relaxin A chain RLN2 SERPING1 P04114 Apolipoprotein B-100 APOB P05156 Complement factor 1 heavy chain CFI P04118 Colipase CLPS P05160 Coagulation factor XIII B chain F13B P04141 Granulocyte-macrophage colony- P05161 Ubiquitin-like protein ISG15 ISG15 CSF2 stimulating factor P05230 Fibroblast growth factor 1 FGF1 P04155 Trefoil factor 1 TFF1 P05231 lnterleukin-6 IL6 P04180 Phosphatidylcholine-sterol LCAT P05305 Big endothelin-1 EDN1 acyltransferase P05408 C-terminal peptide SCG5 P04196 Histidine-rich glycoprotein HRG P05451 Lithostathine-l-alpha REG1A P04217 Alpha-lB-glycoprotein A1BG P05452 Tetranectin CLEC3B P04275 von Willebrand antigen 2 VWF P05543 Thyroxine-binding globulin P04278 Sex hormone-binding globulin SHBG SERPINA7 P04279 Alpha-inhibin-31 SEMG1 P05814 Beta-casein CSN2 P04280 Basic salivary proline-rich protein 1 P05997 Collagen alpha-2(V) chain COL5A2 PRB1 P06276 Cholinesterase BCHE P04628 Proto-oncogene Wnt-1 WNT1 P06307 Cholecystokinin-12 CCK P04745 Alpha-amylase 1 AMY1A P06396 Gelsolin GSN P04746 Pancreatic alpha-amylase AMY2A P06681 Complement C2 C2 P04808 Prorelaxin HI RLN1 P06702 Protein S100-A9 S100A9 P06727 Apolipoprotein A-IV APOA4 P08218 Chymotrypsin-like elastase family P06734 Low affinity immunoglobulin epsilon member 2B, CELA2B Fc receptor soluble form, FCER2 P0825372 kDa type IV collagenase MMP2 P06744 Glucose-6-phosphate isomerase GPI P08254 Stromelysin-1 MMP3 P06850 Corticoliberin CRH P08294 Extracellular superoxide dismutase P06858 Lipoprotein lipase LPL [Cu- SOD3Zn] P06881 Calcitonin gene-related peptide 1 P08476 Inhibin beta A chain IN HBA CALCA P08493 Matrix Gla protein MGP P07093 Glia-derived nexin SERPINE2 P08572 Collagen alpha -2(IV) chain COL4A2 P07098 Gastric triacylglycerol lipase LIPF P08581 Hepatocyte growth factor receptor P07225 Vitamin K-dependent protein S PROS1 MET P07237 Protein disulfide-isomerase P4HB P08603 Complement factor H CFH P07288 Prostate-specific antigen KLK3 P08620 Fibroblast growth factor 4 FGF4 P07306 Asialoglycoprotein receptor 1 ASGR1 P08637 Low affinity immunoglobulin gamma P07355 Annexin A2 ANXA2 Fc region receptor lll-A, FCGR3A P07357 Complement component C8 alpha P08697 Alpha-2-antiplasmin, SERPINF2 chain C8A P08700 lnterleukin-3 IL3 P07358 Complement component C8 beta chain P08709 Coagulation factor VII F7 C8B P08833 Insulin-like growth factor-binding P07360 Complement component C8 gamma protein 1, IGFBP1 C8G chain P08887 lnterleukin-6 receptor subunit alpha P07477 Alpha-trypsin chain 2 PRSS1 IL6R P07478 Trypsin-2 PRSS2 P08949 Neuromedin-B-32 NMB P07492 Neuromedin-C GRP P08F94 Fibrocystin PKH D1 P07498 Kappa -casein CSN3 P09038 Fibroblast growth factor 2 FGF2 P07585 Decorin DCN P09228 Cystatin-SA CST2 P07911 Uromodulin UMOD P09237 Matrilysin MMP7 P07942 Laminin subunit beta-1 LAMB1 P09238 Stromelysin-2 MMP10 P07988 Pulmonary surfactant-associated P09341 Growth-regulated alpha protein protein B, SFTPB CXCL1 P07998 Ribonuclease pancreatic RNASE1 P09382 Galectin-1 LGALS1 P08118 Beta-microseminoprotein MSM B P09466 Glycodelin PAEP P08123 Collagen alpha-2(l) chain COL1A2 P09486 SPARC SPARC P08185 Corticosteroid-binding globulin P09529 Inhibin beta B chain IN HBB SERPINA6 P09544 Protein Wnt-2 WNT2 P08217 Chymotrypsin-like elastase family P09603 Processed macrophage colony- member 2A, CELA2A stimulating factor 1, CSF1 P09681 Gastric inhibitory polypeptide GIP P10124 Serglycin SRGN P09683 Secretin SCT P10145 MDNCF-a IL8 P09919 Granulocyte colony-stimulating factor P10147 MIP-l-alpha(4-69) CCL3 CSF3 P10163 Peptide P-D PRB4 P0C091 FRASl-related extracellular matrix P10451 Osteopontin SPP1 FREM3 protein 3 P10599 Thioredoxin TXN P0C0L4 C4d-A C4A P10600 Transforming growth factor beta-3 P0C0L5 Complement C4-B alpha chain C4B TGFB3 P0C0P6 Neuropeptide S NPS P10643 Complement component C7 C7 P0C7L1 Serine protease inhibitor Kazal-type 8 P10645 Vasostatin-2 CHGA SPIN K8 P10646 Tissue factor pathway inhibitor TFPI P0C862 Complement Clq and tumor necrosis P10720 Platelet factor 4 variant(4-74) PF4V1 factor-related protein 9A, C1QTN F9 P10745 Retinol-binding protein 3 RBP3 P0C8F1 Prostate and testis expressed protein 4 P10767 Fibroblast growth factor 6 FGF6 PATE4 P10909 Clusterin alpha chain CLU POCGOl Gastrokine-3 GKN3P P10912 Growth hormone receptor GHR P0CG36 Cryptic family protein IB CFC1B P10915 Hyaluronan and proteoglycan link P0CG37 Cryptic protein CFC1 protein 1, HAPLN 1 P0CJ68 Humanin-like protein 1, MTRN R2L1 P10966 T-cell surface glycoprotein CD8 beta P0CJ69 Humanin-like protein 2, MTRN R2L2 chain, CD8B P0CJ70 Humanin-like protein 3, MTRN R2L3 P10997 Islet amyloid polypeptide IAPP P0CJ71 Humanin-like protein 4, MTRN R2L4 P11047 Laminin subunit gamma-1 LAMC1 P0CJ72 Humanin-like protein 5, MTRN R2L5 P11150 Hepatic triacylglycerol lipase UPC P0CJ73 Humanin-like protein 6, MTRN R2L6 P11226 Mannose-binding protein C MBL2 P0CJ74 Humanin-like protein 7, MTRN R2L7 P11464 Pregnancy-specific beta-l-glycoprotein P0CJ75 Humanin-like protein 8, MTRN R2L8 1 PSG1 P0CJ76 Humanin-like protein 9, MTRN R2L9 P11465 Pregnancy-specific beta-l-glycoprotein P0CJ77 Humanin-like protein 10, MTRN 2 PSG2 R2L10 P11487 Fibroblast growth factor 3 FGF3 P0DJD7 Pepsin A-4, PGA4 P11597 Cholesteryl ester transfer protein CETP P0DJD8 Pepsin A-3, PGA3 P11684 Uteroglobin SCGB1A1 P0DJD9 Pepsin A-5, PGA5 P11686 Pulmonary surfactant-associated P0DJI8 Amyloid protein A, SAA1 protein C, SFTPC P0DJI9 Serum amyloid A-2 protein, SAA2 P12034 Fibroblast growth factor 5 FGF5 P10082 Peptide YY(3-36), PYY P12107 Collagen alpha-l(XI) chain COL11A1 P10092 Calcitonin gene-related peptide 2, P12109 Collagen alpha-l(VI) chain COL6A1 CALCB P12110 Collagen alpha-2(VI) chain COL6A2 P12111 Collagen alpha-3(VI) chain COL6A3 P14543 Nidogen-1, NIDI P12259 Coagulation factor V F5 P14555 Phospholipase A2, membrane P12272 PTHrP[l-36] PTHLH associated, PLA2G2A P12273 Prolactin-inducible protein PIP P14625 Endoplasmin, HSP90B1 P12544 Granzyme A GZMA P14735 Insulin-degrading enzyme IDE P12643 Bone morphogenetic protein 2 BMP2 P14778 lnterleukin-1 receptor type 1, soluble P12644 Bone morphogenetic protein 4 BMP4 IL1R1 form P12645 Bone morphogenetic protein 3 BMP3 P1478082 kDa matrix metalloproteinase-9, P12724 Eosinophil cationic protein RNASE3 MMP9 P12821 Angiotensin-converting enzyme, P15018 Leukemia inhibitory factor LIF soluble ACE form P15085 Carboxypeptidase Al CPA1 P12838 Neutrophil defensin 4 DEFA4 P15086 Carboxypeptidase B CPB1 P12872 Motilin MLN P15151 Poliovirus receptor PVR P13232 lnterleukin-7 IL7 P15169 Carboxypeptidase N catalytic chain P13236 C-C motif chemokine 4 CCL4 CPN1 P13284 Gamma-interferon-inducible lysosomal P15248 lnterleukin-9 IL9 IFI30 thiol reductase P15291 N-acetyllactosamine synthase P13500 C-C motif chemokine 2 CCL2 B4GALT1 P13501 C-C motif chemokine 5 CCL5 P15309 PAPf39 ACPP P13521 Secretogranin-2, SCG2 P15328 Folate receptor alpha FOLR1 P13591 Neural cell adhesion molecule 1, P15374 Ubiquitin carboxyl-terminal hydrolase NCAM 1 isozyme L3, UCHL3 P13611 Versican core protein, VCAN P15502 Elastin ELN P13671 Complement component C6, C6 P15509 Granulocyte-macrophage colony- P13688 Carcinoembryonic antigen-related cell stimulating factor receptor subunit alpha, adhesion molecule 1, CEACAM1 CSF2RA P13725 Oncostatin-M, OSM P15515 Histatin-1 HTN1 P13726 Tissue factor F3 P15516 His3-(31-51)-peptide HTN3 P13727 Eosinophil granule major basic protein, P15692 Vascular endothelial growth factor A PRG2 VEGFA P13942 Collagen alpha-2(XI) chain, COL11A2 P15814 Immunoglobulin lambda-like P13987 CD59 glycoprotein CD59 polypeptide 1, IGLL1 P14138 Endothelin-3 EDN3 P15907 Beta-galactoside alpha-2,6- P14174 Macrophage migration inhibitory factor sialyltransferase 1, ST6GAL1 MIF P15941 Mucin-1 subunit beta MUC1 P14207 Folate receptor beta FOLR2 P16035 Metalloproteinase inhibitor 2, TIM P2 P14222 Perforin-1 PRF1 P16112 Aggrecan core protein 2, ACAN P16233 Pancreatic triacylglycerol lipase, P19801 Amiloride-sensitive amine oxidase PNLIP ABP1 P16442 Histo-blood group ABO system ABO P19823 Inter-alpha-trypsin inhibitor heavy transferase chain H2, ITIH2 P16471 Prolactin receptor PRLR P19827 Inter-alpha-trypsin inhibitor heavy P16562 Cysteine-rich secretory protein 2, chain H1, ITIH1 CRISP2 P19835 Bile salt-activated lipase CEL P16619 C-C motif chemokine 3-like 1, P19875 C-X-C motif chemokine 2 CXCL2 CCL3L1 P19876 C-X-C motif chemokine 3 CXCL3 P16860 BN P(3-29) NPPB P19883 Follistatin FST P16870 Carboxypeptidase E CPE P19957 Elafin PI3 P16871 lnterleukin-7 receptor subunit alpha P19961 Alpha-amylase 2B AMY2B IL7R P20061 Transcobalamin-1 TCN 1 P17213 Bactericidal permeability-increasing P20062 Transcobalamin-2 TCN2 BPI protein P20142 Gastricsin PGC P17538 Chymotrypsinogen B, CTRBl P20155 Serine protease inhibitor Kazal-type 2 P17931 Galectin-3 LGALS3 SPIN K2 P17936 Insulin-like growth factor-binding P20231 Tryptase beta-2 TPSB2 protein 3, IGFBP3 P20333 Tumor necrosis factor receptor P17948 Vascular endothelial growth factor superfamily member IB, TNFRSF1B receptor 1, FLT1 P20366 Substance P TAC1 P18065 Insulin-like growth factor-binding P20382 Melanin-concentrating hormone protein 2, IGFBP2 PMCH P18075 Bone morphogenetic protein 7 BMP7 P20396 Thyroliberin TRH P18428 Lipopolysaccharide-binding protein P20742 Pregnancy zone protein PZP LBP P20774 Mimecan OGN P18509 PACAP-related peptide ADCYAP1 P20783 Neurotrophin-3 NTF3 P18510 lnterleukin-1 receptor antagonist P20800 Endothelin-2 EDN2 protein IL1RN P20809 lnterleukin-11 IL11 P18827 Syndecan-1 SDC1 P20827 Ephrin-Al EFNA1 P19021 Peptidylglycine alpha-hydroxylating P20849 Collagen alpha-l(IX) chain COL9A1 monooxygenase, PAM P20851 C4b-binding protein beta chain C4BPB P19235 Erythropoietin receptor, EPOR P20908 Collagen alpha-l(V) chain COL5A1 P19438 Tumor necrosis factor-binding protein P21128 Poly(U)-specific endoribonuclease 1, TNFRSF1A ENDOU P19652 Alpha-l-acid glycoprotein 2, ORM2 P21246 Pleiotrophin PTN P21583 Kit ligand KITLG P21741 Midkine MDK P24043 Laminin subunit alpha-2 LAMA2 P21754 Zona pellucida sperm-binding protein 3 P24071 Immunoglobulin alpha Fc receptor ZP3 FCAR P21781 Fibroblast growth factor 7 FGF7 P24347 Stromelysin-3 MMP11 P21802 Fibroblast growth factor receptor 2 P24387 Corticotropin-releasing factor-binding FGFR2 CRHBP protein P21810 Biglycan BGN P24592 Insulin-like growth factor-binding P21815 Bone sialoprotein 2 IBSP protein 6, IGFBP6 P21860 Receptor tyrosine-protein kinase erbB- P24593 Insulin-like growth factor-binding 3 ERBB3 protein 5, IGFBP5 P21941 Cartilage matrix protein MATN 1 P24821 Tenascin TNC P22003 Bone morphogenetic protein 5 BMP5 P24855 Deoxyribonuclease-1 DNASE1 P22004 Bone morphogenetic protein 6 BMP6 P25067 Collagen alpha-2(VIII) chain COL8A2 P22079 Lactoperoxidase LPO P25311 Zinc-alpha-2-glycoprotein AZGP1 P22105 Tenascin-X TNXB P25391 Laminin subunit alpha-1 LAMA1 P22301 lnterleukin-10 IL10 P25445 Tumor necrosis factor receptor FAS P22303 Acetylcholinesterase ACHE superfamily member 6 P22352 Glutathione peroxidase 3 GPX3 P25940 Collagen alpha-3(V) chain COL5A3 P22362 C-C motif chemokine 1 CCL1 P25942 Tumor necrosis factor receptor CD40 P22455 Fibroblast growth factor receptor 4 superfamily member 5 FGFR4 P26022 Pentraxin-related protein PTX3 PTX3 P22466 Galanin message-associated peptide P26927 Hepatocyte growth factor-like protein GAL MST1 beta chain P22692 Insulin-like growth factor-binding P27169 Serum paraoxonase/arylesterase 1 protein 4, IGFBP4 PON1 P22749 Granulysin GN LY P27352 Gastric intrinsic factor GIF P22792 Carboxypeptidase N subunit 2 CPN2 P27487 Dipeptidyl peptidase 4 membrane form P22891 Vitamin K-dependent protein Z PROZ DPP4 P22894 Neutrophil collagenase MMP8 P27539 Embryonic growth/differentiation P23142 Fibulin-1 FBLN 1 factor 1, GDF1 P23280 Carbonic anhydrase 6 CA6 P27658 Vastatin COL8A1 P23352 Anosmin-1 KALI P27797 Calreticulin CALR P23435 Cerebellin-1 CBLN1 P27918 Properdin CFP P23560 Brain-derived neurotrophic factor BDN P28039 Acyloxyacyl hydrolase AOAH F P28300 Protein-lysine 6-oxidase LOX P23582 C-type natriuretic peptide NPPC P28325 Cystatin-D CST5 P23946 Chymase CMA1 P28799 Granulin-1 GRN P29122 Proprotein convertase subtilisin/kexin P35916 Vascular endothelial growth factor type 6, PCSK6 FLT4 receptor 3 P29279 Connective tissue growth factor CTGF P35968 Vascular endothelial growth factor P29320 Ephrin type-A receptor 3 EPHA3 KDR receptor 2 P29400 Collagen alpha-5(IV) chain COL4A5 P36222 Chitinase-3-like protein 1 CHI3L1 P29459 lnterleukin-12 subunit alpha IL12A P36952 Serpin B5 SERPINB5 P29460 lnterleukin-12 subunit beta IL12B P36955 Pigment epithelium-derived factor P29508 Serpin B3 SERPINB3 SERPINF1 P29622 Kallistatin SERPINA4 P36980 Complement factor H-related protein 2 P29965 CD40 ligand, soluble form CD40LG CFHR2 P30990 Neurotensin/neuromedin N NTS P39059 Collagen alpha-l (XV) chain COL15A1 P31025 Lipocalin-1 LCN 1 P39060 Collagen alpha-l (XVIII) chain P31151 Protein S100-A7 S100A7 COL18A1 P31371 Fibroblast growth factor 9 FGF9 P39877 Calcium-dependent phospholipase A2 P31431 Syndecan-4 SDC4 PLA2G5 P3194714-3-3 protein sigma SFN P39900 Macrophage metalloelastase MMP12 P32455 Interferon-induced guanylate-binding P39905 Glial cell line-derived neurotrophic GBP1 protein 1 factor GDNF P32881 Interferon alpha-8 IFNA8 P40225 Thrombopoietin THPO P34096 Ribonuclease 4 RNASE4 P40967 M-alpha PMEL P34130 Neurotrophin-4 NTF4 P41159 Leptin LEP P34820 Bone morphogenetic protein 8B P41221 Protein Wnt-5a WNT5A BMP8B P41222 Prostaglandin-H2 D-isomerase PTGDS P35030 Trypsin-3 PRSS3 P41271 Neuroblastoma suppressor of NBL1 P35052 Secreted glypican-1 GPC1 tumorigenicity 1 P35070 Betacellulin BTC P41439 Folate receptor gamma FOLR3 P35225 lnterleukin-13 IL13 P42127 Agouti-signaling protein ASIP P35247 Pulmonary surfactant-associated P42702 Leukemia inhibitory factor receptor protein D, SFTPD LIFR P35318 ADM ADM P42830 ENA-78(9-78) CXCL5 P35542 Serum amyloid A-4 protein SAA4 P43026 Growth/differentiation factor 5 GDF5 P35555 Fibrillin-1 FBN1 P43251 Biotinidase BTD P35556 Fibrillin-2 FBN2 P43652 Afamin AFM P35625 Metalloproteinase inhibitor 3 TIM P3 P45452 Collagenase 3 MMP13 P35858 Insulin-like growth factor-binding P47710 Casoxin-D CSN1S1 protein complex acid labile subunit, IGFALS P47929 Galectin-7 LGALS7B P47972 Neuronal pentraxin-2 NPTX2 P47989 Xanthine oxidase XDH P51884 Lumican LUM P47992 Lymphotactin XCL1 P51888 Prolargin PRELP P48023 Tumor necrosis factor ligand P52798 Ephrin-A4 EFNA4 superfamily FASLG member 6, membrane P52823 Stanniocalcin-1 STC1 form P53420 Collagen alpha-4(IV) chain COL4A4 P48052 Carboxypeptidase A2 CPA2 P53621 Coatomer subunit alpha COPA P48061 Stromal cell-derived factor 1 CXCL12 P54108 Cysteine-rich secretory protein 3 P48304 Lithostathine-l-beta REG1B CRISP3 P48307 Tissue factor pathway inhibitor 2 P54315 Pancreatic lipase-related protein 1 TFPI2 PNLIPRP1 P48357 Leptin receptor LEPR P54317 Pancreatic lipase-related protein 2 P48594 Serpin B4 SERPINB4 PNLIPRP2 P48645 Neuromedin-U-25 NMU P54793 Arylsulfatase F ARSF P48740 Mannan-binding lectin serine protease P55000 Secreted Ly-6/uPAR-related protein 1 1 MASP1 SLURP1 P48745 Protein NOV homolog NOV P55001 Microfibrillar-associated protein 2 P48960 CD97 antigen subunit beta CD97 MFAP2 P49223 Kunitz-type protease inhibitor 3 P55056 Apolipoprotein C-IV APOC4 SPINT3 P55058 Phospholipid transfer protein PLTP P49747 Cartilage oligomeric matrix protein P55075 Fibroblast growth factor 8 FGF8 COM P P55081 Microfibrillar-associated protein 1 P49763 Placenta growth factor PGF MFAP1 P49765 Vascular endothelial growth factor B P55083 Microfibril-associated glycoprotein 4 VEGFB MFAP4 P49767 Vascular endothelial growth factor C P55107 Bone morphogenetic protein 3B VEGFC GDF10 P49771 Fms-related tyrosine kinase 3 ligand P55145 Mesencephalic astrocyte-derived MAN FLT3LG F neurotrophic factor P49862 Kallikrein-7 KLK7 P55259 Pancreatic secretory granule membrane P49863 Granzyme K GZMK GP2 major glycoprotein, GP2 P49908 Selenoprotein P SEPP1 P55268 Laminin subunit beta-2 LAMB2 P49913 Antibacterial protein FALL-39 CAMP P55773 CCL23(30-99) CCL23 P50607 Tubby protein homolog TUB P55774 C-C motif chemokine 18 CCL18 P51124 Granzyme M GZMM P55789 FAD-linked sulfhydryl oxidase ALR P51512 Matrix metalloproteinase-16 MMP16 GFER P51654 Glypican-3 GPC3 P56703 Proto-oncogene Wnt-3 WNT3 P51671 Eotaxin CCL11 P56704 Protein Wnt-3a WNT3A P56705 Protein Wnt-4 WNT4 P61366 Osteocrin OSTN P56706 Protein Wnt-7b WNT7B P61626 Lysozyme C LYZ P56730 Neurotrypsin PRSS12 P61769 Beta-2-microglobulin B2M P56851 Epididymal secretory protein E3-beta P61812 Transforming growth factor beta-2 EDDM3B TGFB2 P56975 Neuregulin-3 NRG3 P61916 Epididymal secretory protein El NPC2 P58062 Serine protease inhibitor Kazal-type 7 P62502 Epididymal-specific lipocalin-6 LCN6 SPIN K7 P62937 Peptidyl-prolyl cis-trans isomerase A P58215 Lysyl oxidase homolog 3 LOXL3 PPIA P58294 Prokineticin-1 PROK1 P67809 Nuclease-sensitive element-binding P58335 Anthrax toxin receptor 2 ANTXR2 YBX1 protein 1 P58397 A disintegrin and metalloproteinase P67812 Signal peptidase complex catalytic with thrombospondin motifs 12, ADAMTS12 SEC11A subunit SEC11A P58417 Neurexophilin-1 NXPH1 P78310 Coxsackievirus and adenovirus P58499 Protein FAM3B FAM3B receptor CXADR P59510 A disintegrin and metalloproteinase P78333 Secreted glypican-5 GPC5 with thrombospondin motifs 20, ADAMTS20 P78380 Oxidized low-density lipoprotein P59665 Neutrophil defensin 1 DEFA1B receptor 1, OLR1 P59666 Neutrophil defensin 3 DEFA3 P78423 Processed fractalkine CX3CL1 P59796 Glutathione peroxidase 6 GPX6 P78509 Reelin RELN P59826 BPI fold-containing family B member P78556 CCL20(2-70) CCL20 3 BPIFB3 P80075 MCP-2(6-76) CCL8 P59827 BPI fold-containing family B member P80098 C-C motif chemokine 7 CCL7 4 BPIFB4 P80108 Phosphatidylinositol-glycan-specific P59861 Beta-defensin 131 DEFB131 phospholipase D, GPLD1 P60022 Beta-defensin 1 DEFB1 P80162 C-X-C motif chemokine 6 CXCL6 P60153 Inactive ribonuclease-like protein 9 P80188 Neutrophil gelatinase-associated RNASE9 lipocalin LCN2 P60827 Complement Clq tumor necrosis factor- P80303 Nucleobindin-2 NUCB2 C1QTN F8 related protein 8 P80511 Calcitermin S100A12 P60852 Zona pellucida sperm-binding protein 1 P81172 Hepcidin-25 HAMP ZP1 P81277 Prolactin-releasing peptide PRLH P60985 Keratinocyte differentiation-associated P81534 Beta-defensin 103 DEFB103A KRTDAP protein P81605 Dermcidin DCD P61109 Kidney androgen-regulated protein P82279 Protein crumbs homolog 1 CRB1 KAP P82987 ADAMTS-like protein 3 ADAMTSL3 P61278 Somatostatin-14 SST P83105 Serine protease HTRA4 HTRA4 P83110 Serine protease HTRA3 HTRA3 Q03692 Collagen alpha-l(X) chain, COL10A1 P83859 Orexigenic neuropeptide QRFP QRFP Q04118 Basic salivary proline-rich protein 3, P98088 Mucin-5AC MUC5AC PRB3 P98095 Fibulin-2 FBLN2 Q04756 Hepatocyte growth factor activator P98160 Basement membrane-specific heparan short chain, HGFAC HSPG2 sulfate proteoglycan core protein Q04900 Sialomucin core protein 24 CD164 P98173 Protein FAM3A, FAM3A Q05315 Eosinophil lysophospholipase CLC Q00604 Norrin NDP Q05707 Collagen alpha-l(XIV) chain Q00796 Sorbitol dehydrogenase SORD COL14A1 Q00887 Pregnancy-specific beta-l-glycoprotein Q05996 Processed zona pellucida sperm- 9, PSG9 binding ZP2 Q00888 Pregnancy-specific beta-l-glycoprotein protein 2 4, PSG4 Q06033 Inter-alpha-trypsin inhibitor heavy Q00889 Pregnancy-specific beta-l-glycoprotein chain ITIH3 6, PSG6 H3 Q01523 HD5(56-94), DEFA5 Q06141 Regenerating islet-derived protein 3- Q01524 Defensin-6, DEFA6 alpha, REG3A Q01955 Collagen alpha-3(IV) chain, COL4A3 Q06828 Fibromodulin FMOD Q02297 Pro-neuregulin-1, membrane-bound Q07092 Collagen alpha-l(XVI) chain, NRG1 isoform COL16A1 Q02325 Plasminogen-like protein B PLGLB1 Q07325 C-X-C motif chemokine 9, CXCL9 Q02383 Semenogelin-2 SEMG2 Q07507 Dermatopontin DPT Q02388 Collagen alpha-l(VII) chain COL7A1 Q075Z2 Binder of sperm protein homolog 1, Q02505 Mucin-3A MUC3A BSPH1 Q02509 Otoconin-90 OC90 Q07654 Trefoil factor 3, TFF3 Q02747 Guanylin GUCA2A Q07699 Sodium channel subunit beta-1, Q02763 Angiopoietin-1 receptor TEK SCN1B Q02817 Mucin-2 MUC2 Q08345 Epithelial discoidin domain-containing Q02985 Complement factor H-related protein receptor 1, DDR1 3, CFHR3 Q08380 Galectin-3-binding protein Q03167 Transforming growth factor beta LGALS3BP receptor type 3, TGFBR3 Q08397 Lysyl oxidase homolog 1 LOXL1 Q03403 Trefoil factor 2, TFF2 Q08431 Lactadherin MFGE8 Q03405 Urokinase plasminogen activator Q08629 Testican-1 SPOCK1 surface receptor, PLAUR Q08648 Sperm-associated antigen 11B Q03591 Complement factor H-related protein SPAG11B 1, CFHR1 Q08830 Fibrinogen-like protein 1 FGL1 Q10471 Polypeptide N- Q13291 Signaling lymphocytic activation acetylgalactosaminyltransferase 2, GALNT2 molecule SLAMF1 Q10472 Polypeptide N- Q13316 Dentin matrix acidic phosphoprotein 1 acetylgalactosaminyltransferase 1, GALNT1 DMP1 Q11201 CMP-N-acetylneuraminate-beta- Q13361 Microfibrillar-associated protein 5 galactosamide-alpha-2,3-sialyltransferase 1, MFAP5 ST3GAL1 Q13410 Butyrophilin subfamily 1 member Al Q11203 CMP-N-acetylneuraminate-beta-1,4- BTN 1A1 galactoside alpha-2,3-sialyltransferase 3, Q13421 Mesothelin, cleaved form MSLN ST3GAL3 Q13429 Insulin-like growth factor 1 IGF-I Q11206 CMP-N-acetylneuraminate-beta- Q13443 Disintegrin and metalloproteinase galactosamide-alpha-2,3-sialyltransferase 4, ADAM9 domain-containing protein 9 ST3GAL4 Q13519 Neuropeptide 1 PNOC Q12794 Hyaluronidase-1, HYAL1 Q13751 Laminin subunit beta-3 LAMB3 Q12805 EGF-containing fibulin-like Q13753 Laminin subunit gamma-2 LAMC2 extracellular matrix protein 1, EFEMP1 Q13790 Apolipoprotein F APOF Q12836 Zona pellucida sperm-binding protein Q13822 Ectonucleotide ENPP2 4 ZP4 pyrophosphatase/phosphodiesterase family Q12841 Follistatin-related protein 1, FSTL1 member 2 Q12904 Aminoacyl tRNA synthase complex- Q14031 Collagen alpha-6(IV) chain COL4A6 interacting multifunctional protein 1, AIMP1 Q14050 Collagen alpha-3(IX) chain COL9A3 Q13018 Soluble secretory phospholipase A2 Q14055 Collagen alpha-2(IX) chain COL9A2 receptor, PLA2R1 Q14112 Nidogen-2 NID2 Q13072 B melanoma antigen 1, BAGE Q14114 Low-density lipoprotein receptor- Q13093 Platelet-activating factor related protein 8, LRP8 acetylhydrolase, PLA2G7 Q14118 Dystroglycan DAG1 Q13103 Secreted phosphoprotein 24 SPP2 Q14314 Fibroleukin FGL2 Q13162 Peroxiredoxin-4 PRDX4 Q14393 Growth arrest-specific protein 6 GAS6 Q13201 Platelet glycoprotein la* MMRN 1 Q14406 Chorionic somatomammotropin Q13214 Semaphorin-3B SEMA3B CSHL1 hormone-like 1 Q13219 Pappalysin-1 PAPPA Q14507 Epididymal secretory protein E3-alpha Q13231 Chitotriosidase-1 CHIT1 EDDM3A Q13253 Noggin NOG Q14508 WAP four-disulfide core domain Q13261 lnterleukin-15 receptor subunit alpha protein 2 WFDC2 IL15RA Q14512 Fibroblast growth factor-binding Q13275 Semaphorin-3F SEMA3F protein 1, FGFBP1 Q14515 SPARC-like protein 1, SPARCL1 Q14520 Hyaluronan-binding protein 227 kDa Q15389 Angiopoietin-1, ANGPT1 light HABP2 chain Q15465 Sonic hedgehog protein, SHH Q14563 Semaphorin-3A, SEMA3A Q15485 Ficolin-2, FCN2 Q14623 Indian hedgehog protein IHH Q15517 Corneodesmosin, CDSN Q14624 Inter-alpha-trypsin inhibitor heavy Q15582 Transforming growth factor-beta- chain H4, ITIH4 induced protein ig-h3, TGFBI Q14667 UPF0378 protein KIAA0100, Q15661 Tryptase alpha/beta-1, TPSAB1 KIAA0100 Q15726 Metastin, KISS1 Q14703 Membrane-bound transcription factor Q15782 Chitinase-3-like protein 2, CHI3L2 site-1 protease, MBTPS1 Q15828 Cystatin-M, CST6 Q14766 Latent-transforming growth factor Q15846 Clusterin-like protein 1, CLU L1 beta- binding protein 1, LTBP1 Q15848 Adiponectin, ADIPOQ Q14767 Latent-transforming growth factor Q16206 Protein disulfide-thiol oxidoreductase, beta- binding protein 2, LTBP2 ENOX2 Q14773 Intercellular adhesion molecule 4, Q16270 Insulin-like growth factor-binding ICAM4 protein 7, IGFBP7 Q14993 Collagen alpha-l(XIX) chain, Q16363 Laminin subunit alpha-4, LAMA4 COL19A1 Q16378 Proline-rich protein 4, PRR4 Q14CN2 Calcium-activated chloride channel Q16557 Pregnancy-specific beta-l-glycoprotein regulator 4, 110 kDa form, CLCA4 3, PSG3 Q15046 Lysine-tRNA ligase KARS Q16568 CART(42-89), CARTPT Q15063 Periostin POSTN Q16610 Extracellular matrix protein 1, ECM 1 Q15109 Advanced glycosylation end product- Q16619 Cardiotrophin-1, CTF1 specific receptor, AGER Q16623 Syntaxin-1A, STX1A Q15113 Procollagen C-endopeptidase enhancer Q16627 HCC-l(9-74), CCL14 1, PCOLCE Q16651 Prostasin light chain, PRSS8 Q15166 Serum paraoxonase/lactonase 3, PON3 Q16661 Guanylate cyclase C-activating peptide Q15195 Plasminogen-like protein A, PLGLA 2, GUCA2B Q15198 Platelet-derived growth factor receptor Q16663 CCL15(29-92), CCL15 like protein, PDGFRL Q16674 Melanoma-derived growth regulatory Q15223 Poliovirus receptor-related protein 1, protein, MIA PVRL1 Q16769 Glutaminyl-peptide cyclotransferase Q15238 Pregnancy-specific beta-l-glycoprotein QPCT 5, PSG5 Q16787 Laminin subunit alpha-3 LAM A3 Q15363 Transmembrane emp24 domain- Q16842 CMP-N-acetylneuraminate-beta- containing protein 2, TMED2 galactosamide-alpha-2,3-sialyltransferase 2, Q15375 Ephrin type-A receptor 7, EPHA7 ST3GAL2 Q17RR3 Pancreatic lipase-related protein 3, Q3B7J2 Glucose-fructose oxidoreductase PNLIPRP3 domain- containing protein 2, GFOD2 Q17RW2 Collagen alpha-l(XXIV) chain, Q3SY79 Protein Wnt WNT3A COL24A1 Q3T906 N-acetylglucosamine-1- Q17RY6 Lymphocyte antigen 6K LY6K phosphotransferase subunits alpha/beta, GN Q1L6U9 Prostate-associated PTAB microseminoprotein MSMP Q495T6 Membrane metallo-endopeptidase-like Q1W4C9 Serine protease inhibitor Kazal-type 1 MMEL1 13 SPIN K13 Q49AH0 Cerebral dopamine neurotrophic Q1ZYL8 Izumo sperm-egg fusion protein 4 factor CDN F IZUM04 Q4G0G5 Secretoglobin family 2B member 2 Q29960 HLA class 1 histocompatibility antigen SCGB2B2 Cw-16 alpha chain, HLA-C Q4G0M1 Protein FAM 132B FAM132B Q2I0M5 R-spondin-4 RSP04 Q4LDE5 Sushi, von Willebrand factor type A, Q2L4Q9 Serine protease 53 PRSS53 and pentraxin domain-containing protein 1, Q2MKA7 R-spondin-1 RSPOl EGF SVEP1 Q2MV58 Tectonic-1 TCTN1 Q4QY38 Beta-defensin 134, DEFB134 Q2TAL6 Brorin VWC2 Q4VAJ4 Protein Wnt, WNT10B Q2UY09 Collagen alpha-l(XXVIII) chain Q4W5P6 Protein TMEM155, TMEM155 COL28A1 Q4ZHG4 Fibronectin type III domain- Q2VPA4 Complement component receptor 1- containing FN DC1 protein 1 like CR1L protein Q53H76 Phospholipase Al member A PLA1A Q2WEN9 Carcinoembryonic antigen-related Q53RD9 Fibulin-7, FBLN7 cell CEACAM16 adhesion molecule 16 Q53S33 BolA-like protein 3, BOLA3 Q30KP8 Beta-defensin 136 DEFB136 Q5BLP8 Neuropeptide-like protein C4orf48, Q30KP9 Beta-defensin 135 DEFB135 C4orf48 Q30KQ1 Beta-defensin 133 DEFB133 Q5DT21 Serine protease inhibitor Kazal-type 9, Q30KQ2 Beta-defensin 130 DEFB130 SPIN K9 Q30KQ4 Beta-defensin 116 DEFB116 Q5EBL8 PDZ domain-containing protein 11, Q30KQ5 Beta-defensin 115 DEFB115 PDZD11 Q30KQ6 Beta-defensin 114 DEFB114 Q5FYB0 Arylsulfatase J, ARSJ Q30KQ7 Beta-defensin 113 DEFB113 Q5FYB1 Arylsulfatase 1, ARSI Q30KQ8 Beta-defensin 112 DEFB112 Q5GAN3 Ribonuclease-like protein 13, Q30KQ9 Beta-defensin 110 DEFB110 RNASE13 Q30KR1 Beta-defensin 109 DEFB109P1 Q5GAN4 Ribonuclease-like protein 12, Q32P28 Prolyl 3-hydroxylase 1 LEPRE1 RNASE12 Q5GAN6 Ribonuclease-like protein 10, Q5VWW1 Complement Clq-like protein 3, RNASE10 C1QL3 Q5GFL6 von Willebrand factor A domain- Q5VXI9 Lipase member N LIPN containing protein 2, VWA2 Q5VXJ0 Lipase member K LIPK Q5H8A3 Neuromedin-S, NMS Q5VXM 1 CUB domain-containing protein 2, Q5H8C1 FRASl-related extracellular matrix CDCP2 protein 1, FREM 1 Q5VYX0 Renalase RN LS Q5IJ48 Protein crumbs homolog 2, CRB2 Q5VYY2 Lipase member M LIPM Q5J5C9 Beta-defensin 121, DEFB121 Q5W186 Cystatin-9 CST9 Q5JS37 NH L repeat-containing protein 3, Q5W5W9 Regulated endocrine-specific protein NHLRC3 18 RESP18 Q5JTB6 Placenta-specific protein 9, PLAC9 Q5XG92 Carboxylesterase 4A CES4A Q5JU69 Torsin-2A, TOR2A Q63HQ2 Pikachurin EGFLAM Q5JXM2 Methyltransferase-like protein 24, Q641Q3 Meteorin-like protein METRN L METTL24 Q66K79 Carboxypeptidase Z CPZ Q5JZY3 Ephrin type-A receptor 10, EPHA10 Q685J3 Mucin-17 MUC17 Q5K4E3 Polyserase-2, PRSS36 Q68BL7 Olfactomedin-like protein 2A Q5SRR4 Lymphocyte antigen 6 complex locus OLFML2A protein G5c, LY6G5C Q68BL8 Olfactomedin-like protein 2B Q5T1H1 Protein eyes shut homolog EYS OLFML2B Q5T4F7 Secreted frizzled-related protein 5 Q68DV7 E3 ubiquitin-protein ligase RNF43 SFRP5 RN F43 Q5T4W7 Artemin ARTN Q6B9Z1 Insulin growth factor-like family Q5T7M4 Protein FAM 132A FAM132A member 4, IGFL4 Q5TEH8 Protein Wnt WNT2B Q6BAA4 Fc receptor-like B FCRLB Q5TIE3 von Willebrand factor A domain- Q6E0U4 Dermokine DMKN containing protein 5B1, VWA5B1 Q6EMK4 Vasorin VASN Q5UCC4 ER membrane protein complex Q6FHJ7 Secreted frizzled-related protein 4 subunit 10, EMC10 SFRP4 Q5VST6 Abhydrolase domain-containing Q6GPI1 Chymotrypsin B2 chain B CTRB2 protein FAM 108B1, FAM108B1 Q6GTS8 Probable carboxypeptidase PM20D1, Q5VTL7 Fibronectin type III domain- PM20D1 containing FNDC7 protein 7 Q6H9L7 lsthmin-2 ISM2 Q5VUM1 UPF0369 protein C6orf57, C6orf57 Q6IE36 Ovostatin homolog 2, OVOS2 Q5VV43 Dyslexia-associated protein Q6IE37 Ovostatin homolog 1, OVOS1 KIAA0319, KIAA0319 Q6IE38 Serine protease inhibitor Kazal-type 14, SPIN K14 Q6ISS4 Leukocyte-associated Q6UW01 Cerebellin-3 CBLN3 immunoglobulin- like receptor 2, LAIR2 Q6UW10 Surfactant-associated protein 2 Q6JVE5 Epididymal-specific lipocalin-12, SFTA2 LCN 12 Q6UW15 Regenerating islet-derived protein 3- Q6JVE6 Epididymal-specific lipocalin-10, gamma, REG3G LCN 10 Q6UW32 Insulin growth factor-like family Q6JVE9 Epididymal-specific lipocalin-8, member 1, IGFL1 LCN8 Q6UW78 UPF0723 protein Cllorf83, Cllorf83 Q6KF10 Growth/differentiation factor 6, GDF6 Q6UW88 Epigen EPGN Q6MZW2 Follistatin-related protein 4, FSTL4 Q6UWE3 Colipase-like protein 2, CLPSL2 Q6NSX1 Coiled-coil domain-containing Q6UWF7 NXPE family member 4, NXPE4 protein 70, CCDC70 Q6UWF9 Protein FAM 180A, FAM180A Q6NT32 Carboxylesterase 5A, CES5A Q6UWM5 GLIPRl-like protein 1, GLIPR1L1 Q6NT52 Choriogonadotropin subunit beta Q6UWN8 Serine protease inhibitor Kazal-type variant 2, CGB2 6, SPIN K6 Q6NU I6 Chondroadherin-like protein, Q6UWP2 Dehydrogenase/reductase SDR CHADL family DHRS11 member 11 Q6NUJ1 Saposin A-like PSAPL1 Q6UWP8 Supra basin SBSN Q6P093 Arylacetamide deacetylase-like 2 Q6UWQ5 Lysozyme-like protein 1 LYZL1 AADACL2 Q6UWQ7 Insulin growth factor-like family Q6P4A8 Phospholipase B-like 1 PLBD1 member 2, IGFL2 Q6P5S2 UPF0762 protein C6orf58 C6orf58 Q6UWR7 Ectonucleotide ENPP6 Q6P988 Protein notum homolog NOTU M pyrophosphatase/phosphodiesterase family Q6PCB0 von Willebrand factor A domain- member 6 soluble form containing protein 1, VWA1 Q6UWT2 Adropin ENHO Q6PDA7 Sperm-associated antigen 11A Q6UWU2 Beta-galactosidase-l-like protein SPAG11A GLB1L Q6PEW0 Inactive serine protease 54 PRSS54 Q6UWW0 Lipocalin-15 LCN 15 Q6PEZ8 Podocan-like protein 1 PODNL1 Q6UWX4 HH IP-like protein 2 HHIPL2 Q6PKH6 Dehydrogenase/reductase SDR Q6UWY0 Arylsulfatase K ARSK family member 4-like 2, DHRS4L2 Q6UWY2 Serine protease 57 PRSS57 Q6Q788 Apolipoprotein A-V APOA5 Q6UWY5 Olfactomedin-like protein 1 Q6SPF0 Atherin SAM D1 OLFML1 Q6UDR6 Kunitz-type protease inhibitor 4 Q6UX06 Olfactomedin-4 OLFM4 SPINT4 Q6UX07 Dehydrogenase/reductase SDR family Q6U RK8 Testis, prostate and placenta- DHRS13 member 13 expressed protein, TEPP Q6UX39 Amelotin, AMTN Q6UX46 Protein FAM 150B, FAM150B Q6WRI0 Immunoglobulin superfamily member Q6UX73 UPF0764 protein C16orf89, C16orf89 10, IGSF10 Q6UXB0 Protein FAM 131A, FAM131A Q6X4U4 Sclerostin domain-containing protein Q6UXB1 Insulin growth factor-like family 1, SOSTDC1 member 3, IGFL3 Q6X784 Zona pellucida-binding protein 2, Q6UXB2 VEGF co-regulated chemokine 1, ZPBP2 CXCL17 Q6XE38 Secretoglobin family ID member 4, Q6UXF7 C-type lectin domain family 18 SCGB1D4 member B, CLEC18B Q6XPR3 Repetin, RPTN Q6UXH0 Hepatocellular carcinoma-associated Q6XZB0 Lipase member 1, LIPI protein TD26, C19orf80 Q6ZMM2 ADAMTS-like protein 5, Q6UXH1 Cysteine-rich with EGF-like domain ADAMTSL5 protein 2, CRELD2 Q6ZMP0 Thrombospondin type-1 domain- Q6UXH8 Collagen and calcium-binding containing protein 4, THSD4 domain-containing protein 1, EGF CCBE1 Q6ZNF0 Iron/zinc purple acid phosphatase-like Q6UXH9 Inactive serine protease PAMR1, protein, PAPL PAMR1 Q6ZRI0 Otogelin, OTOG Q6UXI7 Vitrin, VIT Q6ZRP7 Sulfhydryl oxidase 2, QSOX2 Q6UXI9 Nephronectin, NPNT Q6ZWJ8 Kielin/chordin-like protein, KCP Q6UXN2 Trem-like transcript 4 protein, Q75N90 Fibrillin-3, FBN3 TREML4 Q765I0 Urotensin-2B, UTS2D Q6UXS0 C-type lectin domain family 19 Q76B58 Protein FAM5C, FAM5C member A CLEC19A Q76LX8 A disintegrin and metalloproteinase Q6UXT8 Protein FAM 150A, FAM150A with thrombospondin motifs 13, ADAMTS13 Q6UXT9 Abhydrolase domain-containing Q76M96 Coiled-coil domain-containing protein protein 15, ABHD15 80, CCDC80 Q6UXV4 Apolipoprotein O-like, APOOL Q7L1S5 Carbohydrate sulfotransferase 9, Q6UXX5 Inter-alpha-trypsin inhibitor heavy CHST9 chain H6, ITIH6 Q7L513 Fc receptor-like A, FCRLA Q6UXX9 R-spondin-2, RSP02 Q7L8A9 Vasohibin-1, VASH1 Q6UY14 ADAMTS-like protein 4, Q7RTM1 Otopetrin-1, OTOP1 ADAMTSL4 Q7RTW8 Otoancorin, OTOA Q6UY27 Prostate and testis expressed protein Q7RTY5 Serine protease 48, PRSS48 2, PATE 2 Q7RTY7 Ovochymase-1, OVCH1 Q6W4X9 Mucin-6, MUC6 Q7RTZ1 Ovochymase-2, OVCH2 Q6WN34 Chordin-like protein 2, CHRDL2 Q7Z304 MAM domain-containing protein 2, MAMDC2 Q7Z3S9 Notch homolog 2 N-terminal-like Q86UX2 Inter-alpha-trypsin inhibitor heavy protein, NOTCH2NL chain H5, ITIH5 Q7Z4H4 Intermedin-short, ADM2 Q86V24 Adiponectin receptor protein 2, Q7Z4P5 Growth/differentiation factor 7, GDF7 ADIPOR2 Q7Z4R8 UPF0669 protein C6orfl20, C6orfl20 Q86VB7 Soluble CD163, CD163 Q7Z4W2 Lysozyme-like protein 2, LYZL2 Q86VR8 Four-jointed box protein 1, FJX1 Q7Z5A4 Serine protease 42, PRSS42 Q86WD7 Serpin A9, SERPINA9 Q7Z5A7 Protein FAM 19A5, FAM19A5 Q86WN2 Interferon epsilon, IFNE Q7Z5A8 Protein FAM 19A3, FAM19A3 Q86WS3 Placenta-specific 1-like protein, Q7Z5A9 Protein FAM 19A1, FAM19A1 PLAC1L Q7Z5J1 Hydroxysteroid 11-beta- Q86X52 Chondroitin sulfate synthase 1, dehydrogenase 1-like protein, HSD11B1L CHSY1 Q7Z5L0 Vitelline membrane outer layer Q86XP6 Gastrokine-2, GKN2 protein 1 homolog, VMOl Q86XS5 Angiopoietin-related protein 5, Q7Z5L3 Complement Clq-like protein 2, ANGPTL5 C1QL2 Q86Y27 B melanoma antigen 5, BAGE5 Q7Z5L7 Podocan, PODN Q86Y28 B melanoma antigen 4, BAGE4 Q7Z5P417-beta-hydroxysteroid dehydrogenase Q86Y29 B melanoma antigen 3, BAGE3 13, HSD17B13 Q86Y30 B melanoma antigen 2, BAGE2 Q7Z5P9 Mucin-19, MUC19 Q86Y38 Xylosyltransferase 1, XYLT1 Q7Z5Y6 Bone morphogenetic protein 8A, Q86Y78 Ly6/PLAUR domain-containing BMP8A protein 6, LYPD6 Q7Z7B7 Beta-defensin 132, DEFB132 Q86YD3 Transmembrane protein 25, TMEM25 Q7Z7B8 Beta-defensin 128, DEFB128 Q86YJ6 Threonine synthase-like 2, THNSL2 Q7Z7C8 Transcription initiation factor TFIID Q86YW7 Glycoprotein hormone beta-5, subunit 8, TAF8 GPHB5 Q7Z7H5 Transmembrane emp24 domain- Q86Z23 Complement Clq-like protein 4, containing protein 4, TMED4 C1QL4 Q86SG7 Lysozyme g-like protein 2, LYG2 Q8IU57 lnterleukin-28 receptor subunit alpha, Q86SI9 Protein CEI, C5orf38 IL28RA Q86TE4 Leucine zipper protein 2, LUZP2 Q8IUA0 WAP four-disulfide core domain Q86TH1 ADAMTS-like protein 2, protein 8, WFDC8 ADAMTSL2 Q8IUB2 WAP four-disulfide core domain Q86U17 Serpin All, SERPINA11 protein 3, WFDC3 Q86UU9 Endokinin-A, TAC4 Q8IUB3 Protein WFDCIOB, WFDCIOB Q86UW8 Hyaluronan and proteoglycan link Q8IUB5 WAP four-disulfide core domain protein 4, HAPLN4 protein 13, WFDC13 Q8IUH2 Protein CREG2, CREG2 Q8IZC6 Collagen alpha-l(XXVII) chain, Q8IUK5 Plexin domain-containing protein 1, COL27A1 PLXDC1 Q8IZJ3 C3 and PZP-like alpha-2- Q8IUL8 Cartilage intermediate layer protein 2, macroglobulin domain-containing protein 8, C2 CILP2 CPAMD8 Q8IUX7 Adipocyte enhancer-binding protein 1, Q8IZN7 Beta-defensin 107, DEFB107B AEBP1 Q8N0V4 Leucine-rich repeat LGI family Q8IUX8 Epidermal growth factor-like protein member 2, LGI2 6, EGFL6 Q8N104 Beta-defensin 106, DEFB106B Q8IVL8 Carboxypeptidase 0, CPO Q8N119 Matrix metalloproteinase-21, MMP21 Q8IVN8 Somatomedin-B and thrombospondin Q8N129 Protein canopy homolog 4, CN PY4 type-1 domain-containing protein, SBSPON Q8N135 Leucine-rich repeat LGI family Q8IVW8 Protein spinster homolog 2, SPNS2 member 4, LGI4 Q8IW75 Serpin A12, SERPINA12 Q8N145 Leucine-rich repeat LGI family Q8IW92 Beta-galactosidase-l-like protein 2, member 3, LGI3 GLB1L2 Q8N158 Glypican-2, GPC2 Q8IWL1 Pulmonary surfactant-associated Q8N1E2 Lysozyme g-like protein 1, LYG1 protein A2, SFTPA2 Q8N2E2 von Willebrand factor D and EGF Q8IWL2 Pulmonary surfactant-associated domain- containing protein, VWDE protein A1, SFTPA1 Q8N2E6 Prosalusin, TOR2A Q8IWV2 Contactin-4, CNTN4 Q8N2S1 Latent-transforming growth factor Q8IWY4 Signal peptide, CU B and EGF-like beta- binding protein 4, LTBP4 domain- containing protein 1, SCU BE1 Q8N302 Angiogenic factor with G patch and Q8IX30 Signal peptide, CU B and EGF-like FHA domains 1, AGGF1 domain- containing protein 3, SCU BE3 Q8N307 Mucin-20, MUC20 Q8IXA5 Sperm acrosome membrane- Q8N323 NXPE family member 1, NXPE1 associated protein 3, membrane form, SPACA3 Q8N387 Mucin-15, MUC15 Q8IXB1 DnaJ homolog subfamily C member Q8N3Z0 Inactive serine protease 35, PRSS35 10, DNAJC10 Q8N436 Inactive carboxypeptidase-like protein Q8IXL6 Extracellular serine/threonine protein X2, CPXM2 kinase Fam20C, FAM20C Q8N474 Secreted frizzled-related protein 1, Q8IYD9 Lung adenoma susceptibility protein SFRP1 2, LAS2 Q8N475 Follistatin-related protein 5, FSTL5 Q8IYP2 Serine protease 58, PRSS58 Q8N4F0 BPI fold-containing family B member Q8IYS5 Osteoclast-associated 2, BPIFB2 immunoglobulin- like receptor, OSCAR Q8N4T0 Carboxypeptidase A6, CPA6 Q8N5W8 Protein FAM24B, FAM24B Q8N687 Beta-defensin 125, DEFB125 Q8N DX9 Lymphocyte antigen 6 complex Q8N688 Beta-defensin 123, DEFB123 locus protein G5b, LY6G5B Q8N690 Beta-defensin 119, DEFB119 Q8N DZ4 Deleted in autism protein 1, C3orf58 Q8N6C5 Immunoglobulin superfamily member Q8N EB7 Acrosin-binding protein, ACRBP 1, IGSF1 Q8NES8 Beta-defensin 124, DEFB124 Q8N6C8 Leukocyte immunoglobulin-like Q8N ET1 Beta-defensin 108B, DEFB108B receptor subfamily A member 3, LILRA3 Q8N EX5 Protein WFDC9, WFDC9 Q8N6G6 ADAMTS-like protein 1, Q8N EX6 Protein WFDC11, WFDC11 ADAMTSL1 Q8N F86 Serine protease 33, PRSS33 Q8N6Y2 Leucine-rich repeat-containing Q8N FM7 lnterleukin-17 receptor D, IL17RD protein 17, LRRC17 Q8N FQ5 BPI fold-containing family B Q8N729 Neuropeptide W-23, NPW member 6, BPIFB6 Q8N8U9 BM P-binding endothelial regulator Q8N FQ6 BPI fold-containing family C protein, BMPER protein, BPIFC Q8N907 DAN domain family member 5, Q8N FU4 Follicular dendritic cell secreted DAND5 peptide, FDCSP Q8NAT1 Glycosyltransferase-like domain- Q8N FW1 Collagen alpha-l(XXII) chain, containing protein 2, GTDC2 COL22A1 Q8NAU1 Fibronectin type III domain- Q8NG35 Beta-defensin 105, DEFB105B containing protein 5, FN DC5 Q8NG41 Neuropeptide B-23, NPB Q8N B37 Parkinson disease 7 domain- Q8N HW6 Otospiralin, OTOS containing protein 1, PDDC1 Q8NI99 Angiopoietin-related protein 6, Q8N BI3 Draxin, DRAXIN ANGPTL6 Q8N BM8 Prenylcysteine oxidase-like, Q8TAA1 Probable ribonuclease 11, RNASE11 PCYOX1L Q8TAG5 V-set and transmembrane domain- Q8NBP7 Proprotein convertase subtilisin/kexin containing protein 2A, VSTM2A type 9, PCSK9 Q8TAL6 Fin bud initiation factor homolog, Q8N BQ5 Estradiol 17-beta-dehydrogenase 11, FIBIN HSD17B11 Q8TAT2 Fibroblast growth factor-binding Q8N BV8 Synaptotagmin-8, SYT8 protein 3, FGFBP3 Q8NCC3 Group XV phospholipase A2, Q8TAX7 Mucin-7, MUC7 PLA2G15 Q8TB22 Spermatogenesis-associated protein Q8NCF0 C-type lectin domain family 18 20, SPATA20 member C, CLEC18C Q8TB73 Protein NDNF, NDNF Q8NCW5 NAD(P)H-hydrate epimerase, Q8TB96 T-cell immunomodulatory protein, APOA1BP ITFG1 Q8N DA2 Hemicentin-2, HMCN2 Q8TC92 Protein disulfide-thiol oxidoreductase, Q8WU66 Protein TSPEAR, TSPEAR ENOX1 Q8WUA8 Tsukushin, TSKU Q8TCV5 WAP four-disulfide core domain Q8WUF8 Protein FAM 172A, FAM172A protein 5, WFDC5 Q8WUJ1 Neuferricin, CYB5D2 Q8TD06 Anterior gradient protein 3 homolog, Q8WUY1 UPF0670 protein THEM6, THEM6 AGR3 Q8WVN6 Secreted and transmembrane protein Q8TD33 Secretoglobin family 1C member 1, 1, SECTM1 SCGB1C1 Q8WVQ1 Soluble calcium-activated Q8TD46 Cell surface glycoprotein CD200 nucleotidase 1, CANT1 receptor 1, CD200R1 Q8WWA0 lntelectin-1, ITLN1 Q8TDE3 Ribonuclease 8, RNASE8 Q8WWG1 Neuregulin-4, NRG4 Q8TDF5 Neuropilin and tolloid-like protein 1, Q8WWQ2 Inactive heparanase-2, HPSE2 NETOl Q8WWU7 lntelectin-2, ITLN2 Q8TDL5 BPI fold-containing family B member Q8WWY7 WAP four-disulfide core domain 1, BPIFB1 protein 12, WFDC12 Q8TE56 A disintegrin and metalloproteinase Q8WWY8 Lipase member H, LIPH with thrombospondin motifs 17, ADAMTS17 Q8WWZ8 Oncoprotein-induced transcript 3 Q8TE57 A disintegrin and metalloproteinase protein, OIT3 with thrombospondin motifs 16, ADAMTS16 Q8WX39 Epididymal-specific lipocalin-9, Q8TE58 A disintegrin and metalloproteinase LCN9 with thrombospondin motifs 15, ADAMTS15 Q8WXA2 Prostate and testis expressed protein Q8TE59 A disintegrin and metalloproteinase 1 PATE1 Secretogranin-3 SCG3, Q8WXD2 with thrombospondin motifs 19, ADAMTS19 Q8WXF3 Relaxin-3 A chain, RLN3 Q8TE60 A disintegrin and metalloproteinase Q8WXI7 Mucin-16, MUC16 with thrombospondin motifs 18, ADAMTS18 Q8WXQ8 Carboxypeptidase A5, CPA5 Q8TE99 Acid phosphatase-like protein 2 Q8WXS8 A disintegrin and metalloproteinase ,ACPL2 with thrombospondin motifs 14, ADAMTS14 Q8TER0 Sushi, nidogen and EGF-like domain- Q92484 Acid sphingomyelinase-like containing protein 1, SNED1 phosphodiesterase 3a, SMPDL3A Q8TEU8 WAP, kazal, immunoglobulin, kunitz Q92485 Acid sphingomyelinase-like and NTR domain-containing protein 2, phosphodiesterase 3b, SMPDL3B WFIKKN2 Q92496 Complement factor H-related protein Q8WTQ1 Beta-defensin 104, DEFB104B 4, CFHR4 Q8WTR8 Netrin-5, NTN5 Q92520 Protein FAM3C, FAM3C Q8WTU2 Scavenger receptor cysteine-rich Q92563 Testican-2, SPOCK2 domain- containing group B protein, Q92583 C-C motif chemokine 17, CCL17 SRCRB4D Q92626 Peroxidasin homolog, PXDN Q92743 Serine protease HTRA1, HTRA1 Q96A99 Pentraxin-4, PTX4 Q92752 Tenascin-R, TNR Q96BH3 Epididymal sperm-binding protein 1, Q92765 Secreted frizzled-related protein 3, ELSPBP1 FRZB Q96BQ1 Protein FAM3D, FAM3D Q92819 Hyaluronan synthase 2, HAS2 Q96CG8 Collagen triple helix repeat- Q92820 Gamma-glutamyl hydrolase, GGH containing protein 1, CTH RC1 Q92824 Proprotein convertase subtilisin/kexin Q96DA0 Zymogen granule protein 16 homolog type 5, PCSK5 B, ZG16B Q92832 Protein kinase C-binding protein Q96DN2 von Willebrand factor C and EGF NELL1, NELL1 domain- containing protein, VWCE Q92838 Ectodysplasin-A, membrane form, Q96DR5 BPI fold-containing family A member EDA 2, BPIFA2 Q92874 Deoxyribonuclease-l-like 2, Q96DR8 Mucin-like protein 1, MUCL1 DNASE1L2 Q96DX4 RING finger and SPRY domain- Q92876 Kallikrein-6, KLK6 containing protein 1, RSPRY1 Q92913 Fibroblast growth factor 13, FGF13 Q96EE4 Coiled-coil domain-containing protein Q92954 Proteoglycan 4 C-terminal part, PRG4 126, CCDC126 Q93038 Tumor necrosis factor receptor Q96GS6 Abhydrolase domain-containing superfamily member 25, TNFRSF25 protein, FAM108A1 Q93091 Ribonuclease K6, RNASE6 Q96GW7 Brevican core protein, BCAN Q93097 Protein Wnt-2b, WNT2B Q96HF1 Secreted frizzled-related protein 2, Q93098 Protein Wnt-8b, WNT8B SFRP2 Q95460 Major histocompatibility complex Q96I82 Kazal-type serine protease inhibitor class 1-related gene protein, MR1 domain-containing protein 1, KAZALD1 Q969D9 Thymic stromal lymphopoietin, TSLP Q96ID5 Immunoglobulin superfamily member Q969E1 Liver-expressed antimicrobial peptide 21, IGSF21 2, LEAP2 Q96II8 Leucine-rich repeat and calponin Q969H8 UPF0556 protein C19orfl0, C19orfl0 homology domain-containing protein 3, Q969Y0 NXPE family member 3, NXPE3 LRCH3 Q96A54 Adiponectin receptor protein 1, Q96IY4 Carboxypeptidase B2, CPB2 ADIPOR1 Q96JB6 Lysyl oxidase homolog 4, LOXL4 Q96A83 Collagen alpha-l(XXVI) chain, Q96JK4 HH IP-like protein 1, HHIPL1 EMID2 Q96KN2 Beta-Ala-His dipeptidase, CNDP1 Q96A84 EMI domain-containing protein 1, Q96KW9 Protein SPACA7, SPACA7 EMID1 Q96KX0 Lysozyme-like protein 4, LYZL4 Q96A98 Tuberoinfundibular peptide of 39 Q96L15 Ecto-ADP-ribosyltransferase 5, ART5 residues, PTH2 Q96LB8 Peptidoglycan recognition protein 4, Q96SL4 Glutathione peroxidase 7, GPX7 PGLYRP4 Q96SM3 Probable carboxypeptidase XI, Q96LB9 Peptidoglycan recognition protein ,3 CPXM 1 PGLYRP3 Q96T91 Glycoprotein hormone alpha-2, Q96LC7 Sialic acid-binding Ig-like lectin 10, GPHA2 SIGLEC10 Q99062 Granulocyte colony-stimulating factor Q96LR4 Protein FAM 19A4, FAM19A4 receptor, CSF3R Q96MK3 Protein FAM20A, FAM20A Q99102 Mucin-4 alpha chain, MUC4 Q96MS3 Glycosyltransferase 1 domain- Q99217 Amelogenin, X isoform, AMELX containing protein 1, GLT1D1 Q99218 Amelogenin, Y isoform, AM ELY Q96NY8 Processed poliovirus receptor-related Q99435 Protein kinase C-binding protein protein 4, PVRL4 NELL2, NELL2 Q96NZ8 WAP, kazal, immunoglobulin, kunitz Q99470 Stromal cell-derived factor 2, SDF2 and NTR domain-containing protein 1, Q99542 Matrix metalloproteinase-19, MMP19 WFIKKN1 Q99574 Neuroserpin, SERPINI1 Q96NZ9 Proline-rich acidic protein 1, PRAP1 Q99584 Protein S100-A13, S100A13 Q96P44 Collagen alpha-l(XXI) chain, Q99616 C-C motif chemokine 13, CCL13 COL21A1 Q99645 Epiphycan, EPYC Q96PB7 Noelin-3, OLFM3 Q99674 Cell growth regulator with EF hand Q96PC5 Melanoma inhibitory activity protein domain protein 1, CGREF1 2, MIA2 Q99715 Collagen alpha-l(XII) chain, Q96PD5 N-acetylmuramoyl-L-alanine amidase, COL12A1 PGLYRP2 Q99727 Metalloproteinase inhibitor 4, TIM P4 Q96PH6 Beta-defensin 118, DEFB118 Q99731 C-C motif chemokine 1,9 CCL19 Q96PL1 Secretoglobin family 3A member 2, Q99748 Neurturin, NRTN SCGB3A2 Q99935 Proline-rich protein 1, PROL1 Q96PL2 Beta-tectorin, TECTB Q99942 E3 ubiquitin-protein ligase RN F5, Q96QH8 Sperm acrosome-associated protein 5, RNF5 SPACA5 Q99944 Epidermal growth factor-like protein 8, Q96QR1 Secretoglobin family 3A member 1, EGFL8 SCGB3A1 Q99954 Submaxillary gland androgen- Q96QU1 Protocadherin-15, PCDH15 regulated protein 3A, SMR3A Q96QV1 Hedgehog-interacting protein, HHIP Q99969 Retinoic acid receptor responder Q96RW7 Hemicentin-1, HMCN 1 protein 2, RARRES2 Q96S42 Nodal homolog, NODAL Q99972 Myocilin, MYOC Q96S86 Hyaluronan and proteoglycan link Q99983 Osteomodulin, OMD protein 3, HAPLN3 Q99985 Semaphorin-3C, SEMA3C Q99988 Growth/differentiation factor 15, Q9BX67 Junctional adhesion molecule C, GDF15 JAM3 Q9BPW4 Apolipoprotein L4, APOL4 Q9BX93 Group XI 1 B secretory phospholipase Q9BQ08 Resistin-like beta, RETN LB A2- like protein, PLA2G12B Q9BQ16 Testican-3, SPOCK3 Q9BXI9 Complement Clq tumor necrosis Q9BQ51 Programmed cell death 1 ligand 2, factor- related protein 6, C1QTN F6 PDCD1LG2 Q9BXJ0 Complement Clq tumor necrosis Q9BQB4 Sclerostin, SOST factor- related protein 5, C1QTN F5 Q9BQI4 Coiled-coil domain-containing protein Q9BXJ1 Complement Clq tumor necrosis 3, CCDC3 factor- related protein 1, C1QTN F1 Q9BQP9 BPI fold-containing family A member Q9BXJ2 Complement Clq tumor necrosis 3, BPIFA3 factor- related protein 7, C1QTN F7 Q9BQR3 Serine protease 27, PRSS27 Q9BXJ3 Complement Clq tumor necrosis Q9BQY6 WAP four-disulfide core domain factor- related protein 4, C1QTN F4 protein 6, WFDC6 Q9BXJ4 Complement Clq tumor necrosis Q9BRR6 ADP-dependent glucokinase, factor- related protein 3, C1QTN F3 ADPGK Q9BXJ5 Complement Clq tumor necrosis Q9BS86 Zona pellucida-binding protein 1, factor- related protein 2, C1QTN F2 ZPBP Q9BXN1 Asporin, ASPN Q9BSG0 Protease-associated domain- Q9BXP8 Pappalysin-2, PAPPA2 containing protein 1, PRADC1 Q9BXR6 Complement factor H-related protein Q9BSG5 Retbindin, RTBDN 5, CFHR5 Q9BT30 Probable alpha-ketoglutarate- Q9BXS0 Collagen alpha-l(XXV) chain, dependent dioxygenase ABH7, ALKBH7 COL25A1 Q9BT56 Spexin, C12orf39 Q9BXX0 EMILIN-2, EMILIN2 Q9BT67 NEDD4 family-interacting protein 1, Q9BXY4 R-spondin-3, RSP03 NDFIP1 Q9BY15 EGF-like module-containing mucin- Q9BTY2 Plasma alpha-L-fucosidase, FUCA2 like hormone receptor-like 3 subunit beta, Q9BU40 Chordin-like protein 1, CH RDL1 EMR3 Q9BUD6 Spondin-2, SPON2 Q9BY50 Signal peptidase complex catalytic Q9BUN1 Protein MENT, MENT SEC11C subunit, SEC11C Q9BUR5 Apolipoprotein 0, APO0 Q9BY76 Angiopoietin-related protein 4, Q9BV94 ER degradation-enhancing alpha- ANGPTL4 mannosidase-like 2, EDEM2 Q9BYF1 Processed angiotensin-converting Q9BWP8 Collectin-11, COLEC11 enzyme 2, ACE2 Q9BWS9 Chitinase domain-containing protein Q9BYJ0 Fibroblast growth factor-binding 1, CHID1 protein, FGFBP2 Q9BYW3 Beta-defensin 126, DEFB126 Q9H106 Signal-regulatory protein delta, Q9BYX4 Interferon-induced helicase C SIRPD domain- containing protein 1, IFIH1 Q9H114 Cystatin-like 1, CSTL1 Q9BYZ8 Regenerating islet-derived protein 4, Q9H173 Nucleotide exchange factor SIL1, REG4 SIL1 Q9BZ76 Contactin-associated protein-like 3, Q9H1E1 Ribonuclease 7, RNASE7 CNTNAP3 Q9H1F0 WAP four-disulfide core domain Q9BZG9 Ly-6/neurotoxin-like protein 1, protein 10A, WFDCIOA LYNX1 Q9H1J5 Protein Wnt-8a, WNT8A Q9BZJ3 Tryptase delta, TPSD1 Q9H1J7 Protein Wnt-5b, WNT5B Q9BZM1 Group XI IA secretory phospholipase Q9H1M3 Beta-defensin 129, DEFB129 A2, PLA2G12A Q9H1M4 Beta-defensin 127, DEFB127 Q9BZM2 Group IIF secretory phospholipase Q9H1Z8 Augurin, C2orf40 A2, PLA2G2F Q9H239 Matrix metalloproteinase-28, MMP28 Q9BZM5 NKG2D ligand 2, ULBP2 Q9H2A7 C-X-C motif chemokine 16, CXCL16 Q9BZP6 Acidic mammalian chitinase, CHIA Q9H2A9 Carbohydrate sulfotransferase 8, Q9BZZ2 Sialoadhesin, SIGLECl CHST8 Q9C0B6 Protein FAM5B, FAM5B Q9H2R5 Kallikrein-15, KLK15 Q9GZM7 Tubulointerstitial nephritis antigen- Q9H2X0 Chordin, CHRD like, TINAGL1 Q9H2X3 C-type lectin domain family 4 Q9GZN4 Brain-specific serine protease 4, member M, CLEC4M PRSS22 Q9H306 Matrix metalloproteinase-27, MMP27 Q9GZP0 Platelet-derived growth factor D, Q9H324 A disintegrin and metalloproteinase receptor-binding form, PDGFD with thrombospondin motifs 10, ADAMTS10 Q9GZT5 Protein Wnt-10a ,WNT10A Q9H336 Cysteine-rich secretory protein LCCL Q9GZU5 Nyctalopin, NYX domain-containing, CRISPLD11 Q9GZV7 Hyaluronan and proteoglycan link Q9H3E2 Sorting nexin-25, SNX25 protein 2, HAPLN2 Q9H3R2 Mucin-13, MUC13 Q9GZV9 Fibroblast growth factor 23, FGF23 Q9H3U7 SPARC-related modular calcium- Q9GZX9 Twisted gastrulation protein homolog binding protein 2, SMOC2 1, TWSG1 Q9H3Y0 Peptidase inhibitor R3H DM L, Q9GZZ7 GDN F family receptor alpha-4, R3HDML GFRA4 Q9H4A4 Aminopeptidase B, RN PEP Q9GZZ8 Extracellular glycoprotein lacritin, Q9H4F8 SPARC-related modular calcium- LACRT binding protein 1, SMOC1 Q9H0B8 Cysteine-rich secretory protein LCCL Q9H4G1 Cystatin-9-like, CST9L domain-containing 2, CRISPLD2 Q9H5V8 CUB domain-containing protein 1, Q9NPH0 Lysophosphatidic acid phosphatase CDCP1 type 6, ACP6 Q9H6B9 Epoxide hydrolase 3, EPHX3 Q9NPH6 Odorant-binding protein 2b, OBP2B Q9H6E4 Coiled-coil domain-containing protein Q9NQ30 Endothelial cell-specific molecule 1, 134, CCDC134 ESM1 Q9H741 UPF0454 protein C12orf49, C12orf49 Q9NQ36 Signal peptide, CU B and EGF-like Q9H772 Gremlin-2, GREM2 domain- containing protein 2, SCU BE2 Q9H7Y0 Deleted in autism-related protein 1, Q9NQ38 Serine protease inhibitor Kazal-type CXorf36 5, SPIN K5 Q9H8L6 Multimerin-2, MMRN2 Q9NQ76 Matrix extracellular Q9H9S5 Fukutin-related protein, FKRP phosphoglycoprotein, MEPE Q9HAT2 Sialate O-acetylesterase, SIAE Q9NQ79 Cartilage acidic protein 1, CRTAC1 Q9HB40 Retinoid-inducible serine Q9NR16 Scavenger receptor cysteine-rich type carboxypeptidase, SCPEP1 1 protein M160, CD163L1 Q9HB63 Netrin-4, NTN4 Q9NR23 Growth/differentiation factor 3, GDF3 Q9HBJ0 Placenta-specific protein 1, PLAC1 Q9NR71 Neutral ceramidase, ASAH2 Q9HC23 Prokineticin-2, PROK2 Q9NR99 Matrix-remodeling-associated protein Q9HC57 WAP four-disulfide core domain 5, MXRA5 protein 1, WFDC1 Q9N RA1 Platelet-derived growth factor C, Q9HC73 Cytokine receptor-like factor 2, PDGFC CRLF2 Q9N RC9 Otoraplin, OTOR Q9HC84 Mucin-5B, MUC5B Q9N RE1 Matrix metalloproteinase-26, Q9HCB6 Spondin-1, SPON 1 MMP26 Q9HCQ7 Neuropeptide NPSF, NPVF Q9N RJ3 C-C motif chemokine 28, CCL28 Q9HCT0 Fibroblast growth factor 22, FGF22 Q9N RM1 Enamelin, ENAM Q9HD89 Resistin, RETN Q9N RN5 Olfactomedin-like protein 3, Q9NNX1 Tuftelin, TUFT1 OLFML3 Q9NNX6 CD209 antigen, CD209 Q9N RR1 Cytokine-like protein 1, CYTL1 Q9NP55 BPI fold-containing family A member Q9NS15 Latent-transforming growth factor 1, BPIFA1 beta- binding protein 3, LTBP3 Q9NP70 Ameloblastin, AMBN Q9NS62 Thrombospondin type-1 domain- Q9NP95 Fibroblast growth factor 20, FGF20 containing protein 1, THSD1 Q9NP99 Triggering receptor expressed on Q9NS71 Gastrokine-1, GKN1 myeloid cells 1, TREM1 Q9NS98 Semaphorin-3G, SEMA3G Q9NPA2 Matrix metalloproteinase-25, MMP25 Q9NSA1 Fibroblast growth factor 21, FGF21 Q9NPE2 Neugrin, NGRN Q9NT22 EMILIN-3, EMILIN3 Q9NTU7 Cerebellin-4, CBLN4 Q9NVR0 Kelch-like protein 11, KLHL11 Q9U BQ6 Exostosin-like 2, EXTL2 Q9NWH7 Spermatogenesis-associated protein Q9UBR5 Chemokine-like factor, CKLF 6, SPATA6 Q9UBS5 Gamma-aminobutyric acid type B Q9NXC2 Glucose-fructose oxidoreductase receptor subunit 1, GABBR1 domain- containing protein 1, GFOD1 Q9U BT3 Dickkopf-related protein 4 short Q9NY56 Odorant-binding protein 2a, OBP2A form, DKK4 Q9NY84 Vascular non-inflammatory molecule Q9U BU2 Dickkopf-related protein 2, DKK2 3, VN N3 Q9U BU3 Ghrelin-28, GHRL Q9NZ20 Group 3 secretory phospholipase A2, Q9U BV4 Protein Wnt-16, WNT16 PLA2G3 Q9U BX5 Fibulin-5, FBLN5 Q9NZC2 Triggering receptor expressed on Q9U BX7 Kallikrein-11, KLK11 myeloid cells 2, TREM2 Q9UEF7 Klotho, KL Q9NZK5 Adenosine deaminase CECR1, Q9UFP1 Protein FAM 198A, FAM198A CECR1 Q9UGM3 Deleted in malignant brain tumors 1 Q9NZK7 Group ME secretory phospholipase protein, DMBT1 A2, PLA2G2E Q9UGM5 Fetuin-B, FETUB Q9NZP8 Complement Clr subcomponent-like Q9UGP8 Translocation protein homolog, protein, C1RL SEC63 Q9NZV1 Cysteine-rich motor neuron 1 protein, Q9UHF0 Neurokinin-B, TAC3 CRIM1 Q9UHF1 Epidermal growth factor-like protein Q9NZW4 Dentin sialoprotein, DSPP 7, EGFL7 Q9P0G3 Kallikrein-14, KLK14 Q9U HG2 ProSAAS, PCSK1N Q9P0W0 Interferon kappa, IFNK Q9UHI8 A disintegrin and metalloproteinase Q9P218 Collagen alpha-l(XX) chain, with thrombospondin motifs 1, ADAMTS1 COL20A1 Q9UHL4 Dipeptidyl peptidase 2, DPP7 Q9P2C4 Transmembrane protein 181, Q9UI42 Carboxypeptidase A4, CPA4 TMEM181 Q9UIG4 Psoriasis susceptibility 1 candidate Q9P2K2 Thioredoxin domain-containing gene 2 protein, PSORS1C2 protein 16, TXN DC16 Q9UIK5 Tomoregulin-2, TMEFF2 Q9P2N4 A disintegrin and metalloproteinase Q9UIQ6 Leucyl-cystinyl aminopeptidase, with thrombospondin motifs 9, ADAMTS9 pregnancy serum form, LN PEP Q9UBC7 Galanin-like peptide, GALP Q9UJA9 Ectonucleotide Q9U BD3 Cytokine SCM-1 beta, XCL2 pyrophosphatase/phosphodiesterase family Q9U BD9 Cardiotrophin-like cytokine factor 1, member 5, ENPP5 CLCF1 Q9UJH8 Meteorin, METRN Q9U BM4 Opticin, OPTC Q9UJJ9 N-acetylglucosamine-1- Q9UBP4 Dickkopf-related protein 3, DKK3 phosphotransferase subunit gamma, GN PTG Q9UJW2 Tubulointerstitial nephritis antigen, Q9UMX5 Neudesin, NENF TINAG Q9UN73 Protocadherin alpha-6, PCDHA6 Q9UK05 Growth/differentiation factor 2, Q9UNA0 A disintegrin and metalloproteinase GDF2 with thrombospondin motifs 5, ADAMTS5 Q9UK55 Protein Z-dependent protease Q9UN I1 Chymotrypsin-like elastase family inhibitor, SERPINA10 member 1, CELA1 Q9UK85 Dickkopf-like protein 1, DKKL1 Q9UN K4 Group IID secretory phospholipase Q9UKJ1 Paired immunoglobulin-like type 2 A2, PLA2G2D receptor alpha, PILRA Q9UP79 A disintegrin and metalloproteinase Q9UKP4 A disintegrin and metalloproteinase with thrombospondin motifs 8, ADAMTS8 with thrombospondin motifs 7, ADAMTS7 Q9UPZ6 Thrombospondin type-1 domain- Q9UKP5 A disintegrin and metalloproteinase containing protein 7A, THSD7A with thrombospondin motifs 6, ADAMTS6 Q9UQ72 Pregnancy-specific beta-l- Q9UKQ2 Disintegrin and metalloproteinase glycoprotein 11, PSG11 domain-containing protein 28, ADAM28 Q9UQ74 Pregnancy-specific beta-l- Q9UKQ9 Kallikrein-9, KLK9 glycoprotein 8, PSG8 Q9UKR0 Kallikrein-12, KLK12 Q9UQC9 Calcium-activated chloride channel Q9UKR3 Kallikrein-13, KLK13 regulator 2, CLCA2 Q9U KU9 Angiopoietin-related protein 2, Q9UQE7 Structural maintenance of ANGPTL2 chromosomes protein 3, SMC3 Q9UKZ9 Procollagen C-endopeptidase Q9UQP3 Tenascin-N, TNN enhancer 2, PCOLCE2 Q9Y223 UDP-N-acetylglucosamine 2- Q9UL52 Transmembrane protease serine HE epimerase, GN E non- catalytic chain, TMPRSS11E Q9Y240 C-type lectin domain family 11 Q9ULC0 Endomucin, EMCN member A, CLEC11A Q9ULI3 Protein HEG homolog 1, HEG1 Q9Y251 Heparanase 8 kDa subunit, HPSE Q9U LZ1 Apelin-13, APLN Q9Y258 C-C motif chemokine 26, CCL26 Q9U LZ9 Matrix metalloproteinase-17, Q9Y264 Angiopoietin-4, ANGPT4 MMP17 Q9Y275 Tumor necrosis factor ligand Q9UM21 Alpha-l,3-mannosyl-glycoprotein 4- superfamily member 13b, membrane form, beta- N-acetylglucosaminyltransferase A, TNFSF13B soluble form, MGAT4A Q9Y287 BRI2 intracellular domain, ITM2B Q9UM22 Mammalian ependymin-related Q9Y2E5 Epididymis-specific alpha- protein 1, EPDR1 mannosidase, MAN2B2 Q9UM73 ALK tyrosine kinase receptor, ALK Q9Y334 von Willebrand factor A domain- Q9UM D997 kDa linear IgA disease antigen, containing protein 7, VWA7 COL17A1 Q9Y337 Kallikrein-5, KLK5 Q9Y3B3 Transmembrane emp24 domain- Q9Y5U5 Tumor necrosis factor receptor containing protein 7, TMED7 superfamily member 18, TNFRSF18 Q9Y3E2 BolA-like protein 1, BOLA1 Q9Y5W5 Wnt inhibitory factor, WIF1 Q9Y426 C2 domain-containing protein 2, Q9Y5X9 Endothelial lipase, LIPG C2CD2 Q9Y625 Secreted glypican-6, GPC6 Q9Y4K0 Lysyl oxidase homolog 2, LOXL2 Q9Y646 Carboxypeptidase Q, CPQ Q9Y4X3 C-C motif chemokine 27, CCL27 Q9Y6C2 EMILIN-1, EMILINl Q9Y5C1 Angiopoietin-related protein 3, Q9Y6F9 Protein Wnt-6, WNT6 ANGPTL3 Q9Y6I9 Testis-expressed sequence 264 protein, Q9Y5I2 Protocadherin alpha-10, PCDHA10 TEX264 Q9Y5I3 Protocadherin alpha-1, PCDHA1 Q9Y6L7 Tolloid-like protein 2, TLL2 Q9Y5K2 Kallikrein-4, KLK4 Q9Y6N3 Calcium-activated chloride channel Q9Y5L2 Hypoxia-inducible lipid droplet- regulator family member 3, CLCA3P associated protein, HILPDA Q9Y6N6 Laminin subunit gamma-3, LAMC3 Q9Y5Q5 Atrial natriuretic peptide-converting Q9Y6R7 IgGFc-binding protein, FCGBP enzyme, CORIN Q9Y6Y9 Lymphocyte antigen 96, LY96 Q9Y5R2 Matrix metalloproteinase-24, MMP24 Q9Y6Z7 Collectin-10, COLEC10 [00829] For each of the above therapeutic proteins, provided are the (a) the Uniprot ID, (b) the protein name, and (c) the gene name. Antibodies [00830] In some embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) and associated compositions and methods described herein provide for the delivery of one or more antibodies or functional fragment thereof, as outlined below. [00831] As used herein, the term “antibody” is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., “functional”). Antibodies are primarily amino acid-based molecules which are monomeric or multimeric polypeptides which comprise at least one amino acid region derived from a known or parental antibody sequence and at least one amino acid region derived from a non-antibody sequence. The antibodies may comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.). For the purposes herein, an “antibody” may comprise a heavy and light variable domain as well as an Fc region. [00832] The encoded products of interest of the herein disclosed RNA payloads may comprise or may encode polypeptides that form one or more functional antibodies. [00833] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may comprise or may encode polypeptides that form or function as any antibody including, but not limited to, antibodies that are known in the art and/or antibodies that are commercially available which may be therapeutic, diagnostic, or for research purposes. Additionally, the encoded products of interest of the herein disclosed RNA payloads may comprise or may encode fragments of such antibodies or antibodies such as, but not limited to, variable domains or complementarity determining regions (CDRs). [00834] As used herein, the term “native antibody” refers to a usually heterotetrameric glycoprotein of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Genes encoding antibody heavy and light chains are known and segments making up each have been well characterized and described (Matsuda, F. et al., 1998. The Journal of Experimental Medicine.188(11); 2151-62 and Li, A. et al., 2004. Blood.103(12: 4602-9, the content of each of which are herein incorporated by reference in their entirety). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (V_H) followed by a number of constant domains. Each light chain has a variable domain at one end (V_L) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. As used herein, the term "light chain" refers to a component of an antibody from any vertebrate species assigned to one of two clearly distinct types, called kappa and lambda based on amino acid sequences of constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains, antibodies can be assigned to different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. [00835] As used herein, the term “variable domain” refers to specific antibody domains found on both the antibody heavy and light chains that differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. Variable domains comprise hypervariable regions. As used herein, the term “hypervariable region” refers to a region within a variable domain comprising amino acid residues responsible for antigen binding. The amino acids present within the hypervariable regions determine the structure of the complementarity determining regions (CDRs) that become part of the antigen-binding site of the antibody. As used herein, the term “CDR” refers to a region of an antibody comprising a structure that is complimentary to its target antigen or epitope. Other portions of the variable domain, not interacting with the antigen, are referred to as framework (FW) regions. The antigen-binding site (also known as the antigen combining site or paratope) comprises the amino acid residues necessary to interact with a particular antigen. The exact residues making up the antigen-binding site are typically elucidated by co- crystallography with bound antigen, however computational assessments can also be used based on comparisons with other antibodies (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA.2012. Ch.3, p47-54, the contents of which are herein incorporated by reference in their entirety). Determining residues making up CDRs may include the use of numbering schemes including, but not limited to, those taught by Kabat [Wu, T.T. et al., 1970, JEM, 132(2):211- 50 and Johnson, G. et al., 2000, Nucleic Acids Res.28(1): 214-8, the contents of each of which are herein incorporated by reference in their entirety], Chothia [Chothia and Lesk, J. Mol. Biol.196, 901 (1987), Chothia et al., Nature 342, 877 (1989) and Al-Lazikani, B. et al., 1997, J. Mol. Biol. 273(4):927-48, the contents of each of which are herein incorporated by reference in their entirety], Lefranc (Lefranc, M.P. et al., 2005, Immunome Res.1:3) and Honegger (Honegger, A. and Pluckthun, A.2001. J. Mol. Biol.309(3):657-70, the contents of which are herein incorporated by reference in their entirety). [00836] VH and VL domains each have three CDRs. VL CDRs are referred to herein as CDR- L1, CDR-L2 and CDR-L3, in order of occurrence when moving from N- to C- terminus along the variable domain polypeptide. VH CDRs are referred to herein as CDR-H1, CDR-H2, and CDR-H3, in order of occurrence when moving from N- to C-terminus along the variable domain polypeptide. Each of CDRs have favored canonical structures with the exception of the CDR-H3, which comprises amino acid sequences that may be highly variable in sequence and length between antibodies resulting in a variety of three-dimensional structures in antigen-binding domains. In some cases, CDR-H3s may be analyzed among a panel of related antibodies to assess antibody diversity. [00837] Various methods of determining CDR sequences are known in the art and may be applied to known antibody sequences. The system described by Kabat, also referred to as “numbered according to Kabat,” “Kabat numbering,” “Kabat definitions,” and “Kabat labeling,” provides an unambiguous residue numbering system applicable to any variable domain of an antibody, and provides precise residue boundaries defining the three CDRs of each chain. (Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md. (1987) and (1991), the contents of which are incorporated by reference in their entirety). Kabat CDRs and comprise about residues 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) in the light chain variable domain, and 31- 35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) in the heavy chain variable domain. Chothia and coworkers found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. (Chothia et al. (1987) J. Mol. Biol.196: 901-917; and Chothia et al. (1989) Nature 342: 877-883, the contents of each of which is herein incorporated by reference in its entirety). These CDRs can be referred to as "Chothia CDRs," "Chothia numbering," or "numbered according to Chothia," and comprise about residues 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) in the light chain variable domain, and 26- 32 (CDR1), 52-56 (CDR2) and 95-102 (CDR3) in the heavy chain variable domain. Mol. Biol. 196:901-917 (1987). The system described by MacCallum, also referred to as "numbered according to MacCallum," or "MacCallum numbering" comprises about residues 30-36 (CDR1), 46-55 (CDR2) and 89-96 (CDR3) in the light chain variable domain, and 30-35 (CDR1), 47-58 (CDR2) and 93-101 (CDR3) in the heavy chain variable domain. (MacCallum et al. ((1996) J. Mol. Biol.262(5):732-745), the contents of which is herein incorporated by reference in its entirety). The system described by AbM, also referred to as "numbering according to AbM," or "AbM numbering" comprises about residues 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) in the light chain variable domain, and 26- 35 (CDR1), 50-58 (CDR2) and 95-102 (CDR3) in the heavy chain variable domain. The IMGT (INTERNATIONAL IMMUNOGENETICS INFORMATION SYSTEM) numbering of variable regions can also be used, which is the numbering of the residues in an immunoglobulin variable heavy or light chain according to the methods of the IIMGT (Lefranc, M.-P., "The IMGT unique numbering for immunoglobulins, T cell Receptors and Ig-like domains", The Immunologist, 7, 132-136 (1999), and is herein incorporated by reference in its entirety by reference). As used herein, "IMGT sequence numbering" or "numbered according to IMTG," refers to numbering of the sequence encoding a variable region according to the IMGT. For the heavy chain variable domain, when numbered according to IMGT, the hypervariable region ranges from amino acid positions 27 to 38 for CDR1, amino acid positions 56 to 65 for CDR2, and amino acid positions 105 to 117 for CDR3. For the light chain variable domain, when numbered according to IMGT, the hypervariable region ranges from amino acid positions 27 to 38 for CDR1, amino acid positions 56 to 65 for CDR2, and amino acid positions 105 to 117 for CDR3. [00838] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibodies which have been produced using methods known in the art such as, but are not limited to immunization and display technologies (e.g., phage display, yeast display, and ribosomal display), hybridoma technology, heavy and light chain variable region cDNA sequences selected from hybridomas or from other sources, [00839] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibodies which were developed using any naturally occurring or synthetic antigen. As used herein, an "antigen" is an entity which induces or evokes an immune response in an organism. An immune response is characterized by the reaction of the cells, tissues and/or organs of an organism to the presence of a foreign entity. Such an immune response typically leads to the production by the organism of one or more antibodies against the foreign entity, e.g., antigen or a portion of the antigen. As used herein, "antigens" also refer to binding partners for specific antibodies or binding agents in a display library. [00840] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous cells (or clones), i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibodies, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen [00841] The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. The monoclonal antibodies herein include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies. [00842] As used herein, the term "humanized antibody" refers to a chimeric antibody comprising a minimal portion from one or more non-human (e.g., murine) antibody source(s) with the remainder derived from one or more human immunoglobulin sources. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the hypervariable region from an antibody of the recipient are replaced by residues from the hypervariable region from an antibody of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and/or capacity. [00843] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibody mimetics. As used herein, the term "antibody mimetic" refers to any molecule which mimics the function or effect of an antibody and which binds specifically and with high affinity to their molecular targets. In some embodiments, antibody mimetics may be monobodies, designed to incorporate the fibronectin type III domain (Fn3) as a protein scaffold. In some embodiments, antibody mimetics may be those known in the art including, but are not limited to affibody molecules, affilins, affitins, anticalins, avimers, Centyrins, DARPINS^TM, fynomers, Kunitz domains, and domain peptides. In other embodiments, antibody mimetics may include one or more non-peptide regions. Antibody fragments and variants [00844] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibody fragments which comprise antigen binding regions from full-length antibodies. Non-limiting examples of antibody fragments include Fab, Fab', F(ab')₂, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site. Also produced is a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen. Compounds and/or compositions of the present disclosure may comprise one or more of these fragments. [00845] In some embodiments, the Fc region may be a modified Fc region wherein the Fc region may have a single amino acid substitution as compared to the corresponding sequence for the wild-type Fc region, wherein the single amino acid substitution yields an Fc region with preferred properties to those of the wild-type Fc region. Non-limiting examples of Fc properties that may be altered by the single amino acid substitution include bind properties or response to pH conditions [00846] As used herein, the term "Fv" refers to an antibody fragment comprising the minimum fragment on an antibody needed to form a complete antigen binding site. These regions consist of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. Fv fragments can be generated by proteolytic cleavage, but are largely unstable. Recombinant methods are known in the art for generating stable Fv fragments, typically through insertion of a flexible linker between the light chain variable domain and the heavy chain variable domain to form a single chain Fv (scFv) or through the introduction of a disulfide bridge between heavy and light chain variable domains. [00847] As used herein, the term "single chain Fv" or "scFv" refers to a fusion protein of V_H and V_L antibody domains, wherein these domains are linked together into a single polypeptide chain by a flexible peptide linker. In some embodiments, the Fv polypeptide linker enables the scFv to form the desired structure for antigen binding. In some embodiments, scFvs are utilized in conjunction with phage display, yeast display or other display methods where they may be expressed in association with a surface member (e.g. phage coat protein) and used in the identification of high affinity peptides for a given antigen. [00848] As used herein, the term "antibody variant" refers to a modified antibody (in relation to a native or starting antibody) or a biomolecule resembling a native or starting antibody in structure and/or function (e.g., an antibody mimetic). Antibody variants may be altered in their amino acid sequence, composition, or structure as compared to a native antibody. Antibody variants may include, but are not limited to, antibodies with altered isotypes (e.g., IgA, IgD, IgE, IgG₁, IgG₂, IgG₃, IgG₄, or IgM), humanized variants, optimized variants, multispecific antibody variants (e.g., bispecific variants), and antibody fragments. Multispecific antibodies [00849] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibodies that bind more than one epitope. As used herein, the terms "multibody" or "multispecific antibody" refer to an antibody wherein two or more variable regions bind to different epitopes. The epitopes may be on the same or different targets. In certain embodiments, a multispecific antibody is a "bispecific antibody," which recognizes two different epitopes on the same or different antigens. [00850] In some embodiments, multi-specific antibodies may be prepared by the methods used by BIOATLA® and described in International Patent publication WO201109726, the contents of which are herein incorporated by reference in their entirety. First a library of homologous, naturally occurring antibodies is generated by any method known in the art (i.e., mammalian cell surface display), then screened by FACSAria or another screening method, for multi-specific antibodies that specifically bind to two or more target antigens. In some embodiments, the identified multi-specific antibodies are further evolved by any method known in the art, to produce a set of modified multi- specific antibodies. These modified multi-specific antibodies are screened for binding to the target antigens. In some embodiments, the multi-specific antibody may be further optimized by screening the evolved modified multi-specific antibodies for optimized or desired characteristics. [00851] In some embodiments, multi-specific antibodies may be prepared by the methods used by BIOATLA® and described in Unites States Publication No. US20150252119, the contents of which are herein incorporated by reference in their entirety. In one approach, the variable domains of two parent antibodies, wherein the parent antibodies are monoclonal antibodies are evolved using any method known in the art in a manner that allows a single light chain to functionally complement heavy chains of two different parent antibodies. Another approach requires evolving the heavy chain of a single parent antibody to recognize a second target antigen. A third approach involves evolving the light chain of a parent antibody so as to recognize a second target antigen. Methods for polypeptide evolution are described in International Publication WO2012009026, the contents of which are herein incorporated by reference in their entirety, and include as non-limiting examples, Comprehensive Positional Evolution (CPE), Combinatorial Protein Synthesis (CPS), Comprehensive Positional Insertion (CPI), Comprehensive Positional Deletion (CPD), or any combination thereof. The Fc region of the multi-specific antibodies described in United States Publication No. US20150252119 may be created using a knob-in-hole approach, or any other method that allows the Fc domain to form heterodimers. The resultant multi-specific antibodies may be further evolved for improved characteristics or properties such as binding affinity for the target antigen. Bispecific antibodies [00852] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode bispecific antibodies. As used herein, the term "bispecific antibody" refers to an antibody capable of binding two different antigens. Such antibodies typically comprise regions from at least two different antibodies. Such antibodies typically comprise antigen-binding regions from at least two different antibodies. For example, a bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein composed of fragments of two different monoclonal antibodies, thus allowing the BsAb to bind to two different types of antigen. [00853] In some cases, the encoded products of interest of the herein disclosed RNA payloads may encode bispecific antibodies comprising antigen-binding regions from two different anti-tau antibodies. For example, such bispecific antibodies may comprise binding regions from two different antibodies [00854] Bispecific antibody frameworks may include any of those described in Riethmuller, G., 2012. Cancer Immunity.12:12-18; Marvin, J.S. et al., 2005. Acta Pharmacologica Sinica. 26(6):649-58; and Schaefer, W. et al., 2011. PNAS.108(27):11187-92, the contents of each of which are herein incorporated by reference in their entirety. [00855] New generations of BsMAb, called "trifunctional bispecific" antibodies, have been developed. These consist of two heavy and two light chains, one each from two different antibodies, where the two Fab regions (the arms) are directed against two antigens, and the Fc region (the foot) comprises the two heavy chains and forms the third binding site. [00856] Of the two paratopes that form the tops of the variable domains of a bispecific antibody, one can be directed against a target antigen and the other against a T-lymphocyte antigen like CD3. In the case of trifunctional antibodies, the Fc region may additionally bind to a cell that expresses Fc receptors, like a macrophage, a natural killer (NK) cell or a dendritic cell. In sum, the targeted cell is connected to one or two cells of the immune system, which subsequently destroy it. [00857] Other types of bispecific antibodies have been designed to overcome certain problems, such as short half-life, immunogenicity and side-effects caused by cytokine liberation. They include chemically linked Fabs, consisting only of the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (scFvs), fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs) and mAb2's, antibodies engineered to contain an Fcab antigen-binding fragment instead of the Fc constant region. [00858] Using molecular genetics, two scFvs can be engineered in tandem into a single polypeptide, separated by a linker domain, called a "tandem scFv" (tascFv). TascFvs have been found to be poorly soluble and require refolding when produced in bacteria, or they may be manufactured in mammalian cell culture systems, which avoids refolding requirements but may result in poor yields. Construction of a tascFv with genes for two different scFvs yields a "bispecific single-chain variable fragments" (bis-scFvs). Only two tascFvs have been developed clinically by commercial firms; both are bispecific agents in active early phase development by Micromet for oncologic indications, and are described as "Bispecific T-cell Engagers (BiTE)." Blinatumomab is an anti-CD19/anti-CD3 bispecific tascFv that potentiates T-cell responses to B-cell non-Hodgkin lymphoma in Phase 2. MT110 is an anti-EP-CAM/anti-CD3 bispecific tascFv that potentiates T-cell responses to solid tumors in Phase 1. [00859] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibodies comprising a single antigen-binding domain. These molecules are extremely small, with molecular weights approximately one-tenth of those observed for full-sized mAbs. Further antibodies may include "nanobodies" derived from the antigen-binding variable heavy chain regions (V_HHs) of heavy chain antibodies found in camels and llamas, which lack light chains. [00860] Disclosed and claimed in PCT Publication WO2014144573 (the contents of which are herein incorporated by reference in its entirety) to Memorial Sloan-Kettering Cancer Center are multimerization technologies for making dimeric multispecific binding agents (e.g., fusion proteins comprising antibody components) with improved properties over multispecific binding agents without the capability of dimerization. [00861] In some cases, the encoded products of interest of the herein disclosed RNA payloads may encode tetravalent bispecific antibodies (TetBiAbs as disclosed and claimed in PCT Publication WO2014144357, the contents of which are herein incorporated in its entirety). TetBiAbs feature a second pair of Fab fragments with a second antigen specificity attached to the C-terminus of an antibody, thus providing a molecule that is bivalent for each of the two antigen specificities. The tetravalent antibody is produced by genetic engineering methods, by linking an antibody heavy chain covalently to a Fab light chain, which associates with its cognate, co-expressed Fab heavy chain. [00862] In some aspects, the encoded products of interest of the herein disclosed RNA payloads may encode biosynthetic antibodies as described in U.S. Patent No.5,091,513 (the contents of which are herein incorporated by reference in their entirety). Such antibody may include one or more sequences of amino acids constituting a region which behaves as a biosynthetic antibody binding site (BABS). The sites comprise 1) non-covalently associated or disulfide bonded synthetic V_H and V_L dimers, 2) V_H-V_L or V_L-V_H single chains wherein the V_H and V_L are attached by a polypeptide linker, or 3) individuals VH or VL domains. The binding domains comprise linked CDR and FR regions, which may be derived from separate immunoglobulins. The biosynthetic antibodies may also include other polypeptide sequences which function, e.g., as an enzyme, toxin, binding site, or site of attachment to an immobilization media or radioactive atom. Methods are disclosed for producing the biosynthetic antibodies, for designing BABS having any specificity that can be elicited by in vivo generation of antibody, and for producing analogs thereof. [00863] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode antibodies with antibody acceptor frameworks taught in U.S. Patent No. 8,399,625. Such antibody acceptor frameworks may be particularly well suited accepting CDRs from an antibody of interest. In some cases, CDRs from anti-tau antibodies known in the art or developed according to the methods presented herein may be used. Miniaturized Antibody [00864] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a "miniaturized" antibody. Among the best examples of mAb miniaturization are the small modular immunopharmaceuticals (SMIPs) from Trubion Pharmaceuticals. These molecules, which can be monovalent or bivalent, are recombinant single-chain molecules containing one V_L, one V_H antigen-binding domain, and one or two constant "effector" domains, all connected by linker domains. Presumably, such a molecule might offer the advantages of increased tissue or tumor penetration claimed by fragments while retaining the immune effector functions conferred by constant domains. At least three "miniaturized" SMIPs have entered clinical development. TRU-015, an anti- CD20 SMIP developed in collaboration with Wyeth, is the most advanced project, having progressed to Phase 2 for rheumatoid arthritis (RA). Earlier attempts in systemic lupus erythrematosus (SLE) and B cell lymphomas were ultimately discontinued. Trubion and Facet Biotechnology are collaborating in the development of TRU-016, an anti-CD37 SMIP, for the treatment of CLL and other lymphoid neoplasias, a project that has reached Phase 2. Wyeth has licensed the anti-CD20 SMIP SBI-087 for the treatment of autoimmune diseases, including RA, SLE, and possibly multiple sclerosis, although these projects remain in the earliest stages of clinical testing. Diabodies [00865] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode diabodies. As used herein, the term "diabody" refers to a small antibody fragment with two antigen-binding sites. Diabodies comprise a heavy chain variable domain V_H connected to a light chain variable domain VL in the same polypeptide chain. By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. [00866] Diabodies are functional bispecific single-chain antibodies (bscAb). These bivalent antigen-binding molecules are composed of non-covalent dimers of scFvs, and can be produced in mammalian cells using recombinant methods. (See, e.g., Mack et al., Proc. Natl. Acad. Sci., 92: 7021- 7025, 1995). Few diabodies have entered clinical development. An iodine-123-labeled diabody version of the anti-CEA chimeric antibody cT84.66 has been evaluated for pre-surgical immunoscintigraphic detection of colorectal cancer in a study sponsored by the Beckman Research Institute of the City of Hope (Clinicaltrials.gov NCT00647153). Unibody [00867] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a "unibody," in which the hinge region has been removed from IgG4 molecules. While IgG4 molecules are unstable and can exchange light-heavy chain heterodimers with one another, deletion of the hinge region prevents heavy chain-heavy chain pairing entirely, leaving highly specific monovalent light/heavy heterodimers, while retaining the Fc region to ensure stability and half-life in vivo. This configuration may minimize the risk of immune activation or oncogenic growth, as IgG4 interacts poorly with FcRs and monovalent unibodies fail to promote intracellular signaling complex formation. These contentions are, however, largely supported by laboratory, rather than clinical, evidence. Other antibodies may be "miniaturized" antibodies, which are compacted 100 kDa antibodies. Intrabodies [00868] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode intrabodies. The term "intrabody" refers to a form of antibody that is not secreted from a cell in which it is produced, but instead targets one or more intracellular proteins. Intrabodies may be used to affect a multitude of cellular processes including, but not limited to intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling, and cell division. In some embodiments, methods of the present disclosure may include intrabody-based therapies. In some such embodiments, variable domain sequences and/or CDR sequences disclosed herein may be incorporated into one or more constructs for intrabody-based therapy. For example, intrabodies may target one or more glycated intracellular proteins or may modulate the interaction between one or more glycated intracellular proteins and an alternative protein. [00869] More than two decades ago, intracellular antibodies against intracellular targets were first described (Biocca, Neuberger and Cattaneo EMBO J.9: 101-108, 1990, the contents of which are herein incorporated by reference in their entirety). The intracellular expression of intrabodies in different compartments of mammalian cells allows blocking or modulation of the function of endogenous molecules (Biocca, et al., EMBO J.9: 101-108, 1990; Colby et al., Proc. Natl. Acad. Sci. U.S.A.101: 17616-21, 2004, the contents of which are herein incorporated by reference in their entirety). Intrabodies can alter protein folding, protein-protein, protein-DNA, protein-RNA interactions and protein modification. They can induce a phenotypic knockout and work as neutralizing agents by direct binding to the target antigen, by diverting its intracellular trafficking or by inhibiting its association with binding partners. They have been largely employed as research tools and are emerging as therapeutic molecules for the treatment of human diseases such as viral pathologies, cancer and misfolding diseases. The fast-growing bio-market of recombinant antibodies provides intrabodies with enhanced binding specificity, stability, and solubility, together with lower immunogenicity, for their use in therapy. [00870] In some embodiments, intrabodies have advantages over interfering RNA (iRNA); for example, iRNA has been shown to exert multiple non-specific effects, whereas intrabodies have been shown to have high specificity and affinity to target antigens. Furthermore, as proteins, intrabodies possess a much longer active half-life than iRNA. Thus, when the active half-life of the intracellular target molecule is long, gene silencing through iRNA may be slow to yield an effect, whereas the effects of intrabody expression can be almost instantaneous. Lastly, it is possible to design intrabodies to block certain binding interactions of a particular target molecule, while sparing others. [00871] Intrabodies are often single chain variable fragments (scFvs) expressed from a recombinant nucleic acid molecule and engineered to be retained intracellularly (e.g., retained in the cytoplasm, endoplasmic reticulum, or periplasm). Intrabodies may be used, for example, to ablate the function of a protein to which the intrabody binds. The expression of intrabodies may also be regulated through the use of inducible promoters in the nucleic acid expression vector comprising the intrabody. Intrabodies may be produced for use in the viral genomes of the disclosure using methods known in the art, such as those disclosed and reviewed in: Marasco et al., 1993 Proc. Natl. Acad. Sci. USA, 90: 7889-7893; Chen et al., 1994, Hum. Gene Ther.5:595-601; Chen et al., 1994, Proc. Natl. Acad. Sci. USA, 91: 5932-5936; Maciejewski et al., 1995, Nature Med., 1: 667-673; Marasco, 1995, Immunotech, 1: 1-19; Mhashilkar, et al., 1995, EMBO J.14: 1542-51; Chen et al., 1996, Hum. Gene Therap., 7: 1515-1525; Marasco, Gene Ther.4:11-15, 1997; Rondon and Marasco, 1997, Annu. Rev. Microbiol.51:257-283; Cohen, et al., 1998, Oncogene 17:2445-56; Proba et al., 1998, J. Mol. Biol. 275:245-253; Cohen et al., 1998, Oncogene 17:2445-2456; Hassanzadeh, et al., 1998, FEBS Lett. 437:81-6; Richardson et al., 1998, Gene Ther.5:635-44; Ohage and Steipe, 1999, J. Mol. Biol. 291:1119-1128; Ohage et al., 1999, J. Mol. Biol.291:1129-1134; Wirtz and Steipe, 1999, Protein Sci. 8:2245-2250; Zhu et al., 1999, J. Immunol. Methods 231:207-222; Arafat et al., 2000, Cancer Gene Ther.7:1250-6; der Maur et al., 2002, J. Biol. Chem.277:45075-85; Mhashilkar et al., 2002, Gene Ther.9:307-19; and Wheeler et al., 2003, FASEB J.17: 1733-5; and references cited therein). In particular, a CCR5 intrabody has been produced by Steinberger et al., 2000, Proc. Natl. Acad. Sci. USA 97:805-810). See generally Marasco, WA, 1998, "Intrabodies: Basic Research and Clinical Gene Therapy Applications" Springer: New York; and for a review of scFvs, see Pluckthun in "The Pharmacology of Monoclonal Antibodies," 1994, vol.113, Rosenburg and Moore eds. Springer- Verlag, New York, pp.269-315; the contents of each of which are each incorporated by reference in their entireties. [00872] Sequences from donor antibodies may be used to develop intrabodies. Intrabodies are often recombinantly expressed as single domain fragments such as isolated VH and VL domains or as a single chain variable fragment (scFv) antibody within the cell. For example, intrabodies are often expressed as a single polypeptide to form a single chain antibody comprising the variable domains of the heavy and light chains joined by a flexible linker polypeptide. Intrabodies typically lack disulfide bonds and are capable of modulating the expression or activity of target genes through their specific binding activity. Single chain antibodies can also be expressed as a single chain variable region fragment joined to the light chain constant region. [00873] As is known in the art, an intrabody can be engineered into recombinant polynucleotide vectors to encode sub-cellular trafficking signals at its N or C terminus to allow expression at high concentrations in the sub-cellular compartments where a target protein is located. For example, intrabodies targeted to the endoplasmic reticulum (ER) are engineered to incorporate a leader peptide and, optionally, a C-terminal ER retention signal. Intrabodies intended to exert activity in the nucleus are engineered to include a nuclear localization signal. Lipid moieties are joined to intrabodies in order to tether the intrabody to the cytosolic side of the plasma membrane. Intrabodies can also be targeted to exert function in the cytosol. For example, cytosolic intrabodies are used to sequester factors within the cytosol, thereby preventing them from being transported to their natural cellular destination. [00874] There are certain technical challenges with intrabody expression. In particular, protein conformational folding and structural stability of the newly-synthesized intrabody within the cell is affected by reducing conditions of the intracellular environment. [00875] Intrabodies of the disclosure may be promising therapeutic agents for the treatment of misfolding diseases, including Tauopathies, prion diseases, Alzheimer's, Parkinson's, and Huntington's, because of their virtually infinite ability to specifically recognize the different conformations of a protein, including pathological isoforms, and because they can be targeted to the potential sites of aggregation (both intra- and extracellular sites). These molecules can work as neutralizing agents against amyloidogenic proteins by preventing their aggregation, and/or as molecular shunters of intracellular traffic by rerouting the protein from its potential aggregation site. Maxibodies [00876] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a maxibody (bivalent scFV fused to the amino terminus of the Fc (CH2-CH3 domains) of IgG. Chimeric Antigen Receptors (CARs) [00877] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a chimeric antigen receptors (CARs) which when transduced into immune cells (e.g., T cells and NK cells), can re-direct the immune cells against the target (e.g., a tumor cell) which expresses a molecule recognized by the extracellular target moiety of the CAR. [00878] As used herein, the term "chimeric antigen receptor (CAR)" refers to a synthetic receptor that mimics TCR on the surface of T cells. In general, a CAR is composed of an extracellular targeting domain, a transmembrane domain/region and an intracellular signaling/activation domain. In a standard CAR receptor, the components: the extracellular targeting domain, transmembrane domain and intracellular signaling/activation domain, are linearly constructed as a single fusion protein. The extracellular region comprises a targeting domain/moiety (e.g., a scFv) that recognizes a specific tumor antigen or other tumor cell-surface molecules. The intracellular region may contain a signaling domain of TCR complex (e.g., the signal region of CD3ζ), and/or one or more costimulatory signaling domains, such as those from CD28, 4-1BB (CD137) and OX-40 (CD134). For example, a "first- generation CAR" only has the CD3ζ signaling domain, whereas in an effort to augment T-cell persistence and proliferation, costimulatory intracellular domains are added, giving rise to second generation CARs having a CD3ζsignal domain plus one costimulatory signaling domain, and third generation CARs having CD3ζ signal domain plus two or more costimulatory signaling domains. A CAR, when expressed by a T cell, endows the T cell with antigen specificity determined by the extracellular targeting moiety of the CAR. In some aspects you could add one or more elements such as homing and suicide genes to develop a more competent and safer architecture of CAR (so called the fourth generation CAR). [00879] In some embodiments, the extracellular targeting domain is joined through the hinge (also called space domain or spacer) and transmembrane regions to an intracellular signaling domain. The hinge connects the extracellular targeting domain to the transmembrane domain which transverses the cell membrane and connects to the intracellular signaling domain. The hinge may need to be varied to optimize the potency of CAR transformed cells toward cancer cells due to the size of the target protein where the targeting moiety binds, and the size and affinity of the targeting domain itself. Upon recognition and binding of the targeting moiety to the target cell, the intracellular signaling domain leads to an activation signal to the CAR T cell, which is further amplified by the "second signal" from one or more intracellular costimulatory domains. The CAR T cell, once activated, can destroy the target cell. [00880] In some embodiments, the CAR may be split into two parts, each part is linked a dimerizing domain, such that an input that triggers the dimerization promotes assembly of the intact functional receptor. Wu and Lim reported a split CAR in which the extracellular CD19 binding domain and the intracellular signaling element are separated and linked to the FKBP domain and the FRB* (T2089L mutant of FKBP-rapamycin binding) domain that heterodimerize in the presence of the rapamycin analog AP21967. The split receptor is assembled in the presence of AP21967 and together with the specific antigen binding, activates T cells (Wu et al., Science, 2015, 625(6258): aab4077, the contents of which are herein incorporated by reference in its entirety). [00881] In some embodiments, the CAR may be designed as an inducible CAR which has an incorporation of a Tet-On inducible system to a CD19 CAR construct. The CD19 CAR is activated only in the presence of doxycycline (Dox). Sakemura reported that Tet-CD19CAR T cells in the presence of Dox were equivalently cytotoxic against CD19+ cell lines and had equivalent cytokine production and proliferation upon CD19 stimulation, compared with conventional CD19CAR T cells (Sakemura et al., Cancer Immuno. Res., 2016, Jun 21, Epub; the contents of which is herein incorporated by reference in its entirety). The dual systems provide more flexibility to turn-on and off of the CAR expression in transduced T cells. [00882] In some embodiments, the cargo or payload may be or may encode a first generation CAR, or a second generation CAR, or a third generation CAR, or a fourth generation CAR. In some embodiments, the cargo or payload may be or may encode a full CAR construct composed of the extracellular domain, the hinge and transmembrane domain and the intracellular signaling region. In other embodiments, the cargo or payload may be or may encode a component of the full CAR construct including an extracellular targeting moiety, a hinge region, a transmembrane domain, an intracellular signaling domain, one or more co-stimulatory domain, and other additional elements that improve CAR architecture and functionality including but not limited to a leader sequence, a homing element and a safety switch, or the combination of such components. [00883] In some embodiments, the CROI of the herein disclosed RNA payloads may encode a tunable CARs. The reversible on-off switch mechanism allows management of acute toxicity caused by excessive CAR-T cell expansion. The ligand conferred regulation of the CAR may be effective in offsetting tumor escape induced by antigen loss, avoiding functional exhaustion caused by tonic signaling due to chronic antigen exposure and improving the persistence of CAR expressing cells in vivo. The tunable CAR may be utilized to down regulate CAR expression to limit on target on tissue toxicity caused by tumor lysis syndrome. Down regulating the expression of the CARs following anti- tumor efficacy may prevent (1) On target off tumor toxicity caused by antigen expression in normal tissue. (2) antigen independent activation in vivo. Extracellular targeting domain / CARs [00884] In some embodiments, the extracellular target moiety of a CAR may be any agent that recognizes and binds to a given target molecule, for example, a neoantigen on tumor cells, with high specificity and affinity. The target moiety may be an antibody and variants thereof that specifically binds to a target molecule on tumor cells, or a peptide aptamer selected from a random sequence pool based on its ability to bind to the target molecule on tumor cells, or a variant or fragment thereof that can bind to the target molecule on tumor cells, or an antigen recognition domain from native T-cell receptor (TCR) (e.g., CD4 extracellular domain to recognize HIV infected cells), or exotic recognition components such as a linked cytokine that leads to recognition of target cells bearing the cytokine receptor, or a natural ligand of a receptor. [00885] In some embodiments, the targeting domain of a CAR may be a Ig NAR, a Fab fragment, a Fab' fragment, a F(ab)'2 fragment, a F(ab)'3 fragment, Fv, a single chain variable fragment (scFv), a bis-scFv, a (scFv)2, a minibody, a diabody, a triabody, a tetrabody, a disulfide stabilized Fv protein (dsFv), a unibody, a nanobody, or an antigen binding region derived from an antibody that specifically recognizes a target molecule, for example a tumor specific antigen (TSA). In one embodiment, the targeting moiety is a scFv antibody. The scFv domain, when it is expressed on the surface of a CAR T cell and subsequently binds to a target protein on a cancer cell, is able to maintain the CAR T cell in proximity to the cancer cell and to trigger the activation of the T cell. A scFv can be generated using routine recombinant DNA technology techniques and is discussed in the present disclosure. [00886] In some embodiments, the targeting moiety of a CAR construct may be an aptamer such as a peptide aptamer that specifically binds to a target molecule of interest. The peptide aptamer may be selected from a random sequence pool based on its ability to bind to the target molecule of interest. [00887] In some embodiments, the targeting moiety of a CAR construct may be a natural ligand of the target molecule, or a variant and/or fragment thereof capable of binding the target molecule. In some aspects, the targeting moiety of a CAR may be a receptor of the target molecule, for example, a full length human CD27, as a CD70 receptor, may be fused in frame to the signaling domain of CD3 ζ forming a CD27 chimeric receptor as an immunotherapeutic agent for CD70- positive malignancies. [00888] In some embodiments, the targeting moiety of a CAR may recognize a tumor specific antigen (TSA), for example a cancer neoantigen which is restrictedly expressed on tumor cells. [00889] As non-limiting examples, the CAR of the present disclosure may comprise the extracellular targeting domain capable of binding to a tumor specific antigen selected from 5T4, 707- AP, A33, AFP (alpha-fetoprotein), AKAP-4 (A kinase anchor protein 4), ALK, α5β1-integrin, androgen receptor, annexin II, alpha- actinin-4, ART-4, B1, B7H3, B7H4, BAGE (B melanoma antigen), BCMA, BCR-ABL fusion protein, beta-catenin, BKT-antigen, BTAA, CA-I (carbonic anhydrase I), CA50 (cancer antigen 50), CA125, CA15-3, CA195, CA242, calretinin, CAIX (carbonic anhydrase), CAMEL (cytotoxic T-lymphocyte recognized antigen on melanoma), CAM43, CAP-1, Caspase-8/m, CD4, CD5, CD7, CD19, CD20, CD22, CD23, CD25, CD27/m, CD28, CD30, CD33, CD34, CD36, CD38, CD40/CD154, CD41, CD44v6, CD44v7/8, CD45,CD49f, CD56, CD68\KP1, CD74, CD79a/CD79b, CD103, CD123, CD133, CD138, CD171, cdc27/m, CDK4 (cyclin dependent kinase 4), CDKN2A, CDS, CEA (carcinoembryonic antigen), CEACAM5, CEACAM6, chromogranin, c-Met, c-Myc, coa-1, CSAp, CT7, CT10, cyclophilin B, cyclin B1, cytoplasmic tyrosine kinases, cytokeratin, DAM-10, DAM-6, dek-can fusion protein, desmin, DEPDC1 (DEP domain containing 1), E2A-PRL, EBNA, EGF-R (epidermal growth factor receptor), EGP- 1(epithelial glycoprotein -1) (TROP-2), EGP-2, EGP-40, EGFR (epidermal growth factor receptor), EGFRvIII, EF-2, ELF2M, EMMPRIN, EpCAM (epithelial cell adhesion molecule), EphA2, Epstein Barr virus antigens, Erb (ErbB1; ErbB3; ErbB4), ETA (epithelial tumor antigen), ETV6-AML1 fusion protein, FAP (fibroblast activation protein), FBP (folate-binding protein), FGF-5, folate receptor, FOS related antigen 1, fucosyl GM1, G250, GAGE (GAGE-1; GAGE-2), galectin, GD2 (ganglioside), GD3, GFAP (glial fibrillary acidic protein), GM2 (oncofetal antigen-immunogenic-1; OFA-I-1), GnT- V, Gp100, H4-RET, HAGE (helicase antigen), HER-2/neu, HIFs (hypoxia inducible factors), HIF-1, HIF-2, HLA-A2, HLA-A*0201-R170I, HLA-Al l, HMWMAA, Hom/Mel-40, HSP70-2M (Heat shock protein 70), HST-2, HTgp-175, hTERT (or hTRT), human papillomavirus-E6/human papillomavirus-E7 and E6, iCE (immune-capture EIA), IGF-1R, IGH-IGK, IL-2R, IL-5, ILK (integrin-linked kinase), IMP3 (insulin-like growth factor II mRNA-binding protein 3), IRF4 (interferon regulatory factor 4), KDR (kinase insert domain receptor), KIAA0205, KRAB-zinc finger protein (KID)-3; KID31, KSA (17-1A), K-ras, LAGE, LCK, LDLR/FUT (LDLR- fucosyltransferaseAS fusion protein), LeY (Lewis Y), MAD-CT-1, MAGE (tyrosinase, melanoma- associated antigen) (MAGE-1; MAGE-3), melan-A tumor antigen (MART), MART-2/Ski, MC1R (melanocortin 1 receptor), MDM2, mesothelin, MPHOSPH1, MSA(muscle-specific actin), mTOR (mammalian targets of rapamycin), MUC-1, MUC-2, MUM-1 (melanoma associated antigen (mutated) 1), MUM-2, MUM-3, Myosin/m, MYL-RAR, NA88-A, N-acetylglucosaminyltransferase, neo-PAP, NF-KB (nuclear factor-kappa B), neurofilament, NSE (neuron- specific enolase), Notch receptors, NuMa, N-Ras, NY-BR-1, NY- CO-1, NY-ESO-1, Oncostatin M, OS-9, OY-TES1, p53 mutants, p190 minor bcr-abl, pl5(58), pl85erbB2, pl80erbB-3, PAGE (prostate associated gene), PAP (prostatic acid phosphatase), PAX3, PAX5, PDGFR (platelet derived growth factor receptor), cytochrome P450 involved in piperidine and pyrrolidine utilization (PIPA), Pml-RAR alpha fusion protein, PR-3 (proteinase 3), PSA (prostate specific antigen), PSM, PSMA (Prostate stem cell antigen), PRAME (preferentially expressed antigen of melanoma), PTPRK, RAGE (renal tumor antigen), Raf (A-Raf, B-Raf and C-Raf), Ras, receptor tyrosine kinases, RCAS1, RGSS, ROR1 (receptor tyrosine kinase-like orphan receptor 1), RU1, RU2, SAGE, SART-1, SART-3, SCP-1, SDCCAG16, SP-17 (sperm protein 17), src-family, SSX (synovial sarcoma X breakpoint)-1, SSX- 2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, STAT-3, STAT-5, STAT-6, STEAD, STn, survivin, syk- ZAP70, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TACSTD1 (tumor associated calcium signal transducer 1), TACSTD2, TAG-72-4, TAGE, TARP (T cell receptor gamma alternate reading frame protein), TEL/AML1 fusion protein, TEM1, TEM8 (endosialin or CD248), TGFβ, TIE2, TLP, TMPRSS2 ETS fusion gene, TNF-receptor (TNF-α receptor, TNF-β receptor; or TNF-γ receptor), transferrin receptor, TPS, TRP-1 (tyrosine related protein 1), TRP-2, TRP-2/INT2, TSP-180, VEGF receptor, WNT, WT-1 (Wilm's tumor antigen) and XAGE. [00890] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CAR which comprises a universal immune receptor which has a targeting moiety capable of binding to a labelled antigen. [00891] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CAR which comprises a targeting moiety capable of binding to a pathogen antigen. [00892] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CAR which comprises a targeting moiety capable of binding to non-protein molecules such as tumor-associated glycolipids and carbohydrates. [00893] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CAR which comprises a targeting moiety capable of binding to a component within the tumor microenvironment including proteins expressed in various tumor stroma cells including tumor associated macrophages (TAMs), immature monocytes, immature dendritic cells, immunosuppressive CD4+CD25+ regulatory T cells (Treg) and MDSCs. [00894] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CAR which comprises a targeting moiety capable of binding to a cell surface adhesion molecule, a surface molecule of an inflammatory cell that appears in an autoimmune disease, or a TCR causing autoimmunity. As non-limiting examples, the targeting moiety of the present disclosure may be a scFv antibody that recognizes a tumor specific antigen (TSA), for example scFvs of antibodies SS, SS1 and HN1 that specifically recognize and bind to human mesothelin, scFv of antibody of GD2, a CD19 antigen binding domain, a NKG2D ligand binding domain, human anti-mesothelin scFvs, an anti-CS1 binding agent, an anti-BCMA binding domain, anti-CD19 scFv antibody, GFR alpha 4 antigen binding fragments, anti-CLL-1 (C-type lectin-like molecule 1) binding domains, CD33 binding domains, a GPC3 (glypican-3) binding domain, a GFR alpha4 (Glycosyl-phosphatidylinositol (GPI)-linked GDNF family α -receptor 4 cell-surface receptor) binding domain, CD123 binding domains, an anti-ROR1 antibody or fragments thereof, scFvs specific to GPC-3, scFv for CSPG4, and scFv for folate receptor alpha. Intracellular signaling domain / CARs [00895] The intracellular domain of a CAR fusion polypeptide, after binding to its target molecule, transmits a signal to the immune effector cell, activating at least one of the normal effector functions of immune effector cells, including cytolytic activity (e.g., cytokine secretion) or helper activity. Therefore, the intracellular domain comprises an "intracellular signaling domain" of a T cell receptor (TCR). [00896] In some aspects, the entire intracellular signaling domain can be employed. In other aspects, a truncated portion of the intracellular signaling domain may be used in place of the intact chain as long as it transduces the effector function signal. [00897] In some embodiments, the intracellular signaling domain may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs (ITAMs). Examples of ITAM containing cytoplasmic signaling sequences include those derived from TCR CD3zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, and CD66d. In one example, the intracellular signaling domain is a CD3 zeta (CD3ζ) signaling domain. [00898] In some embodiments, the intracellular region further comprises one or more costimulatory signaling domains which provide additional signals to the immune effector cells. These costimulatory signaling domains, in combination with the signaling domain can further improve expansion, activation, memory, persistence, and tumor-eradicating efficiency of CAR engineered immune cells (e.g., CAR T cells). In some cases, the costimulatory signaling region contains 1, 2, 3, or 4 cytoplasmic domains of one or more intracellular signaling and /or costimulatory molecules. The costimulatory signaling domain may be the intracellular/cytoplasmic domain of a costimulatory molecule, including but not limited to CD2, CD7, CD27, CD28, 4-1BB (CD137), OX40 (CD134), CD30, CD40, ICOS (CD278), GITR (glucocorticoid-induced tumor necrosis factor receptor), LFA-1 (lymphocyte function-associated antigen- 1), LIGHT, NKG2C, B7-H3. In one example, the costimulatory signaling domain is derived from the cytoplasmic domain of CD28. In another example, the costimulatory signaling domain is derived from the cytoplasmic domain of 4-1BB (CD137). In another example, the co-stimulatory signaling domain may be an intracellular domain of GITR as taught in U.S. Pat. NO.: 9, 175, 308; the contents of which are incorporated herein by reference in its entirety. [00899] In some embodiments, the intracellular region may comprise a functional signaling domain from a protein selected from the group consisting of an MHC class I molecule, a TNF receptor protein, an immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphocytic activation protein (SLAM) such as CD48, CD229, 2B4, CD84, NTB-A, CRACC, BLAME,CD2F-10, SLAMF6, SLAMF7, an activating NK cell receptor, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4- 1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, IL-15Ra, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, NKD2C SLP76, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, CD270 (HVEM), GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds with CD83, DAP 10, TRIM, ZAP70, Killer immunoglobulin receptors (KIRs) such as KIR2DL1, KIR2DL2/L3, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1/S1, KIR3DL2, KIR3DL3, and KIR2DP1; lectin related NK cell receptors such as Ly49, Ly49A, and Ly49C. [00900] In some embodiments, the intracellular signaling domain of the present disclosure may contain signaling domains derived from JAK-STAT. In other embodiments, the intracellular signaling domain of the present disclosure may contain signaling domains derived from DAP-12 (Death associated protein 12) (Topfer et al., Immunol., 2015, 194: 3201-3212; and Wang et al., Cancer Immunol., 2015, 3: 815-826). DAP-12 is a key signal transduction receptor in NK cells. The activating signals mediated by DAP-12 play important roles in triggering NK cell cytotoxicity responses toward certain tumor cells and virally infected cells. The cytoplasmic domain of DAP12 contains an Immunoreceptor Tyrosine-based Activation Motif (ITAM). Accordingly, a CAR containing a DAP12-derived signaling domain may be used for adoptive transfer of NK cells. Transmembrane domains / CARs [00901] In some embodiments, the CAR may comprise a transmembrane domain. As used herein, the term "Transmembrane domain (TM)" refers broadly to an amino acid sequence of about 15 residues in length which spans the plasma membrane. The transmembrane domain may include at least 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 amino acid residues and spans the plasma membrane. In some embodiments, the transmembrane domain may be derived either from a natural or from a synthetic source. The transmembrane domain of a CAR may be derived from any naturally membrane-bound or transmembrane protein. For example, the transmembrane region may be derived from (i.e. comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD3 epsilon, CD4, CD5, CD8, CD8α, CD9, CD16, CD22, CD33, CD28, CD37, CD45, CD64, CD80, CD86, CD134, CD137, CD152, or CD154. [00902] Alternatively, the transmembrane domain of the present disclosure may be synthetic. In some aspects, the synthetic sequence may comprise predominantly hydrophobic residues such as leucine and valine. [00903] In some embodiments, the transmembrane domain may be selected from the group consisting of a CD8α transmembrane domain, a CD4 transmembrane domain, a CD 28 transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, and a human IgG4 Fc region. [00904] In some embodiments, the CAR may comprise an optional hinge region (also called spacer). A hinge sequence is a short sequence of amino acids that facilitates flexibility of the extracellular targeting domain that moves the target binding domain away from the effector cell surface to enable proper cell/cell contact, target binding and effector cell activation. The hinge sequence may be positioned between the targeting moiety and the transmembrane domain. The hinge sequence can be any suitable sequence derived or obtained from any suitable molecule. The hinge sequence may be derived from all or part of an immunoglobulin (e.g., IgGl, IgG2, IgG3, IgG4) hinge region, i.e., the sequence that falls between the CHI and CH2 domains of an immunoglobulin, e.g., an IgG4 Fc hinge, the extracellular regions of type 1 membrane proteins such as CD8α CD4, CD28 and CD7, which may be a wild-type sequence or a derivative. Some hinge regions include an immunoglobulin CH3 domain or both a CH3 domain and a CH2 domain. In certain embodiments, the hinge region may be modified from an IgG1, IgG2, IgG3, or IgG4 that includes one or more amino acid residues, for example, 1, 2, 3, 4 or 5 residues, substituted with an amino acid residue different from that present in an unmodified hinge. [00905] In some embodiments, the CAR may comprise one or more linkers between any of the domains of the CAR. The linker may be between 1-30 amino acids long. In this regard, the linker may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids in length. In other embodiments, the linker may be flexible. [00906] In some embodiments, the components including the targeting moiety, transmembrane domain and intracellular signaling domains may be constructed in a single fusion polypeptide. The fusion polypeptide may be the payload of an effector module of the disclosure. [00907] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CD19 specific CAR targeting different B cell malignancies and HER2- specific CAR targeting sarcoma, glioblastoma, and advanced Her2-positive lung malignancy. Tandem CAR (TanCAR) [00908] In some embodiments, the CAR may be a tandem chimeric antigen receptor (TanCAR) which is able to target two, three, four, or more tumor specific antigens. In some aspects, The CAR is a bispecific TanCAR including two targeting domains which recognize two different TSAs on tumor cells. The bispecific TanCAR may be further defined as comprising an extracellular region comprising a targeting domain (e.g., an antigen recognition domain) specific for a first tumor antigen and a targeting domain (e.g., an antigen recognition domain) specific for a second tumor antigen. In other aspects, the CAR is a multispecific TanCAR that includes three or more targeting domains configured in a tandem arrangement. The space between the targeting domains in the TanCAR may be between about 5 and about 30 amino acids in length, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 amino acids. Split CARs [00909] In some embodiments, the CAR components including the targeting moiety, transmembrane domain and intracellular signaling domains may be split into two or more parts such that it is dependent on multiple inputs that promote assembly of the intact functional receptor. As a non-limiting example, the split CAR consists of two parts that assemble in a small molecule- dependent manner; one part of the receptor features an extracellular antigen binding domain (e.g., scFv) and the other part has the intracellular signaling domains, such as the CD3ζ intracellular domain. [00910] In other aspects, the split parts of the CAR system can be further modified to increase signal. As a non-limiting example, the second part of cytoplasmic fragment may be anchored to the plasma membrane by incorporating a transmembrane domain (e.g., CD8α transmembrane domain) to the construct. An additional extracellular domain may also be added to the second part of the CAR system, for instance an extracellular domain that mediates homo-dimerization. These modifications may increase receptor output activity, i.e., T cell activation. [00911] In some embodiments, the two parts of the split CAR system contain heterodimerization domains that conditionally interact upon binding of a heterodimerizing small molecule. As such, the receptor components are assembled in the presence of the small molecule, to form an intact system which can then be activated by antigen engagement. Any known heterodimerizing components can be incorporated into a split CAR system. Other small molecule dependent heterodimerization domains may also be used, including, but not limited to, gibberellin- induced dimerization system (GID1-GAI), trimethoprim-SLF induced ecDHFR and FKBP dimerization and ABA (abscisic acid) induced dimerization of PP2C and PYL domains. The dual regulation using inducible assembly (e.g., ligand dependent dimerization) and degradation (e.g., destabilizing domain induced CAR degradation) of the split CAR system may provide more flexibility to control the activity of the CAR modified T cells. Switchable CARs [00912] In some embodiments, the CAR may be a switchable CAR which is a controllable CARs that can be transiently switched on in response to a stimulus (e.g. a small molecule). In this CAR design, a system is directly integrated in the hinge domain that separate the scFv domain from the cell membrane domain in the CAR. Such system is possible to split or combine different key functions of a CAR such as activation and costimulation within different chains of a receptor complex, mimicking the complexity of the TCR native architecture. This integrated system can switch the scFv and antigen interaction between on/off states controlled by the absence/presence of the stimulus. Reversible CARs [00913] In some embodiments, the CAR may be a reversible CAR system. In this CAR architecture, a LID domain (ligand-induced degradation) is incorporated into the CAR system. The CAR can be temporarily down-regulated by adding a ligand of the LID domain. Inhibitory CARs (iCARs) [00914] In some embodiments, the CAR may be an inhibitory CAR. Inhibitory CAR (iCAR) refers to a bispecific CAR design wherein a negative signal is used to enhance the tumor specificity and limit normal tissue toxicity. This design incorporates a second CAR having a surface antigen recognition domain combined with an inhibitory signal domain to limit T cell responsiveness even with concurrent engagement of an activating receptor. This antigen recognition domain is directed towards a normal tissue specific antigen such that the T cell can be activated in the presence of first target protein, but if the second protein that binds to the iCAR is present, the T cell activation is inhibited. [00915] As a non-limiting example, iCARs against Prostate specific membrane antigen (PMSA) based on CTLA4 and PD1 inhibitory domains demonstrated the ability to selectively limit cytokine secretion, cytotoxicity and proliferation induced by T cell activation. Chimeric switch receptors [00916] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads encodes a chimeric switch receptor which can switch a negative signal to a positive signal. As used herein, the term "chimeric switch receptor" refers to a fusion protein comprising a first extracellular domain and a second transmembrane and intracellular domain, wherein the first domain includes a negative signal region and the second domain includes a positive intracellular signaling region. In some aspects, the fusion protein is a chimeric switch receptor that contains the extracellular domain of an inhibitory receptor on T cell fused to the transmembrane and cytoplasmic domain of a co-stimulatory receptor. This chimeric switch receptor may convert a T cell inhibitory signal into a T cell stimulatory signal. [00917] As a non-limiting example, the chimeric switch receptor may comprise the extracellular domain of PD-1 fused to the transmembrane and cytoplasmic domain of CD28. In some aspects, extracellular domains of other inhibitory receptors such as CTLA-4, LAG-3, TIM-3, KIRs and BTLA may also be fused to the transmembrane and cytoplasmic domain derived from costimulatory receptors such as CD28, 4-1BB, CD27, OX40, CD40, GTIR and ICOS. [00918] In some embodiments, chimeric switch receptors may include recombinant receptors comprising the extracellular cytokine-binding domain of an inhibitory cytokine receptor (e.g., IL-13 receptor α (IL-13Rα1), IL-10R, and IL-4Rα) fused to an intracellular signaling domain of a stimulatory cytokine receptor such as IL-2R (IL-2Ra, IL-2Rβ and IL-2Rgamma) and IL-7Rα. One example of such chimeric cytokine receptor is a recombinant receptor containing the cytokine-binding extracellular domain of IL-4Rα linked to the intracellular signaling domain of IL-7Rα. [00919] In some embodiments, the chimeric switch receptor may be a chimeric TGFβ receptor. The chimeric TGFβ receptor may comprise an extracellular domain derived from a TGFβ receptor such as TGFβ receptor 1, TGFβ receptor 2, TGFβ receptor 3, or any other TGFβ receptor or variant thereof; and a non- TGFβ receptor intracellular domain. The non-TGFβ receptor intracellular domain may be the intracellular domain or fragment thereof derived from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CD28, 4-1BB (CD137), OX40 (CD134), CD3zeta, CD40, CD27, or a combination thereof. Activation-conditional CAR [00920] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode an activation-conditional chimeric antigen receptor, which is only expressed in an activated immune cell. The expression of the CAR may be coupled to activation conditional control region which refers to one or more nucleic acid sequences that induce the transcription and/or expression of a sequence e.g., a CAR under its control. Such activation conditional control regions may be promoters of genes that are upregulated during the activation of the immune effector cell e.g. IL2 promoter or NFAT binding sites. CAR targeting to tumor cells with specific proteoglycan markers [00921] In some embodiments, the encoded products of interest of the herein disclosed RNA payloads may encode a CAR that targets specific types of cancer cells. Human cancer cells and metastasis may express unique and otherwise abnormal proteoglycans, such as polysaccharide chains (e.g., chondroitin sulfate (CS), dermatan sulfate (DS or CSB), heparan sulfate (HS) and heparin). Accordingly, the CAR may be fused with a binding moiety that recognizes cancer associated proteoglycans. In one example, a CAR may be fused with VAR2CSA polypeptide (VAR2-CAR) that binds with high affinity to a specific type of chondroitin sulfate A (CSA) attached to proteoglycans. The extracellular ScFv portion of the CAR may be substituted with VAR2CSA variants comprising at least the minimal CSA binding domain, generating CARs specific to chondroitin sulfate A (CSA) modifications. Alternatively, the CAR may be fused with a split-protein binding system to generate a spy-CAR, in which the scFv portion of the CAR is substituted with one portion of a split-protein binding system such as SpyTag and Spy-catcher and the cancer-recognition molecules (e.g. scFv and or VAR2-CSA) are attached to the CAR through the split-protein binding system. CAR Treatment Methods [00922] In some embodiments, an LNP of the present disclosure comprising an RNA encoding a CAR can be used to treat a disease. The present disclosure contemplates a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an LNP or pharmaceutical composition comprising an LNP disclosed and described herein. In certain embodiments, the LNP comprises an RNA encoding a CAR protein described herein. In certain embodiments, the LNP delivers the RNA encoding the CAR protein to a T cell. In certain embodiments, the LNP delivers the RNA encoding the CAR protein to an NK cell. In certain embodiments, the LNP delivers the RNA encoding the CAR protein to both a T cell and an NK cell. Interestingly, LNPs of the present disclosure have been found to demonstrate high delivery to both T cells and NK cells (see Example 9). Methods and compositions of the present disclosure can enable simultaneous generation of CAR T cells and CAR NK cells, in vivo, increasing the therapeutic applications and efficacy over other delivery systems that target only one variety of immune cell. In certain embodiments, the disease is a tumor or cancer. C. Vaccine antigens [00923] In some embodiments, the RNA payloads (e.g., linear and/or circular mRNA payloads encoding one or more products of interest) and associated compositions and methods described herein provide for the delivery of a wide variety of antigens, e.g., virus antigens, cancer antigens, and/or infectious disease antigens. [00924] In certain embodiments, the antigen is a protein (including recombinant proteins), polypeptide, or peptide (including synthetic peptides). The compositions provided herein can contain one or more antigens (e.g., at least two, three, four, five, or six antigens). [00925] In specific embodiments, antigens can be selected from the group consisting of the following: (a) polypeptides suitable to induce an immune response against cancer cells; (b) polypeptides suitable to induce an immune response against infectious diseases; (c) polypeptides suitable to induce an immune response against allergens; and (d) polypeptides suitable to induce an immune response in farm animals or pets. [00926] In certain embodiments, the compositions of the disclosure can be used in combination with an immunoregulatory therapy to target either activating receptors or inhibitory receptors. See, e.g., Mellman et al., 2013, Nature 480:480-489. The immunoregulatory therapy can be, for example, a T cell engaging agent selected from agonistic antibodies which bind to human OX40, to GITR, to CD27, or to 4-IBB, and T-cell bispecific antibodies (e.g. T cell-engaging BiTE™ antibodies CD3-CD19, CD3-EpCam, CD3-EGFR), IL-2 (Proleukin), Interferon (IFN) alpha, antagonizing antibodies which bind to human CTLA-4 (e.g. ipilimumab), to PD-1, to PD-L1, to TIM- 3, to BTLA, to VISTA, to LAG-3, or to CD25. [00927] Exemplary antigens include those from a pathogen (e.g. virus, bacterium, parasite, fungus) and tumors (especially tumor-associated antigens or “tumor markers”). Other exemplary antigens include autoantigens. [00928] In some embodiments, the antigen or antigenic determinant is one that is useful for the prevention of infectious disease. Such treatment will be useful to treat a wide variety of infectious diseases affecting a wide range of hosts, preferably human, but including cow, sheep, pig, dog, cat, and other mammalian species and non-mammalian species. Thus, antigens or antigenic determinants selected for the compositions will be well known to those in the medical art. [00929] Examples of antigens or antigenic determinants include the following: SARS-CoV-2 spike protein, coronavirus spike proteins and/or envelope proteins, the RSV F or G antigens, Chlamydia antigens such as the Major outer membrane protein (mOMP), the Dengue type 1 to 4 envelope proteins, the HIV antigens gp140 and gp160; the influenza antigens hemagglutinin, M2 protein, and neuraminidase; hepatitis B surface antigen or core; and circumsporozoite protein of malaria, or fragments thereof. Other antigens include those antigen polypeptides listed in Tables 6-18 of U.S. Patent No.10,709,779, or any variant thereof having at least 80% , 85%, 90%, 95%, or 99% or up to 100% sequence identity with any of the polypeptide antigens of Tables 6-18 of U.S. Patent No.10,709,779 (which is incorporated herein by reference). [00930] Appropriate antigens for use with this LNP technology may be derived from, but not limited to, pathogenic bacterial, fungal, or viral organisms, Streptococcus species, Candida species, Brucella species, Salmonella species, Shigella spe cies, Pseudomonas species, Bordetella species, Clostridium species, Norwalk virus, Bacillus anthracis, Mycobacterium tuberculosis, human immunodeficiency virus (HIV), Chlamydia species, human Papillomaviruses, Influenza virus, Paramyxovirus species, Herpes virus, Cytomegalovirus, Varicella-Zoster virus, Epstein-Barr virus, Hepatitis viruses, Plasmodium species, Trichomonas species, Ebola, sexually transmitted disease agents, viral encephalitis agents, protozoan disease agents, fungal disease agents, cancer cells, or mixtures thereof. Other appropriate molecules incorporated in the nanoparticle vaccines may include self-antigens, adhesins, or surface exposed cell signaling receptors or ligands. A variety of diseases and disorders may be treated by the LNP RNA delivery systems described herein, including: inflammatory diseases, infectious diseases, cancer, genetic disorders, organ transplant rejection, autoimmune diseases and immunological disorders. [00931] Examples of infectious disease include, but are not limited to, viral infectious diseases, such as AIDS, Respiratory Syncytial Virus (RSV), Chickenpox (Varicella), Common cold, Cytomegalovirus Infection, Colorado tick fever, Dengue fever, Ebola hemorrhagic fever, Hand, foot and mouth disease, Hepatitis, Herpes simplex, Herpes zoster, HPV, Influenza (Flu), Lassa fever, Measles, Marburg hemorrhagic fever, Infectious mononucleosis, Mumps, Norovirus, Poliomyelitis, Progressive multifocal leukencephalopathy, Rabies, Rubella, SARS, Smallpox (Variola), Viral encephalitis, Viral gastroenteritis, Viral meningitis, Viral pneumonia, West Nile disease and Yellow fever; bacterial infectious diseases, such as Anthrax, Bacterial Meningitis, Botulism, Brucellosis, Campylobacteriosis, Cat Scratch Disease, Cholera, Diphtheria, Epidemic Typhus, Gonorrhea, Impetigo, Legionellosis, Leprosy (Hansen's Disease), Leptospirosis, Listeriosis, Lyme disease, Melioidosis, Rheumatic Fever, MRSA infection, Nocardiosis, Pertussis (Whooping Cough), Plague, Pneumococcal pneumonia, Psittacosis, Q fever, Rocky Mountain Spotted Fever (RMSF), Salmonellosis, Scarlet Fever, Shigellosis, Syphilis, Tetanus, Trachoma, Tuberculosis, Tularemia, Typhoid Fever, Typhus and Urinary Tract Infections; parasitic infectious diseases, such as African trypanosomiasis, Amebiasis, Ascariasis, Babesiosis, Chagas Disease, Clonorchiasis, Cryptosporidiosis, Cysticercosis, Diphyllobothriasis, Dracunculiasis, Echinococcosis, Enterobiasis, Fascioliasis, Fasciolopsiasis, Filariasis, Free-living amebic infection, Giardiasis, Gnathostomiasis, Hymenolepiasis, Isosporiasis, Kalaazar, Leishmaniasis, Malaria, Metagonimiasis, Myiasis, Onchocerciasis, Pediculosis, Pinworm Infection, Scabies, Schistosomiasis, Taeniasis, Toxocariasis, Toxoplasmosis, Trichinellosis, Trichinosis, Trichuriasis, Trichomoniasis and Trypanosomiasis; fungal infectious disease, such as Aspergillosis, Blastomycosis, Candidiasis, Coccidioidomycosis, Cryptococcosis, Histoplasmosis, Tinea pedis (Athlete's Foot) and Tinea cruris; prion infectious diseases, such as Alpers' disease, Fatal Familial Insomnia, Gerstmann-Straussler-Scheinker syndrome, Kuru and Variant Creutzfeldt-Jakob disease. [00932] Examples of cancers include, but are not limited to breast cancer; biliary tract cancer; bladder cancer; brain cancer including glioblastomas; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including acute lymphocytic and myelogenous leukemia, e.g., B Cell CLL; T-cell acute lymphoblastic leukemia/lymphoma; hairy cell leukemia; chronic myelogenous leukemia, multiple myeloma; AIDS- associated leukemias and adult T-cell leukemia/lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer; lung cancer; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cell carcinoma; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell cancer; testicular cancer including germinal tumors such as seminoma, non-seminoma (teratomas, choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor. [00933] Any antigen associated with any of the diseases or conditions provided herein can be used in the compositions and methods described herein. These include antigens associated with cancer, infections or infectious disease or degenerative or non-autoimmune disease. Antigens associated with HIV, malaria, leischmaniasis, a human filovirus infection, a togavirus infection, a alphavirus infection, an arenavirus infection, a bunyavirus infection, a flavivirus infection, a human papillomavirus infection, a human influenza A virus infection, a hepatitis B infection or a hepatitis C infection are also included. [00934] Examples of cancer antigens include HER 2 (pi 85), CD20, CD33, GD3 ganglioside, GD2 ganglioside, carcinoembryonic antigen (CEA), CD22, milk mucin core protein, TAG-72, Lewis A antigen, ovarian associated antigens such as OV-TL3 and MOvl8, high Mr melanoma antigens recognized by antibody 9.2.27, HMFG-2, SM-3, B72.3, PR5C5, PR4D2, and the like. Further examples include MAGE, MART-1/Melan-A, gplOO, Dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein (ADAbp), FAP, cyclophilin b, Colorectal associated antigen (CRC)— C017-1A/GA733, Carcinoembryonic Antigen (CEA) and its immunogenic epitopes CAP-1 and CAP- 2, etv6, amll, prostatic acid phosphatase (PAP), Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-1, PSA-2, and PSA-3, pro state-specific membrane antigen (PSMA), T-cell receptor/CD3-zeta chain, MAGE-family of tumor antigens (e.g., MAGE-I or MAGE-II families) (e.g., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1, MAGE-C2, MAGE-C3, MAGE-C4, MAGE- C5), GAGE-family of tumor antigens (e.g., GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, GAGE-9), BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM-1, CDK4, tyrosinase, p53, MUC family, HER2/neu, p21ras, RCAS1, a-fetoprotein, E-cadherin, a-catenin, β- catenin and γ-catenin, pl20ctn, gplOOPmell 17, PRAME, NY-ESO-1, cdc27, adenomatous polyposis coli protein (APC), fodrin, Connexin 37, Ig-idiotype, pl5, gp75, GM2 and GD2 gangliosides, viral products such as human papilloma virus proteins, Smad family of tumor antigens, lmp-1, PIA, EBV- encoded nuclear antigen (EBNA)-1, brain glycogen phosphorylase, SSX-1, SSX-2 (HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1 and CT-7, CD20 and c-erbB-2. [00935] In another embodiment, antigens associated with infection or infectious disease are associated with any of the infectious agents provided herein. In one embodiment, the infectious agent is a virus of the Adenoviridae, Picornaviridae, Herpesviridae, Hepadnaviridae, Flaviviridae, Retroviridae, Orthomyxoviridae, Paramyxoviridae, Papillomaviridae, Rhabdoviridae, Togaviridae or Paroviridae family. In still another embodiment, the infectious agent is adenovirus, coxsackievirus, hepatitis A virus, poliovirus, Rhinovirus, Herpes simplex virus, Varicella-zoster virus, Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, Hepatitis B virus, Hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, HIV, Influenza virus, Measles virus, Mumps virus, Parainfluenza virus, Respiratory syncytial virus, Human metapneumovirus, Human papillomavirus, Rabies virus, Rubella virus, Human bocarivus or Parvovirus B19. In yet another embodiment, the infectious agent is a bacteria of the Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia and Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema Vibrio or Yersinia genus. In a further embodiment, the infectious agent is Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum, Vibrio cholerae or Yersinia pestis. In another embodiment, the infectious agent is a fungus of the Candida, Aspergillus, Cryptococcus, Histoplasma, Pneumocystis or Stachybotrys genus. In still another embodiment, the infectious agent is C. albicans, Aspergillus fumigatus, Aspergillus flavus, Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, Cryptococcus gattii, Histoplasma capsulatum, Pneumocystis jirovecii or Stachybotrys chartarum. [00936] In yet another embodiment, the antigen associated with infection or infectious disease is one that comprises VI, VII, E1A, E3-19K, 52K, VP1, surface antigen, 3A protein, capsid protein, nucleocapsid, surface projection, transmembrane proteins, UL6, UL18, UL35, UL38, UL19, early antigen, capsid antigen, Pp65, gB, p52, latent nuclear antigen-1, NS3, envelope protein, envelope protein E2 domain, gpl20, p24, lipopeptides Gag (17-35), Gag (253-284), Nef (66-97), Nef (116-145), Pol (325-355), neuraminidase, nucleocapsid protein, matrix protein, phosphoprotein, fusion protein, hemagglutinin, hemagglutinin-neuraminidase, glycoprotein, E6, E7, envelope lipoprotein or non- structural protein (NS). In another embodiment, the antigen comprises pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), fimbriae (FIM 2/3), VlsE; DbpA, OspA, Hia, PrpA, MltA, L7/L12, D15, 0187, VirJ, Mdh, AfuA, L7/L12, out membrane protein, LPS, antigen type A, antigen type B, antigen type C, antigen type D, antigen type E, FliC, FliD, Cwp84, alpha-toxin, theta-toxin, fructose 1,6-biphosphate-aldolase (FBA), glyceraldehydes-3-phosphate dehydrogenase (GPD), pyruvate:ferredoxin oxidoreductase (PFOR), elongation factor-G (EF-G), hypothetical protein (HP), T toxin, Toxoid antigen, capsular polysaccharide, Protein D, Mip, nucleoprotein (NP), RD1, PE35, PPE68, EsxA, EsxB, RD9, EsxV, Hsp70, lipopolysaccharide, surface antigen, Sp1, Sp2, Sp3, Glycerophosphodiester Phosphodiesterase, outer membrane protein, chaperone-usher protein, capsular protein (Fl) or V protein. In yet another embodiment, the antigen is one that comprises capsular glycoprotein, Yps3P, Hsp60, Major surface protein, MsgC1, MsgC3, MsgC8, MsgC9 or SchS34. [00937] As a non-limiting example, the polynucleotides (e.g., linear or circular mRNA payloads of the LNP delivery systems described herein) encoding an immunogen may be delivered to cells to trigger multiple innate response pathways (see International Pub. No. WO2012006377 and US Patent Publication No. US20130177639; herein incorporated by reference in its entirety). As another non-limiting example, the polynucleotides of the LNP delivery systems described herein encoding an immunogen may be delivered to a vertebrate in a dose amount large enough to be immunogenic to the vertebrate (see International Pub. No. WO2012006372 and WO2012006369 and US Publication No. US20130149375 and US20130177640; the contents of each of which are herein incorporated by reference in their entirety). [00938] A non-limiting list of infectious diseases that the polynucleotide vaccines may treat includes, viral infectious diseases such as Covid-19 (SARS-CoV-2), AIDS (HIV), HIV resulting in mycobacterial infection, AIDS related Cacheixa, AIDS related Cytomegalovirus infection, HIV- associated nephropathy, Lipodystrophy, AID related cryptococcal meningitis, AIDS related neutropaenia, Pneumocysitis jiroveci (Pneumocystis carinii) infections, AID related toxoplasmosis, hepatitis A, B, C, D or E, herpes, herpes zoster (chicken pox), German measles (rubella virus), yellow fever, dengue fever etc. (flavi viruses), flu (influenza viruses), haemorrhagic infectious diseases (Marburg or Ebola viruses), bacterial infectious diseases such as Legionnaires' disease (Legionella), gastric ulcer (Helicobacter), cholera (Vibrio), E. coli infections, staphylococcal infections, salmonella infections or streptococcal infections, tetanus (Clostridium tetani), protozoan infectious diseases (malaria, sleeping sickness, leishmaniasis, toxoplasmosis, i.e. infections caused by plasmodium, trypanosomes, leishmania and toxoplasma), diphtheria, leprosy, measles, pertussis, rabies, tetanus, tuberculosis, typhoid, varicella, diarrheal infections such as Amoebiasis, Clostridium difficile- associated diarrhea (CDAD), Cryptosporidiosis, Giardiasis, Cyclosporiasis and Rotaviral gastroenteritis, encephalitis such as Japanese encephalitis, Wester equine encephalitis and Tick-borne encephalitis (TBE), fungal skin diseases such as candidiasis, onychomycosis, Tinea captis/scal ringworm, Tinea corporis/body ringworm, Tinea cruris/jock itch, sporotrichosis and Tinea pedis/Athlete's foot, Meningitis such as Haemophilus influenza type b (Hib), Meningitis, viral, meningococcal infections and pneumococcal infection, neglected tropical diseases such as Argentine haemorrhagic fever, Leishmaniasis, Nematode/roundworm infections, Ross river virus infection and West Nile virus (WNV) disease, Non-HIV STDs such as Trichomoniasis, Human papillomavirus (HPV) infections, sexually transmitted chlamydial diseases, Chancroid and Syphilis, Non-septic bacterial infections such as cellulitis, lyme disease, MRSA infection, pseudomonas, staphylococcal infections, Boutonneuse fever, Leptospirosis, Rheumatic fever, Botulism, Rickettsial disease and Mastoiditis, parasitic infections such as Cysticercosis, Echinococcosis, Trematode/Fluke infections, Trichinellosis, Babesiosis, Hypodermyiasis, Diphyllobothriasis and Trypanosomiasis, respiratory infections such as adenovirus infection, aspergillosis infections, avian (H5N1) influenza, influenza, RSV infections, severe acute respiratory syndrome (SARS), sinusitis, Legionellosis, Coccidioidomycosis and swine (H1N1) influenza, sepsis such as bacteraemia, sepsis/septic shock, sepsis in premature infants, urinary tract infection such as vaginal infections (bacterial), vaginal infections (fungal) and gonococcal infection, viral skin diseases such as B19 parvovirus infections, warts, genital herpes, orofacial herpes, shingles, inner ear infections, fetal cytomegalovirus syndrome, foodborn illnesses such as brucellosis (Brucella species), Clostridium perfringens (Epsilon toxin), E. Coli O157:H7 (Escherichia coli), Salmonellosis (Salmonella species), Shingellosis (Shingella), Vibriosis and Listeriosis, bioterrorism and potential epidemic diseases such as Ebola haemorrhagic fever, Lassa fever, Marburg haemorrhagic fever, plague, Anthrax Nipah virus disease, Hanta virus, Smallpox, Glanders (Burkholderia mallei), Melioidosis (Burkholderia pseudomallei), Psittacosis (Chlamydia psittaci), Q fever (Coxiella burnetii), Tularemia (Fancisella tularensis), rubella, mumps and polio. [00939] The LNP delivery systems described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non- limiting example, the LNP delivery systems disclosed herein may be utilized to treat and/or prevent influenza infection, i.e. diseases and conditions related to influenza virus infection (seasonal and pandemic). [00940] The LNP delivery systems described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non- limiting example, the LNP delivery systems disclosed herein may be utilized to treat and/or prevent coronavirus infection, i.e. diseases and conditions related to coronavirus virus infection (seasonal and pandemic). [00941] The LNP delivery systems described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non- limiting example, the LNP delivery systems disclosed herein may be utilized to treat and/or prevent SARS-CoV-2 infection, i.e. diseases and conditions related to SARS-CoV-2 virus infection (seasonal and pandemic), e.g., Covid-19. D. Signal peptides [00942] In some embodiments, the polypeptide products (e.g., vaccine antigens and/or therapeutic proteins) of the RNA payload disclosed herein may comprise a signal peptide. Signal peptides, comprising the about N-terminal 15-60 amino acids of proteins, are typically needed for the translocation across the membrane on the secretory pathway and thus universally control the entry of most proteins both in eukaryotes and prokaryotes to the secretory pathway. Signal peptides generally include three regions: an N-terminal region of differing length, which usually comprises positively charged amino acids, a hydrophobic region, and a short carboxy-terminal peptide region. In eukaryotes, the signal peptide of a nascent precursor protein (pre-protein) directs the ribosome to the rough endoplasmic reticulum (ER) membrane and initiates the transport of the growing peptide chain across it. The signal peptide is not responsible for the final destination of the mature protein, however. Secretory proteins devoid of further address tags in their sequence are by default secreted to the external environment. Signal peptides are cleaved from precursor proteins by an endoplasmic reticulum (ER)-resident signal peptidase or they remain uncleaved and function as a membrane anchor. [00943] In various embodiments, the polypeptide products (e.g., vaccine antigens and/or therapeutic proteins) of the RNA payload disclosed herein may comprise artificial signal peptides, wherein the signal peptide coding sequence is operably linked to and is in frame with the coding sequence of the encoded polypeptide product. Thus, polypeptides produced by the RNA payload disclosed herein may comprise a fusion with a signal peptide (either naturally occurring signal peptide or an artificial signal peptide). The signal peptide can be fused to either the N-terminus or the C-terminus of an encoded polypeptide product produced by an RNA payload disclosed herein. In some embodiments, a signal peptide can be fused to both the N- terminus and the C-terminus of an encoded polypeptide product produced by an RNA payload disclosed herein. [00944] Any signal peptide that is known in the art to facilitate targeting of a protein to ER for processing and/or targeting of a protein to the cell membrane may be used in accordance with the present disclosure. [00945] A signal peptide may have a length of about 10-60 amino acids. For example, a signal peptide may have a length of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids. In some embodiments, a signal peptide may have a length of 20-60, 25-60, 30-60, 35-60, 40-60, 45-60, 50-60, 55-60, 15-55, 20-55, 25- 55, 30-55, 35-55, 40-55, 45-55, 50-55, 15-50, 20-50, 25-50, 30-50, 35-50, 40-50, 45-50, 15-45, 20-45, 25-45, 30-45, 35-45, 40-45, 15-40, 20-40, 25-40, 30-40, 35-40, 15-35, 20-35, 25-35, 30- 35, 15-30, 20-30, 25-30, 15-25, 20-25, or 15-20 amino acids. E. Fusion proteins [00946] In some embodiments, the polypeptide products (e.g., vaccine antigens and/or therapeutic proteins) of the RNA payload disclosed herein may be in the form of a fusion protein. Thus, the encoded polypeptides may include two or more proteins (e.g., protein and/or protein fragment) joined together, e.g., by a linker. In some embodiments, the fusion partner can provide an additional function to the encode polypeptide product, such as, but not limited to intracellular targeting, signaling, enzymatic function, stability, scaffolds, enhanced immunogenicity (in the case where the polypeptide encoded by the RNA payload is an antigen). The disclosure contemplates that the polypeptide products (e.g., vaccine antigens and/or therapeutic proteins) of the RNA payload disclosed herein may be fused to any useful fusion partner known in the art. F. Scaffold Moieties [00947] In various embodiments, the RNA payloads of the LNP delivery systems described herein encode fusion proteins which comprise antigens linked to scaffold moieties. In some embodiments, such scaffold moieties impart desired properties to an antigen encoded by a nucleic acid of the disclosure. For example scaffold proteins may improve the immunogenicity of an antigen, e.g., by altering the structure of the antigen, altering the uptake and processing of the antigen, and/or causing the antigen to bind to a binding partner. [00948] In some embodiments, the scaffold moiety is a protein that can self-assemble into protein nanoparticles that are highly symmetric, stable, and structurally organized, with diameters of 10-150 nm, a highly suitable size range for optimal interactions with various cells of the immune system. In one embodiment, viral proteins or virus-like particles can be used to form stable nanoparticle structures. Examples of such viral proteins are known in the art. For example, in some embodiments, the scaffold moiety is a hepatitis B surface antigen (HBsAg). HBsAg forms spherical particles with an average diameter of ˜22 nm and which lacked nucleic acid and hence are non- infectious (Lopez-Sagaseta, J. et al. Computational and Structural Biotechnology Journal 14 (2016) 58-68). In some embodiments, the scaffold moiety is a hepatitis B core antigen (HBcAg) self- assembles into particles of 24-31 nm diameter, which resembled the viral cores obtained from HBV- infected human liver. HBcAg produced in self-assembles into two classes of differently sized nanoparticles of 300 Å and 360 Å diameter, corresponding to 180 or 240 protomers. In some embodiments an antigen is fused to HBsAG or HBcAG to facilitate self-assembly of nanoparticles displaying the antigen. [00949] In another embodiment, bacterial protein platforms may be used. Non-limiting examples of these self-assembling proteins include ferritin, lumazine and encapsulin. [00950] Ferritin is a protein whose main function is intracellular iron storage. Ferritin is made of 24 subunits, each composed of a four-alpha-helix bundle, that self-assemble in a quaternary structure with octahedral symmetry (Cho K. J. et al. J Mol Biol.2009; 390:83-98). Several high- resolution structures of ferritin have been determined, confirming that Helicobacter pylori ferritin is made of 24 identical protomers, whereas in animals, there are ferritin light and heavy chains that can assemble alone or combine with different ratios into particles of 24 subunits (Granier T. et al. J Biol Inorg Chem.2003; 8:105-111; Lawson D. M. et al. Nature.1991; 349:541-544). Ferritin self- assembles into nanoparticles with robust thermal and chemical stability. Thus, the ferritin nanoparticle is well-suited to carry and expose antigens. [00951] Lumazine synthase (LS) is also well-suited as a nanoparticle platform for antigen display. LS, which is responsible for the penultimate catalytic step in the biosynthesis of riboflavin, is an enzyme present in a broad variety of organisms, including archaea, bacteria, fungi, plants, and eubacteria (Weber S. E. Flavins and Flavoproteins. Methods and Protocols, Series: Methods in Molecular Biology.2014). The LS monomer is 150 amino acids long, and consists of beta-sheets along with tandem alpha-helices flanking its sides. A number of different quaternary structures have been reported for LS, illustrating its morphological versatility: from homopentamers up to symmetrical assemblies of 12 pentamers forming capsids of 150 Å diameter. Even LS cages of more than 100 subunits have been described (Zhang X. et al. J Mol Biol.2006; 362:753-770). [00952] Encapsulin, a novel protein cage nanoparticle isolated from thermophile Thermotoga maritima, may also be used as a platform to present antigens on the surface of self-assembling nanoparticles. Encapsulin is assembled from 60 copies of identical 31 kDa monomers having a thin and icosahedral T=1 symmetric cage structure with interior and exterior diameters of 20 and 24 nm, respectively (Sutter M. et al. Nat Struct Mol Biol.2008, 15: 939-947). Although the exact function of encapsulin in T. maritima is not clearly understood yet, its crystal structure has been recently solved and its function was postulated as a cellular compartment that encapsulates proteins such as DyP (Dye decolorizing peroxidase) and Flp (Ferritin like protein), which are involved in oxidative stress responses (Rahmanpour R. et al. FEBS J.2013, 280: 2097-2104). G. Linkers and Cleavable Peptides [00953] In some embodiments, the mRNA payloads of the disclosure encode more than one polypeptide, referred to herein as fusion proteins. In some embodiments, the mRNA further encodes a linker located between at least one or each domain of the fusion protein. The linker can be, for example, a cleavable linker or protease-sensitive linker. In some embodiments, the linker is selected from the group consisting of F2A linker, P2A linker, T2A linker, E2A linker, and combinations thereof. This family of self-cleaving peptide linkers, referred to as 2A peptides, has been described in the art (see for example, Kim, J. H. et al. (2011) PLoS ONE 6:e18556). In some embodiments, the linker is an F2A linker. In some embodiments, the linker is a GGGS linker. In some embodiments, the fusion protein contains three domains with intervening linkers, having the structure: domain-linker- domain-linker-domain. [00954] Cleavable linkers known in the art may be used in connection with the disclosure. Exemplary such linkers include: F2A linkers, T2A linkers, P2A linkers, E2A linkers (See, e.g., WO2017127750). The skilled artisan will appreciate that other art-recognized linkers may be suitable for use in the constructs of the disclosure (e.g., encoded by the nucleic acids of the disclosure). The skilled artisan will likewise appreciate that other polycistronic constructs (mRNA encoding more than one antigen/polypeptide separately within the same molecule) may be suitable for use as provided herein. H. Functional domains [00955] In some embodiments, the polypeptides encoded by the RNA payloads described herein may further comprise additional sequences or functional domains. For example, the antigen polypeptides of the present disclosure may comprise one or more linker sequences. In some embodiments, the antigen polypeptide may comprise a polypeptide tag, such as an affinity tag (chitin binding protein (CBP), maltose binding protein (MBP), glutathione-S-transferase (GST), SBP-tag, Strep-tag, AviTag, Calmodulin-tag); solubilization tag; chromatography tag (polyanionic amino acid tag, such as FLAG-tag); epitope tag (short peptide sequences that bind to high-affinity antibodies, such as V5-tag, Myc-tag, VSV-tag, Xpress tag, E-tag, S-tag, and HA-tag); fluorescence tag (e.g., GFP). In some embodiments, the antigen may comprise an amino acid tag, such as one or more lysines, histidines, or glutamates, which can be added to the polypeptide sequences (e.g., at the N- terminal or C-terminal ends). Lysines can be used to increase peptide solubility or to allow for biotinylation. Protein and amino acid tags are peptide sequences genetically grafted onto a recombinant protein. Sequence tags are attached to proteins for various purposes, such as peptide purification, identification, or localization, for use in various applications including, for example, affinity purification, protein array, western blotting, immunofluorescence, and immunoprecipitation. Such tags are subsequently removable by chemical agents or by enzymatic means, such as by specific proteolysis or intein splicing. [00956] Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support. I. Codon optimization [00957] The LNP-based RNA vaccines and therapeutics described herein may comprise one or more RNA payloads (e.g., linear or circular mRNA) having nucleotide sequences which may be codon optimized. [00958] For example, a nucleotide sequence (e.g., as part of an RNA payload) encoding an antigen of the disclosure is codon optimized. Codon optimization methods are known in the art. For example, a protein encoding sequence of any one or more of the sequences provided herein may be codon optimized. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove/add post translation modification sites in encoded protein (e.g., glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translational rates to allow the various domains of the protein to fold properly; or reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art—non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park Calif.) and/or proprietary methods. In some embodiments, the protein encoding sequence is optimized using optimization algorithms. [00959] In some embodiments, a codon optimized sequence shares less than 95% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an antigen). In some embodiments, a codon optimized sequence shares less than 90% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally- occurring or wild-type mRNA sequence encoding an antigen). In some embodiments, a codon optimized sequence shares less than 85% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an antigen). In some embodiments, a codon optimized sequence shares less than 80% sequence identity to a naturally- occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an antigen). In some embodiments, a codon optimized sequence shares less than 75% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an antigen). [00960] In some embodiments, a codon optimized sequence shares between 65% and 85% (e.g., between about 67% and about 85% or between about 67% and about 80%) sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an Influenza antigen). In some embodiments, a codon optimized sequence shares between 65% and 75% or about 80% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an Influenza antigen). [00961] In some embodiments, a codon-optimized sequence encodes an antigen that is as immunogenic as, or more immunogenic than (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 200% more), than an antigen encoded by a non-codon- optimized) sequence. [00962] When transfected into mammalian cells, the modified mRNA payloads have a stability of between 12-18 hours, or greater than 18 hours, e.g., 24, 36, 48, 60, 72, or greater than 72 hours. [00963] In some embodiments, a codon optimized RNA may be one in which the levels of G/C are enhanced. The G/C-content of nucleic acid molecules (e.g., mRNA) may influence the stability of the RNA. RNA having an increased amount of guanine (G) and/or cytosine (C) residues may be functionally more stable than RNA containing a large amount of adenine (A) and thymine (T) or uracil (U) nucleotides. As an example, WO02/098443 discloses a pharmaceutical composition containing an mRNA stabilized by sequence modifications in the translated region. Due to the degeneracy of the genetic code, the modifications work by substituting existing codons for those that promote greater RNA stability without changing the resulting amino acid. The approach is limited to coding regions of the RNA. V. LNP pharmaceutical compositions [00964] The LNP-based RNA vaccines, RNA therapeutics and pharmaceutical compositions thereof described herein can be formulate using one or more excipients to: (1) increase stability; (2) increase cell transfection or transduction; (3) permit the sustained or delayed expression of the payload; (4) alter the biodistribution (e.g., target the viral particle to specific tissues or cell types); (5) increase the translation of encoded protein; (6) alter the release profile of encoded protein; and/or (7) allow for regulatable expression of an RNA payload expression product. [00965] Formulations can include, without limitation, saline, liposomes, lipid nanoparticles, polymers, peptides, proteins, cells transfected with viral vectors (e.g., for transfer or transplantation into a subject) and combinations thereof. [00966] Formulations of the LNP-based RNA vaccines, RNA therapeutics and pharmaceutical compositions thereof described herein may be prepared by any method known or hereafter developed in the art of pharmacology. As used herein the term "pharmaceutical composition" refers to compositions comprising at least one active ingredient and optionally one or more pharmaceutically acceptable excipients. [00967] In general, such preparatory methods include the step of associating the active ingredient (e.g., encapsulated LNP with an mRNA payload expressing a protein of interest) with an excipient and/or one or more other accessory ingredients. As used herein, the phrase "active ingredient" can refer to an LNP encapsulated with a payload mRNA, as well as to the mRNA payload construct itself, including originator constructs and benchmark construct as described herein. [00968] Formulations of the encapsulated LNPs, the payload mRNA constructs, and pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit. [00969] A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. [00970] In some embodiments, a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use for humans and for veterinary use. In some embodiments, an excipient may be approved by United States Food and Drug Administration. In some embodiments, an excipient may be of pharmaceutical grade. In some embodiments, an excipient may meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia. [00971] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 99% (w/w) of the active ingredient. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, or at least 80% (w/w) active ingredient. [00972] Excipients, as used herein, include, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition. [00973] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof. [00974] In some embodiments, formulations described herein may comprise at least one inactive ingredient. As used herein, the term "inactive ingredient" refers to one or more agents that do not contribute to the activity of the active ingredient of the pharmaceutical composition included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present disclosure may be approved by the US Food and Drug Administration (FDA). [00975] In one embodiment, the formulations described herein comprise at least one inactive ingredient such as, but not limited to, 1,2,6-Hexanetriol; 1,2-Dimyristoyl-Sn-Glycero-3-(Phospho-S- (1-Glycerol)); 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine; 1,2-Dioleoyl-Sn-Glycero-3- Phosphocholine; 1,2-Dipalmitoyl-Sn-Glycero-3-(Phospho-Rac-(1-Glycerol)); 1,2-Distearoyl-Sn- Glycero-3-(Phospho-Rac-(1-Glycerol)); 1,2-Distearoyl-Sn-Glycero-3-Phosphocholine; 1-O- Tolylbiguanide; 2-Ethyl-1,6-Hexanediol; Acetic Acid; Acetic Acid, Glacial; Acetic Anhydride; Acetone; Acetone Sodium Bisulfite; Acetylated Lanolin Alcohols; Acetylated Monoglycerides; Acetylcysteine; Acetyltryptophan, DL-; Acrylates Copolymer; Acrylic Acid-Isooctyl Acrylate Copolymer; Acrylic Adhesive 788; Activated Charcoal; Adcote 72A103; Adhesive Tape; Adipic Acid; Aerotex Resin 3730; Alanine; Albumin Aggregated; Albumin Colloidal; Albumin Human; Alcohol; Alcohol, Dehydrated; Alcohol, Denatured; Alcohol, Diluted; Alfadex; Alginic Acid; Alkyl Ammonium Sulfonic Acid Betaine; Alkyl Aryl Sodium Sulfonate; Allantoin; Allyl .Alpha.-Ionone; Almond Oil; Alpha-Terpineol; Alpha-Tocopherol; Alpha-Tocopherol Acetate, Dl-; Alpha- Tocopherol, Dl-; Aluminum Acetate; Aluminum Chlorhydroxy Allantoinate; Aluminum Hydroxide; Aluminum Hydroxide - Sucrose, Hydrated; Aluminum Hydroxide Gel; Aluminum Hydroxide Gel F 500; Aluminum Hydroxide Gel F 5000; Aluminum Monostearate; Aluminum Oxide; Aluminum Polyester; Aluminum Silicate; Aluminum Starch Octenylsuccinate; Aluminum Stearate; Aluminum Subacetate; Aluminum Sulfate Anhydrous; Amerchol C; Amerchol-Cab; Aminomethylpropanol; Ammonia; Ammonia Solution; Ammonia Solution, Strong; Ammonium Acetate; Ammonium Hydroxide; Ammonium Lauryl Sulfate; Ammonium Nonoxynol-4 Sulfate; Ammonium Salt Of C-12- C-15 Linear Primary Alcohol Ethoxylate; Ammonium Sulfate; Ammonyx; Amphoteric-2; Amphoteric-9; Anethole; Anhydrous Citric Acid; Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium Citrate; Aniseed Oil; Anoxid Sbn; Antifoam; Antipyrine; Apaflurane; Apricot Kernel Oil Peg-6 Esters; Aquaphor; Arginine; Arlacel; Ascorbic Acid; Ascorbyl Palmitate; Aspartic Acid; Balsam Peru; Barium Sulfate; Beeswax; Beeswax, Synthetic; Beheneth-10; Bentonite; Benzalkonium Chloride; Benzenesulfonic Acid; Benzethonium Chloride; Benzododecinium Bromide; Benzoic Acid; Benzyl Alcohol; Benzyl Benzoate; Benzyl Chloride; Betadex; Bibapcitide; Bismuth Subgallate; Boric Acid; Brocrinat; Butane; Butyl Alcohol; Butyl Ester Of Vinyl Methyl Ether/Maleic Anhydride Copolymer (125000 Mw); Butyl Stearate; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylene Glycol; Butylparaben; Butyric Acid; C20-40 Pareth-24; Caffeine; Calcium; Calcium Carbonate; Calcium Chloride; Calcium Gluceptate; Calcium Hydroxide; Calcium Lactate; Calcobutrol; Caldiamide Sodium; Caloxetate Trisodium; Calteridol Calcium; Canada Balsam; Caprylic/Capric Triglyceride; Caprylic/Capric/Stearic Triglyceride; Captan; Captisol; Caramel; Carbomer 1342; Carbomer 1382; Carbomer 934; Carbomer 934p; Carbomer 940; Carbomer 941; Carbomer 980; Carbomer 981; Carbomer Homopolymer Type B (Allyl Pentaerythritol Crosslinked); Carbomer Homopolymer Type C (Allyl Pentaerythritol Crosslinked); Carbon Dioxide; Carboxy Vinyl Copolymer; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Carboxypolymethylene; Carrageenan; Carrageenan Salt; Castor Oil; Cedar Leaf Oil; Cellulose; Cellulose, Microcrystalline; Cerasynt-Se; Ceresin; Ceteareth-12; Ceteareth-15; Ceteareth-30; Cetearyl Alcohol/Ceteareth-20; Cetearyl Ethylhexanoate; Ceteth-10; Ceteth-2; Ceteth-20; Ceteth-23; Cetostearyl Alcohol; Cetrimonium Chloride; Cetyl Alcohol; Cetyl Esters Wax; Cetyl Palmitate; Cetylpyridinium Chloride; Chlorobutanol; Chlorobutanol Hemihydrate; Chlorobutanol, Anhydrous; Chlorocresol; Chloroxylenol; Cholesterol; Choleth; Choleth-24; Citrate; Citric Acid; Citric Acid Monohydrate; Citric Acid, Hydrous; Cocamide Ether Sulfate; Cocamine Oxide; Coco Betaine; Coco Diethanolamide; Coco Monoethanolamide; Cocoa Butter; Coco-Glycerides; Coconut Oil; Coconut Oil, Hydrogenated; Coconut Oil/Palm Kernel Oil Glycerides, Hydrogenated; Cocoyl Caprylocaprate; Cola Nitida Seed Extract; Collagen; Coloring Suspension; Corn Oil; Cottonseed Oil; Cream Base; Creatine; Creatinine; Cresol; Croscarmellose Sodium; Crospovidone; Cupric Sulfate; Cupric Sulfate Anhydrous; Cyclomethicone; Cyclomethicone/Dimethicone Copolyol; Cysteine; Cysteine Hydrochloride; Cysteine Hydrochloride Anhydrous; Cysteine, Dl-; D&C Red No.28; D&C Red No. 33; D&C Red No.36; D&C Red No.39; D&C Yellow No.10; Dalfampridine; Daubert 1-5 Pestr (Matte) 164z; Decyl Methyl Sulfoxide; Dehydag Wax Sx; Dehydroacetic Acid; Dehymuls E; Denatonium Benzoate; Deoxycholic Acid; Dextran; Dextran 40; Dextrin; Dextrose; Dextrose Monohydrate; Dextrose Solution; Diatrizoic Acid; Diazolidinyl Urea; Dichlorobenzyl Alcohol; Dichlorodifluoromethane; Dichlorotetrafluoroethane; Diethanolamine; Diethyl Pyrocarbonate; Diethyl Sebacate; Diethylene Glycol Monoethyl Ether; Diethylhexyl Phthalate; Dihydroxyaluminum Aminoacetate; Diisopropanolamine; Diisopropyl Adipate; Diisopropyl Dilinoleate; Dimethicone 350; Dimethicone Copolyol; Dimethicone Mdx4-4210; Dimethicone Medical Fluid 360; Dimethyl Isosorbide; Dimethyl Sulfoxide; Dimethylaminoethyl Methacrylate - Butyl Methacrylate - Methyl Methacrylate Copolymer; Dimethyldioctadecylammonium Bentonite; Dimethylsiloxane/Methylvinylsiloxane Copolymer; Dinoseb Ammonium Salt; Dipalmitoylphosphatidylglycerol, Dl-; Dipropylene Glycol; Disodium Cocoamphodiacetate; Disodium Laureth Sulfosuccinate; Disodium Lauryl Sulfosuccinate; Disodium Sulfosalicylate; Disofenin; Divinylbenzene Styrene Copolymer; Dmdm Hydantoin; Docosanol; Docusate Sodium; Duro-Tak 280-2516; Duro-Tak 387-2516; Duro-Tak 80-1196; Duro-Tak 87-2070; Duro-Tak 87-2194; Duro-Tak 87-2287; Duro-Tak 87-2296; Duro-Tak 87-2888; Duro-Tak 87-2979; Edetate Calcium Disodium; Edetate Disodium; Edetate Disodium Anhydrous; Edetate Sodium; Edetic Acid; Egg Phospholipids; Entsufon; Entsufon Sodium; Epilactose; Epitetracycline Hydrochloride; Essence Bouquet 9200; Ethanolamine Hydrochloride; Ethyl Acetate; Ethyl Oleate; Ethylcelluloses; Ethylene Glycol; Ethylene Vinyl Acetate Copolymer; Ethylenediamine; Ethylenediamine Dihydrochloride; Ethylene-Propylene Copolymer; Ethylene-Vinyl Acetate Copolymer (28% Vinyl Acetate); Ethylene- Vinyl Acetate Copolymer (9% Vinylacetate); Ethylhexyl Hydroxystearate; Ethylparaben; Eucalyptol; Exametazime; Fat, Edible; Fat, Hard; Fatty Acid Esters; Fatty Acid Pentaerythriol Ester; Fatty Acids; Fatty Alcohol Citrate; Fatty Alcohols; Fd&C Blue No.1; Fd&C Green No.3; Fd&C Red No.4; Fd&C Red No.40; Fd&C Yellow No.10 (Delisted); Fd&C Yellow No.5; Fd&C Yellow No.6; Ferric Chloride; Ferric Oxide; Flavor 89-186; Flavor 89-259; Flavor Df-119; Flavor Df-1530; Flavor Enhancer; Flavor Fig 827118; Flavor Raspberry Pfc-8407; Flavor Rhodia Pharmaceutical No. Rf 451; Fluorochlorohydrocarbons; Formaldehyde; Formaldehyde Solution; Fractionated Coconut Oil; Fragrance 3949-5; Fragrance 520a; Fragrance 6.007; Fragrance 91-122; Fragrance 9128-Y; Fragrance 93498g; Fragrance Balsam Pine No.5124; Fragrance Bouquet 10328; Fragrance Chemoderm 6401-B; Fragrance Chemoderm 6411; Fragrance Cream No.73457; Fragrance Cs-28197; Fragrance Felton 066m; Fragrance Firmenich 47373; Fragrance Givaudan Ess 9090/1c; Fragrance H-6540; Fragrance Herbal 10396; Fragrance Nj-1085; Fragrance P O Fl-147; Fragrance Pa 52805; Fragrance Pera Derm D; Fragrance Rbd-9819; Fragrance Shaw Mudge U-7776; Fragrance Tf 044078; Fragrance Ungerer Honeysuckle K 2771; Fragrance Ungerer N5195; Fructose; Gadolinium Oxide; Galactose; Gamma Cyclodextrin; Gelatin; Gelatin, Crosslinked; Gelfoam Sponge; Gellan Gum (Low Acyl); Gelva 737; Gentisic Acid; Gentisic Acid Ethanolamide; Gluceptate Sodium; Gluceptate Sodium Dihydrate; Gluconolactone; Glucuronic Acid; Glutamic Acid, Dl-; Glutathione; Glycerin; Glycerol Ester Of Hydrogenated Rosin; Glyceryl Citrate; Glyceryl Isostearate; Glyceryl Laurate; Glyceryl Monostearate; Glyceryl Oleate; Glyceryl Oleate/Propylene Glycol; Glyceryl Palmitate; Glyceryl Ricinoleate; Glyceryl Stearate; Glyceryl Stearate - Laureth-23; Glyceryl Stearate/Peg Stearate; Glyceryl Stearate/Peg-100 Stearate; Glyceryl Stearate/Peg-40 Stearate; Glyceryl Stearate- Stearamidoethyl Diethylamine; Glyceryl Trioleate; Glycine; Glycine Hydrochloride; Glycol Distearate; Glycol Stearate; Guanidine Hydrochloride; Guar Gum; Hair Conditioner (18n195-1m); Heptane; Hetastarch; Hexylene Glycol; High Density Polyethylene; Histidine; Human Albumin Microspheres; Hyaluronate Sodium; Hydrocarbon; Hydrocarbon Gel, Plasticized; Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydrocortisone; Hydrogel Polymer; Hydrogen Peroxide; Hydrogenated Castor Oil; Hydrogenated Palm Oil; Hydrogenated Palm/Palm Kernel Oil Peg-6 Esters; Hydrogenated Polybutene 635-690; Hydroxide Ion; Hydroxyethyl Cellulose; Hydroxyethylpiperazine Ethane Sulfonic Acid; Hydroxymethyl Cellulose; Hydroxyoctacosanyl Hydroxystearate; Hydroxypropyl Cellulose; Hydroxypropyl Methylcellulose 2906; Hydroxypropyl-Beta-cyclodextrin; Hypromellose 2208 (15000 Mpa.S); Hypromellose 2910 (15000 Mpa.S); Hypromelloses; Imidurea; Iodine; Iodoxamic Acid; Iofetamine Hydrochloride; Irish Moss Extract; Isobutane; Isoceteth-20; Isoleucine; Isooctyl Acrylate; Isopropyl Alcohol; Isopropyl Isostearate; Isopropyl Myristate; Isopropyl Myristate - Myristyl Alcohol; Isopropyl Palmitate; Isopropyl Stearate; Isostearic Acid; Isostearyl Alcohol; Isotonic Sodium Chloride Solution; Jelene; Kaolin; Kathon Cg; Kathon Cg II; Lactate; Lactic Acid; Lactic Acid, Dl-; Lactic Acid, L-; Lactobionic Acid; Lactose; Lactose Monohydrate; Lactose, Hydrous; Laneth; Lanolin; Lanolin Alcohol - Mineral Oil; Lanolin Alcohols; Lanolin Anhydrous; Lanolin Cholesterols; Lanolin Nonionic Derivatives; Lanolin, Ethoxylated; Lanolin, Hydrogenated; Lauralkonium Chloride; Lauramine Oxide; Laurdimonium Hydrolyzed Animal Collagen; Laureth Sulfate; Laureth-2; Laureth-23; Laureth-4; Lauric Diethanolamide; Lauric Myristic Diethanolamide; Lauroyl Sarcosine; Lauryl Lactate; Lauryl Sulfate; Lavandula Angustifolia Flowering Top; Lecithin; Lecithin Unbleached; Lecithin, Egg; Lecithin, Hydrogenated; Lecithin, Hydrogenated Soy; Lecithin, Soybean; Lemon Oil; Leucine; Levulinic Acid; Lidofenin; Light Mineral Oil; Light Mineral Oil (85 Ssu); Limonene, (+/-)-; Lipocol Sc-15; Lysine; Lysine Acetate; Lysine Monohydrate; Magnesium Aluminum Silicate; Magnesium Aluminum Silicate Hydrate; Magnesium Chloride; Magnesium Nitrate; Magnesium Stearate; Maleic Acid; Mannitol; Maprofix; Mebrofenin; Medical Adhesive Modified S-15; Medical Antiform A-F Emulsion; Medronate Disodium; Medronic Acid; Meglumine; Menthol; Metacresol; Metaphosphoric Acid; Methanesulfonic Acid; Methionine; Methyl Alcohol; Methyl Gluceth-10; Methyl Gluceth-20; Methyl Gluceth-20 Sesquistearate; Methyl Glucose Sesquistearate; Methyl Laurate; Methyl Pyrrolidone; Methyl Salicylate; Methyl Stearate; Methylboronic Acid; Methylcellulose (4000 Mpa.S); Methylcelluloses; Methylchloroisothiazolinone; Methylene Blue; Methylisothiazolinone; Methylparaben; Microcrystalline Wax; Mineral Oil; Mono and Diglyceride; Monostearyl Citrate; Monothioglycerol; Multisterol Extract; Myristyl Alcohol; Myristyl Lactate; Myristyl-.Gamma.-Picolinium Chloride; N-(Carbamoyl-Methoxy Peg-40)-1,2- Distearoyl-Cephalin Sodium; N,N-Dimethylacetamide; Niacinamide; Nioxime; Nitric Acid; Nitrogen; Nonoxynol Iodine; Nonoxynol-15; Nonoxynol-9; Norflurane; Oatmeal; Octadecene-1/Maleic Acid Copolymer; Octanoic Acid; Octisalate; Octoxynol-1; Octoxynol-40; Octoxynol-9; Octyldodecanol; Octylphenol Polymethylene; Oleic Acid; Oleth-10/Oleth-5; Oleth-2; Oleth-20; Oleyl Alcohol; Oleyl Oleate; Olive Oil; Oxidronate Disodium; Oxyquinoline; Palm Kernel Oil; Palmitamine Oxide; Parabens; Paraffin; Paraffin, White Soft; Parfum Creme 45/3; Peanut Oil; Peanut Oil, Refined; Pectin; Peg 6-32 Stearate/Glycol Stearate; Peg Vegetable Oil; Peg-100 Stearate; Peg-12 Glyceryl Laurate; Peg-120 Glyceryl Stearate; Peg-120 Methyl Glucose Dioleate; Peg-15 Cocamine; Peg-150 Distearate; Peg-2 Stearate; Peg-20 Sorbitan Isostearate; Peg-22 Methyl Ether/Dodecyl Glycol Copolymer; Peg-25 Propylene Glycol Stearate; Peg-4 Dilaurate; Peg-4 Laurate; Peg-40 Castor Oil; Peg-40 Sorbitan Diisostearate; Peg-45/Dodecyl Glycol Copolymer; Peg-5 Oleate; Peg-50 Stearate; Peg-54 Hydrogenated Castor Oil; Peg-6 Isostearate; Peg-60 Castor Oil; Peg-60 Hydrogenated Castor Oil; Peg-7 Methyl Ether; Peg-75 Lanolin; Peg-8 Laurate; Peg-8 Stearate; Pegoxol 7 Stearate; Pentadecalactone; Pentaerythritol Cocoate; Pentasodium Pentetate; Pentetate Calcium Trisodium; Pentetic Acid; Peppermint Oil; Perflutren; Perfume 25677; Perfume Bouquet; Perfume E-1991; Perfume Gd 5604; Perfume Tana 90/42 Scba; Perfume W-1952-1; Petrolatum; Petrolatum, White; Petroleum Distillates; Phenol; Phenol, Liquefied; Phenonip; Phenoxyethanol; Phenylalanine; Phenylethyl Alcohol; Phenylmercuric Acetate; Phenylmercuric Nitrate; Phosphatidyl Glycerol, Egg; Phospholipid; Phospholipid, Egg; Phospholipon 90g; Phosphoric Acid; Pine Needle Oil (Pinus Sylvestris); Piperazine Hexahydrate; Plastibase-50w; Polacrilin; Polidronium Chloride; Poloxamer 124; Poloxamer 181; Poloxamer 182; Poloxamer 188; Poloxamer 237; Poloxamer 407; Poly(Bis(P- Carboxyphenoxy)Propane Anhydride):Sebacic Acid; Poly(Dimethylsiloxane/Methylvinylsiloxane/Methylhydrogensiloxane) Dimethylvinyl Or Dimethylhydroxy Or Trimethyl Endblocked; Poly(Dl-Lactic-Co-Glycolic Acid), (50:50; Poly(Dl- Lactic-Co-Glycolic Acid), Ethyl Ester Terminated, (50:50; Polyacrylic Acid (250000 Mw); Polybutene (1400 Mw); Polycarbophil; Polyester; Polyester Polyamine Copolymer; Polyester Rayon; Polyethylene Glycol 1000; Polyethylene Glycol 1450; Polyethylene Glycol 1500; Polyethylene Glycol 1540; Polyethylene Glycol 200; Polyethylene Glycol 300; Polyethylene Glycol 300-1600; Polyethylene Glycol 3350; Polyethylene Glycol 400; Polyethylene Glycol 4000; Polyethylene Glycol 540; Polyethylene Glycol 600; Polyethylene Glycol 6000; Polyethylene Glycol 8000; Polyethylene Glycol 900; Polyethylene High Density Containing Ferric Oxide Black (<1%); Polyethylene Low Density Containing Barium Sulfate (20-24%); Polyethylene T; Polyethylene Terephthalates; Polyglactin; Polyglyceryl-3 Oleate; Polyglyceryl-4 Oleate; Polyhydroxyethyl Methacrylate; Polyisobutylene; Polyisobutylene (1100000 Mw); Polyisobutylene (35000 Mw); Polyisobutylene 178- 236; Polyisobutylene 241-294; Polyisobutylene 35-39; Polyisobutylene Low Molecular Weight; Polyisobutylene Medium Molecular Weight; Polyisobutylene/Polybutene Adhesive; Polylactide; Polyols; Polyoxyethylene - Polyoxypropylene 1800; Polyoxyethylene Alcohols; Polyoxyethylene Fatty Acid Esters; Polyoxyethylene Propylene; Polyoxyl 20 Cetostearyl Ether; Polyoxyl 35 Castor Oil; Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Polyoxyl 400 Stearate; Polyoxyl 6 And Polyoxyl 32 Palmitostearate; Polyoxyl Distearate; Polyoxyl Glyceryl Stearate; Polyoxyl Lanolin; Polyoxyl Palmitate; Polyoxyl Stearate; Polypropylene; Polypropylene Glycol; Polyquaternium-10; Polyquaternium-7 (70/30 Acrylamide/Dadmac; Polysiloxane; Polysorbate 20; Polysorbate 40; Polysorbate 60; Polysorbate 65; Polysorbate 80; Polyurethane; Polyvinyl Acetate; Polyvinyl Alcohol; Polyvinyl Chloride; Polyvinyl Chloride-Polyvinyl Acetate Copolymer; Polyvinylpyridine; Poppy Seed Oil; Potash; Potassium Acetate; Potassium Alum; Potassium Bicarbonate; Potassium Bisulfite; Potassium Chloride; Potassium Citrate; Potassium Hydroxide; Potassium Metabisulfite; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic; Potassium Soap; Potassium Sorbate; Povidone Acrylate Copolymer; Povidone Hydrogel; Povidone K17; Povidone K25; Povidone K29/32; Povidone K30; Povidone K90; Povidone K90f; Povidone/Eicosene Copolymer; Povidones; Ppg-12/Smdi Copolymer; Ppg-15 Stearyl Ether; Ppg-20 Methyl Glucose Ether Distearate; Ppg-26 Oleate; Product Wat; Proline; Promulgen D; Promulgen G; Propane; Propellant A-46; Propyl Gallate; Propylene Carbonate; Propylene Glycol; Propylene Glycol Diacetate; Propylene Glycol Dicaprylate; Propylene Glycol Monolaurate; Propylene Glycol Monopalmitostearate; Propylene Glycol Palmitostearate; Propylene Glycol Ricinoleate; Propylene Glycol/Diazolidinyl Urea/Methylparaben/Propylparben; Propylparaben; Protamine Sulfate; Protein Hydrolysate; Pvm/Ma Copolymer; Quaternium-15; Quaternium-15 Cis-Form; Quaternium-52; Ra-2397; Ra-3011; Saccharin; Saccharin Sodium; Saccharin Sodium Anhydrous; Safflower Oil; Sd Alcohol 3a; Sd Alcohol 40; Sd Alcohol 40-2; Sd Alcohol 40b; Sepineo P 600; Serine; Sesame Oil; Shea Butter; Silastic Brand Medical Grade Tubing; Silastic Medical Adhesive,Silicone Type A; Silica, Dental; Silicon; Silicon Dioxide; Silicon Dioxide, Colloidal; Silicone; Silicone Adhesive 4102; Silicone Adhesive 4502; Silicone Adhesive Bio-Psa Q7- 4201; Silicone Adhesive Bio-Psa Q7-4301; Silicone Emulsion; Silicone/Polyester Film Strip; Simethicone; Simethicone Emulsion; Sipon Ls 20np; Soda Ash; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Alkyl Sulfate; Sodium Ascorbate; Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfate; Sodium Bisulfite; Sodium Borate; Sodium Borate Decahydrate; Sodium Carbonate; Sodium Carbonate Decahydrate; Sodium Carbonate Monohydrate; Sodium Cetostearyl Sulfate; Sodium Chlorate; Sodium Chloride; Sodium Chloride Injection; Sodium Chloride Injection, Bacteriostatic; Sodium Cholesteryl Sulfate; Sodium Citrate; Sodium Cocoyl Sarcosinate; Sodium Desoxycholate; Sodium Dithionite; Sodium Dodecylbenzenesulfonate; Sodium Formaldehyde Sulfoxylate; Sodium Gluconate; Sodium Hydroxide; Sodium Hypochlorite; Sodium Iodide; Sodium Lactate; Sodium Lactate, L-; Sodium Laureth-2 Sulfate; Sodium Laureth-3 Sulfate; Sodium Laureth-5 Sulfate; Sodium Lauroyl Sarcosinate; Sodium Lauryl Sulfate; Sodium Lauryl Sulfoacetate; Sodium Metabisulfite; Sodium Nitrate; Sodium Phosphate; Sodium Phosphate Dihydrate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Dodecahydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate; Sodium Polyacrylate (2500000 Mw); Sodium Pyrophosphate; Sodium Pyrrolidone Carboxylate; Sodium Starch Glycolate; Sodium Succinate Hexahydrate; Sodium Sulfate; Sodium Sulfate Anhydrous; Sodium Sulfate Decahydrate; Sodium Sulfite; Sodium Sulfosuccinated Undecyclenic Monoalkylolamide; Sodium Tartrate; Sodium Thioglycolate; Sodium Thiomalate; Sodium Thiosulfate; Sodium Thiosulfate Anhydrous; Sodium Trimetaphosphate; Sodium Xylenesulfonate; Somay 44; Sorbic Acid; Sorbitan; Sorbitan Isostearate; Sorbitan Monolaurate; Sorbitan Monooleate; Sorbitan Monopalmitate; Sorbitan Monostearate; Sorbitan Sesquioleate; Sorbitan Trioleate; Sorbitan Tristearate; Sorbitol; Sorbitol Solution; Soybean Flour; Soybean Oil; Spearmint Oil; Spermaceti; Squalane; Stabilized Oxychloro Complex; Stannous 2-Ethylhexanoate; Stannous Chloride; Stannous Chloride Anhydrous; Stannous Fluoride; Stannous Tartrate; Starch; Starch 1500, Pregelatinized; Starch, Corn; Stearalkonium Chloride; Stearalkonium Hectorite/Propylene Carbonate; Stearamidoethyl Diethylamine; Steareth-10; Steareth-100; Steareth-2; Steareth-20; Steareth-21; Steareth-40; Stearic Acid; Stearic Diethanolamide; Stearoxytrimethylsilane; Steartrimonium Hydrolyzed Animal Collagen; Stearyl Alcohol; Sterile Water For Inhalation; Styrene/Isoprene/Styrene Block Copolymer; Succimer; Succinic Acid; Sucralose; Sucrose; Sucrose Distearate; Sucrose Polyesters; Sulfacetamide Sodium; Sulfobutylether .Beta.-Cyclodextrin; Sulfur Dioxide; Sulfuric Acid; Sulfurous Acid; Surfactol Qs; Tagatose, D-; Talc; Tall Oil; Tallow Glycerides; Tartaric Acid; Tartaric Acid, Dl-; Tenox; Tenox-2; Tert-Butyl Alcohol; Tert-Butyl Hydroperoxide; Tert-Butylhydroquinone; Tetrakis(2-Methoxyisobutylisocyanide)Copper(I) Tetrafluoroborate; Tetrapropyl Orthosilicate; Tetrofosmin; Theophylline; Thimerosal; Threonine; Thymol; Tin; Titanium Dioxide; Tocopherol; Tocophersolan; Total parenteral nutrition, lipid emulsion; Triacetin; Tricaprylin; Trichloromonofluoromethane; Trideceth-10; Triethanolamine Lauryl Sulfate; Trifluoroacetic Acid; Triglycerides, Medium Chain; Trihydroxystearin; Trilaneth-4 Phosphate; Trilaureth-4 Phosphate; Trisodium Citrate Dihydrate; Trisodium Hedta; Triton 720; Triton X-200; Trolamine; Tromantadine; Tromethamine (TRIS); Tryptophan; Tyloxapol; Tyrosine; Undecylenic Acid; Union 76 Amsco-Res 6038; Urea; Valine; Vegetable Oil; Vegetable Oil Glyceride, Hydrogenated; Vegetable Oil, Hydrogenated; Versetamide; Viscarin; Viscose/Cotton; Vitamin E; Wax, Emulsifying; Wecobee Fs; White Ceresin Wax; White Wax; Xanthan Gum; Zinc; Zinc Acetate; Zinc Carbonate; Zinc Chloride; and Zinc Oxide. [00976] In some embodiments, formulations disclosed herein may include cations or anions. The formulations include metal cations such as, but not limited to, Zn²⁺, Ca²⁺, Cu²⁺, Mn²⁺, Mg²⁺, and combinations thereof. As a non-limiting example, formulations may include polymers and complexes with a metal cation. [00977] Formulations of the disclosure may also include one or more pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non- toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. [00978] Solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAC), 1,3- dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a "hydrate." [00979] Solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that comprises organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a "hydrate." [00980] In some embodiments, the payloads are encapsulated in nanoparticles (e.g., LNPs) for delivery. In embodiments, a nanoparticle can include an ionizable lipid, a phospholipid, a PEG lipid, and a structural lipid. [00981] In some embodiments, provided herein are pharmaceutical compositions comprising: a) at least one lipid nanoparticle comprising at least one Lipid of the Disclosure; and b) at least one nucleobase editing system. In some embodiments, the nucleobase editing system comprises a CRISPR-Cas gene editing system. In some embodiments, the nucleobase editing system comprises a prime editing system or components thereof. In some embodiments, the nucleobase editing system comprises a retron editing system, a TnpB editing system, an integrase editing system, an epigenetic editing system, a gene writing system, a gene inactivating system, a zinc finger nuclease, a TALE Nuclease, a TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, meganuclease, or a combination thereof. [00982] In some embodiments, provided herein are pharmaceutical compositions comprising: a) at least one lipid nanoparticle comprising at least one Lipid of the Disclosure; and b) at least one nucleic acid encoding a therapeutic protein. In some embodiments, at least one nucleic acid encoding a therapeutic protein is an mRNA or a circular RNA (oRNA). In some embodiments, the therapeutic protein is a CAR or TCR complex protein. In some embodiments, the CAR or TCR complex protein comprises an antigen binding domain specific for an antigen selected from the group: CD 19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule- 1, CD33, epidermal growth factor receptor variant III (EGFRvIII), disialoganglioside GD2, disaloganglioside GD3, TNF receptor family member, B cell maturation antigen (BCMA), Tn antigen ((Tn Ag) or (GalNAca-Ser/Thr)), prostate- specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms- Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD 117), Interleukin- 13 receptor subunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL-l lRa), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, HER2, HER3, Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gplOO), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type- A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (0AcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1/CD248), tumor endothelial marker 7 -related (TEM7R), claudin 6 (CLDN6), claudin 18.2 (CLDN18.2), thyroid stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, and CD179a. VI. Routes of Administration [00983] The LNP-based RNA vaccines, RNA therapeutics and pharmaceutical compositions thereof described herein may be administered by any delivery route which results in a therapeutically effective outcome. These include, but are not limited to, enteral (into the intestine), gastroenteral, epidural (into the dura mater), oral (by way of the mouth), transdermal, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intravenous bolus, intravenous drip, intra-arterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraparenchymal (into brain tissue), intraperitoneal (infusion or injection into the peritoneum), intravesical infusion, intravitreal (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracoronal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intramyocardial (within the myocardium), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique (topical route administration which is then covered by a dressing which occludes the area), ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), soft tissue, subarachnoid, subconjunctival, submucosal, topical, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis, and spinal. [00984] In some embodiments, compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier. The originator constructs, benchmark constructs, and targeting systems may be administered in any suitable form, either as a liquid solution or suspension, as a solid form suitable for liquid solution or suspension in a liquid solution. The originator constructs, benchmark constructs, and targeting systems may be formulated with any appropriate and pharmaceutically acceptable excipient. [00985] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered to a subject via a single route administration. [00986] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered to a subject via a multi-site route of administration. A subject may be administered at 2, 3, 4, 5, or more than 5 sites. [00987] In some embodiments, a subject may be administered the originator constructs, benchmark constructs, and targeting systems using a bolus infusion. [00988] In some embodiments, a subject may be administered originator constructs, benchmark constructs, and targeting systems using sustained delivery over a period of minutes, hours, or days. The infusion rate may be changed depending on the subject, distribution, formulation or another delivery parameter. [00989] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by intramuscular delivery route. Non-limiting examples of intramuscular administration include an intravenous injection or a subcutaneous injection. [00990] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by oral administration. Non-limiting examples of oral delivery include a digestive tract administration and a buccal administration. [00991] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by intraocular delivery route. A non-limiting example of intraocular delivery include an intravitreal injection. [00992] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by intranasal delivery route. Non-limiting examples of intranasal delivery include nasal drops or nasal sprays. [00993] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by peripheral injections. Non-limiting examples of peripheral injections include intraperitoneal, intramuscular, intravenous, conjunctival, or joint injection. [00994] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by injection into the cerebrospinal fluid. Non-limiting examples of delivery to the cerebrospinal fluid include intrathecal and intracerebroventricular administration. [00995] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by systemic delivery. As a non-limiting example, the systemic delivery may be by intravascular administration. [00996] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intracranial delivery. [00997] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intraparenchymal administration. [00998] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intramuscular administration. [00999] In some embodiments, the originator constructs, benchmark constructs, and targeting systems are administered to a subject and transduce muscle of a subject. As a non-limiting example, the originator constructs, benchmark constructs, and targeting systems are administered by intramuscular administration. [001000] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intravenous administration. [001001] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by subcutaneous administration. [001002] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by topical administration. [001003] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by more than one route of administration. [001004] The originator constructs, benchmark constructs, and targeting systems described herein may be co-administered in conjunction with one or more originator constructs, benchmark constructs, targeting systems, or therapeutic agents or moieties. [001005] In some embodiments, pharmaceutical compositions and/or formulations described herein may be administered parenterally. Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such as CREMOPHOR^®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof. In other embodiments, surfactants are included such as hydroxypropylcellulose. [001006] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables. [001007] Injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [001008] In order to prolong the effect of active ingredients, it is often desirable to slow the absorption of active ingredients from subcutaneous or intramuscular injections. This may be accomplished by the use of liquid suspensions of crystalline or amorphous material with poor water solubility. The rate of absorption of active ingredients depends upon the rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. [001009] In some embodiments, pharmaceutical compositions and/or formulations described herein may be formulated for administration topically. The skin may be an ideal target site for delivery as it is readily accessible. Three routes are commonly considered to deliver pharmaceutical compositions and/or formulations described herein to the skin: (i) topical application (e.g. for local/regional treatment and/or cosmetic applications); (ii) intradermal injection (e.g. for local/regional treatment and/or cosmetic applications); and (iii) systemic delivery (e.g. for treatment of dermatologic diseases that affect both cutaneous and extracutaneous regions). [001010] In some embodiments, pharmaceutical compositions and/or formulations described herein may be delivered using a variety of dressings (e.g., wound dressings) or bandages (e.g., adhesive bandages) for conveniently and/or effectively carrying out methods described herein. Typically dressing or bandages may comprise sufficient amounts of pharmaceutical compositions and/or formulations described herein to allow users to perform multiple treatments. [001011] Dosage forms for topical and/or transdermal administration may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, active ingredients are admixed under sterile conditions with pharmaceutically acceptable excipients and/or any needed preservatives and/or buffers. Additionally, contemplated herein is the use of transdermal patches, which often have the added advantage of providing controlled delivery of pharmaceutical compositions and/or formulations described herein to the body. Such dosage forms may be prepared, for example, by dissolving and/or dispensing pharmaceutical compositions and/or formulations described herein in the proper medium. Alternatively, or additionally, rates may be controlled by either providing rate controlling membranes and/or by dispersing pharmaceutical compositions and/or formulations described herein in a polymer matrix and/or gel. [001012] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions. [001013] Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [001014] In some embodiments, pharmaceutical compositions and/or formulations described herein may be prepared, packaged, and/or sold in formulations suitable for ophthalmic and/or otic administration. Such formulations may, for example, be in the form of eye and/or ear drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in aqueous and/or oily liquid excipients. Such drops may further comprise buffering agents, salts, and/or one or more other of any additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise active ingredients in microcrystalline form and/or in liposomal preparations. Subretinal inserts may also be used as forms of administration. [001015] In some embodiments, pharmaceutical compositions and/or formulations described herein may be administered orally. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, an active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient such as sodium citrate or dicalcium phosphate and/or fillers or extenders (e.g. starches, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), humectants (e.g. glycerol), disintegrating agents (e.g. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g. paraffin), absorption accelerators (e.g. quaternary ammonium compounds), wetting agents (e.g. cetyl alcohol and glycerol monostearate), absorbents (e.g. kaolin and bentonite clay), and lubricants (e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents. [001016] In some embodiments, pharmaceutical compositions and/or formulations described herein are formulated in depots for extended release. [001017] In some embodiments, pharmaceutical compositions and/or formulations described herein are spatially retained within or proximal to target tissues. Provided are methods of providing pharmaceutical compositions and/or formulations described herein to target tissues of mammalian subjects by contacting target tissues (which comprise one or more target cells) with pharmaceutical compositions and/or formulations described herein under conditions such that they are substantially retained in target tissues, meaning that at least 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the composition is retained in the target tissues. Advantageously, retention is determined by measuring the amount of pharmaceutical compositions and/or formulations described herein that enter one or more target cells. For example, at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or greater than 99.99% of pharmaceutical compositions and/or formulations described herein administered to subjects are present intracellularly at a period of time following administration. For example, intramuscular injection to mammalian subjects may be performed using aqueous compositions comprising an active ingredient and one or more transfection reagents, and retention is determined by measuring the amount of active ingredient present in muscle cells. [001018] In some embodiments, provided are methods for delivering pharmaceutical compositions and/or formulations described herein to target tissues of mammalian subjects, by contacting target tissues (comprising one or more target cells) with pharmaceutical compositions and/or formulations described herein under conditions such that they are substantially retained in such target tissues. Pharmaceutical compositions and/or formulations described herein comprise enough active ingredient such that the effect of interest is produced in at least one target cell. In some embodiments, pharmaceutical compositions and/or formulations described herein generally comprise one or more cell penetration agents, although "naked" formulations (such as without cell penetration agents or other agents) are also contemplated, with or without pharmaceutically acceptable carriers. [001019] In some embodiments, pharmaceutical compositions and/or formulations described herein may be prepared, packaged, and/or sold in formulations suitable for pulmonary administration. In some embodiments, such administration is via the buccal cavity. In some embodiments, formulations may comprise dry particles comprising active ingredients. In such embodiments, dry particles may have a diameter in the range from about 0.5 nm to about 7 nm or from about 1 nm to about 6 nm. In some embodiments, formulations may be in the form of dry powders for administration using devices comprising dry powder reservoirs to which streams of propellant may be directed to disperse such powder. In some embodiments, self-propelling solvent/powder dispensing containers may be used. In such embodiments, active ingredients may be dissolved and/or suspended in low-boiling propellant in sealed containers. Such powders may comprise particles wherein at least 98% of the particles by weight have diameters greater than 0.5 nm and at least 95% of the particles by number have diameters less than 7 nm. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nm and at least 90% of the particles by number have a diameter less than 6 nm. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. [001020] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, propellants may constitute 50% to 99.9% (w/w) of the composition, and active ingredient may constitute 0.1% to 20% (w/w) of the composition. Propellants may further comprise additional ingredients such as liquid non-ionic and/or solid anionic surfactant and/or solid diluent (which may have particle sizes of the same order as particles comprising active ingredients). [001021] Pharmaceutical compositions formulated for pulmonary delivery may provide active ingredients in the form of droplets of solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredients, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. Droplets provided by this route of administration may have an average diameter in the range from about 0.1 nm to about 200 nm. [001022] In some embodiments, pharmaceutical compositions and/or formulations described herein may be administered nasally and/or intranasal. In some embodiments, formulations described herein useful for pulmonary delivery may also be useful for intranasal delivery. In some embodiments, formulations for intranasal administration comprise a coarse powder comprising the active ingredient and having an average particle from about 0.2 mm to 500 mm. Such formulations are administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose. [001023] Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise powders and/or an aerosolized and/or atomized solutions and/or suspensions comprising active ingredients. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may comprise average particle and/or droplet sizes in the range of from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein. [001024] In some embodiments, pharmaceutical compositions and/or formulations described herein may be administered rectally and/or vaginally. Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. VII. Methods of use (including vaccination and treatment) [001025] The LNP-based RNA vaccines and therapeutics and compositions described herein may be used to deliver a protein of interest (e.g., an antigen or therapeutic protein) to a cell, tissue, or organ. In addition, the LNP-based RNA vaccines and therapeutics and compositions described herein may be used to deliver an immunogenic protein of interest to a subject in need as a means for vaccination against an infectious disease (e.g., virus or bacteria) or cancer. Still further, the LNP- based RNA vaccines and therapeutics and compositions described herein may be used to deliver a therapeutic protein of interest to a subject in need as a means for treating a patient for a disease, such as a disease of the CNS or muscle, or for treating cancer. A. Methods of producing polypeptides in cells [001026] The present disclosure provides methods of producing a polypeptide of interest in a mammalian cell. Methods of producing polypeptides involve contacting a cell with an LNP-based RNA vaccine or therapeutic and/or a formulation or composition thereof as described herein. Upon contacting the cell with the lipid nanoparticle, the mRNA may be taken up and translated in the cell to produce the polypeptide of interest, e.g., an antigen or therapeutic protein. [001027] In general, the step of contacting a mammalian cell with a LNP including an mRNA encoding a polypeptide of interest may be performed in vivo, ex vivo, in culture, or in vitro. The amount of lipid nanoparticle contacted with a cell, and/or the amount of mRNA therein, may depend on the type of cell or tissue being contacted, the means of administration, the physiochemical characteristics of the lipid nanoparticle and the mRNA (e.g., size, charge, and chemical composition) therein, and other factors. In general, an effective amount of the lipid nanoparticle will allow for efficient polypeptide production in the cell. Metrics for efficiency may include polypeptide translation (indicated by polypeptide expression), level of mRNA degradation, and immune response indicators. [001028] The step of contacting an LNP including an mRNA with a cell may involve or cause transfection. A phospholipid including in the lipid component of a LNP may facilitate transfection and/or increase transfection efficiency, for example, by interacting and/or fusing with a cellular or intracellular membrane. Transfection may allow for the translation of the mRNA within the cell. [001029] In some embodiments, the lipid nanoparticles described herein is used therapeutically. For example, an mRNA included in an LNP may encode a therapeutic polypeptide (e.g., in a translatable region) and produce the therapeutic polypeptide upon contacting and/or entry (e.g., transfection) into a cell. In other embodiments, an mRNA included in a LNP may encode a polypeptide that may improve or increase the immunity of a subject. In some embodiments, an mRNA may encode a granulocyte-colony stimulating factor or trastuzumab. [001030] In some embodiments, an mRNA included in an LNP may encode a recombinant polypeptide that may replace one or more polypeptides that is substantially absent in a cell contacted with the lipid nanoparticle. The one or more substantially absent polypeptides may be lacking due to a genetic mutation of the encoding gene or a regulatory pathway thereof. Alternatively, a recombinant polypeptide produced by translation of the mRNA may antagonize the activity of an endogenous protein present in, on the surface of, or secreted from the cell. An antagonistic recombinant polypeptide may be desirable to combat deleterious effects caused by activities of the endogenous protein, such as altered activities or localization caused by mutation. In another alternative, a recombinant polypeptide produced by translation of the mRNA may indirectly or directly antagonize the activity of a biological moiety present in, on the surface of, or secreted from the cell. Antagonized biological moieties may include, but are not limited to, lipids (e.g., cholesterol), lipoproteins (e.g., low density lipoprotein), nucleic acids, carbohydrates, and small molecule toxins. Recombinant polypeptides produced by translation of the mRNA may be engineered for localization within the cell, such as within a specific compartment such as the nucleus, or may be engineered for secretion from the cell or for translocation to the plasma membrane of the cell. [001031] In some embodiments, contacting a cell with an LNP including an mRNA may reduce the innate immune response of a cell to an exogenous nucleic acid. A cell may be contacted with a first lipid nanoparticle including a first amount of a first exogenous mRNA including a translatable region and the level of the innate immune response of the cell to the first exogenous mRNA may be determined. Subsequently, the cell may be contacted with a second composition including a second amount of the first exogenous mRNA, the second amount being a lesser amount of the first exogenous mRNA compared to the first amount. Alternatively, the second composition may include a first amount of a second exogenous mRNA that is different from the first exogenous mRNA. The steps of contacting the cell with the first and second compositions may be repeated one or more times. Additionally, efficiency of polypeptide production (e.g., translation) in the cell may be optionally determined, and the cell may be re-contacted with the first and/or second composition repeatedly until a target protein production efficiency is achieved. B. Therapeutic methods using LNPs described herein [001032] Provided herein are therapeutic methods for treating a disease or disorder by using the LNP-based RNA compositions described herein to deliver one or more therapeutic agents encoded on a payload RNA (e.g., linear or circular mRNA payload) to a cell, organ, or tissue. Delivery may be in vitro or ex vivo to cells, or to a cell, tissue, or organ in vivo. [001033] Delivery of a therapeutic and/or prophylactic to a cell involves administering a composition of the disclosure that comprises a LNP encapsulated with a payload RNA (e.g., a linear or circular RNA) that encodes a therapeutic and/or prophylactic, where administration of the composition involves contacting the cell with the composition. In some embodiments, a protein, cytotoxic agent, radioactive ion, chemotherapeutic agent, or nucleic acid (such as an RNA, e.g., mRNA) is delivered to a cell or organ. In some embodiments, the mRNA payload itself may be regarded as the therapeutic and/or prophylactic as it encodes a therapeutic and/or prophylactic. Upon contacting a cell with the lipid nanoparticle, a translatable mRNA may be translated in the cell to produce a polypeptide of interest. However, mRNAs that are substantially not translatable may also be delivered to cells. Substantially non-translatable mRNAs may be useful as vaccines and/or may sequester translational components of a cell to reduce expression of other species in the cell. [001034] In some embodiments, an LNP may target a particular type or class of cells (e.g., cells of a particular organ or system thereof). In some embodiments, a LNP including an RNA payload coding for a therapeutic and/or prophylactic of interest is specifically delivered to a mammalian liver, kidney, spleen, femur, or lung. “Specific delivery” to a particular class of cells, an organ, or a system or group thereof implies that a higher proportion of lipid nanoparticles including a therapeutic and/or prophylactic are delivered to the destination (e.g., tissue) of interest relative to other destinations, e.g., upon administration of an LNP to a mammal. In some embodiments, specific delivery may result in a greater than 2-fold, 5-fold, 10-fold, 15-fold, or 20-fold increase in the amount of therapeutic and/or prophylactic per 1 g of tissue of the targeted destination (e.g., tissue of interest, such as a liver) as compared to another destination (e.g., the spleen). In some embodiments, the tissue of interest is selected from the group consisting of a liver, kidney, a lung, a spleen, a femur, vascular endothelium in vessels (e.g., intra-coronary or intra-femoral) or kidney, and tumor tissue (e.g., via intratumoral injection). [001035] As another example of targeted or specific delivery, an mRNA that encodes a protein- binding partner (e.g., an antibody or functional fragment thereof, a scaffold protein, or a peptide) or a receptor on a cell surface may be included in an LNP. An mRNA may additionally or instead be used to direct the synthesis and extracellular localization of lipids, carbohydrates, or other biological moieties. Alternatively, other therapeutics and/or prophylactics or elements (e.g., lipids or ligands) of an LNP may be selected based on their affinity for particular receptors (e.g., low density lipoprotein receptors) such that a LNP may more readily interact with a target cell population including the receptors. In some embodiments, ligands may include, but are not limited to, members of a specific binding pair, antibodies, monoclonal antibodies, Fv fragments, single chain Fv (scFv) fragments, Fab' fragments, F(ab')2 fragments, single domain antibodies, camelized antibodies and fragments thereof, humanized antibodies and fragments thereof, and multivalent versions thereof; multivalent binding reagents including mono- or bi-specific antibodies such as disulfide stabilized Fv fragments, scFv tandems, diabodies, tribodies, or tetrabodies; and aptamers, receptors, and fusion proteins. [001036] In some embodiments, a ligand is a surface-bound antibody, which can permit tuning of cell targeting specificity. This is especially useful since highly specific antibodies can be raised against an epitope of interest for the desired targeting site. In some embodiments, multiple antibodies are expressed on the surface of a cell, and each antibody can have a different specificity for a desired target. Such approaches can increase the avidity and specificity of targeting interactions. [001037] A ligand can be selected, e.g., by a person skilled in the biological arts, based on the desired localization or function of the cell. In some embodiments an estrogen receptor ligand, such as tamoxifen, can target cells to estrogen-dependent breast cancer cells that have an increased number of estrogen receptors on the cell surface. Other non-limiting examples of ligand/receptor interactions include CCR1 (e.g., for treatment of inflamed joint tissues or brain in rheumatoid arthritis, and/or multiple sclerosis), CCR7, CCR8 (e.g., targeting to lymph node tissue), CCR6, CCR9, CCR10 (e.g., to target to intestinal tissue), CCR4, CCR10 (e.g., for targeting to skin), CXCR4 (e.g., for general enhanced transmigration), HCELL (e.g., for treatment of inflammation and inflammatory disorders, bone marrow), Alpha4beta7 (e.g., for intestinal mucosa targeting), and VLA-4NCAM-1 (e.g., targeting to endothelium). In general, any receptor involved in targeting (e.g., cancer metastasis) can be harnessed for use in the methods and compositions described herein. [001038] Targeted cells may include, but are not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, and tumor cells. [001039] In some embodiments, an LNP may target hepatocytes. Apolipoproteins such as apolipoprotein E (apoE) have been shown to associate with neutral or near neutral lipid-containing lipid nanoparticles in the body, and are known to associate with receptors such as low-density lipoprotein receptors (LDLRs) found on the surface of hepatocytes. Thus, an LNP including a lipid component with a neutral or near neutral charge that is administered to a subject may acquire apoE in a subject's body and may subsequently deliver a therapeutic and/or prophylactic (e.g., an RNA) to hepatocytes including LDLRs in a targeted manner. [001040] Lipid nanoparticles described herein are useful for treating a disease, disorder, or condition. In particular, such compositions are useful in treating a disease, disorder, or condition characterized by missing or aberrant protein or polypeptide activity. In some embodiments, a formulation of the disclosure that comprises an LNP including an mRNA encoding a missing or aberrant polypeptide is administered or delivered to a cell. Subsequent translation of the mRNA may produce the polypeptide, thereby reducing or eliminating an issue caused by the absence of or aberrant activity caused by the polypeptide. Because translation may occur rapidly, the methods and compositions may be useful in the treatment of acute diseases, disorders, or conditions such as sepsis, stroke, and myocardial infarction. A therapeutic and/or prophylactic included in an LNP may also be capable of altering the rate of transcription of a given species, thereby affecting gene expression. [001041] Diseases, disorders, and/or conditions characterized by dysfunctional or aberrant protein or polypeptide activity for which a composition may be administered include, but are not limited to, rare diseases, infectious diseases (as both vaccines and therapeutics), cancer and proliferative diseases, genetic diseases (e.g., cystic fibrosis), muscle-related conditions, autoimmune diseases, diabetes, neurodegenerative diseases, cardio- and reno-vascular diseases, and metabolic diseases. Multiple diseases, disorders, and/or conditions may be characterized by missing (or substantially diminished such that proper protein function does not occur) protein activity. Such proteins may not be present, or they may be essentially non-functional. A specific example of a dysfunctional protein is the missense mutation variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which produce a dysfunctional protein variant of CFTR protein, which causes cystic fibrosis. The present disclosure provides a method for treating such diseases, disorders, and/or conditions in a subject by administering a LNP including an RNA and a lipid component including a PEGylated lipid compound disclosed herein, a phospholipid (optionally unsaturated), optionally a second PEGylated lipid, and a structural lipid, wherein the RNA may be an mRNA encoding a polypeptide that antagonizes or otherwise overcomes an aberrant protein activity present in the cell of the subject. Treatment of CNS disorders [001042] Provided herein are therapeutic methods for treating a CNS disease or disorder by using the LNP-based RNA compositions described herein to deliver one or more therapeutic agents encoded on a payload RNA (e.g., linear or circular mRNA payload) to a cell, organ, or tissue of the central nervous system. Delivery may be in vitro or ex vivo to cells, or to a cell, tissue, or organ in vivo. [001043] The present disclosure provides, among other things, improved methods and compositions for efficient LNP delivery of mRNA payloads (e.g., circular mRNA and/or linear mRNA), encoding a therapeutic protein, to neurons and other cell types of the CNS. In various embodiments, the mRNA-encapsulated nanoparticles (e.g., LNPs) can be administered directly into the CNS space (e.g., via intrathecal administration) and effectively penetrate neuronal cell membrane, resulting in intracellular delivery of mRNA in neurons in the brain and/or spinal cord. [001044] Thus, in one aspect, the disclosure provides methods of LNP delivery of mRNA payloads (e.g., circular mRNA and/or linear mRNA) to the central nervous system (CNS). In some embodiments, an inventive method according to the present disclosure includes administering intrathecally to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the intracellular delivery of mRNA in neurons in the brain and/or spinal cord. [001045] In some embodiments, the LNP-encapsulated mRNA therapeutics described comprising one or more mRNA payloads (e.g., linear or circular mRNA) are delivered to neurons located within the brain. In some embodiments, the mRNA payloads are delivered to neurons located within the spinal cord. In some embodiments, the mRNA payloads are delivered to motor neurons. In some embodiments, the mRNA payloads are delivered to upper motor neurons and/or lower motor neurons. In some embodiments, the motor neurons are located within the anterior horn and/or dorsal root ganglia of the spinal cord. [001046] In other embodiments, the present disclosure provides, among other things, methods and compositions for effective delivery of messenger RNA (mRNA) to the central nervous system (CNS). In particular, the present disclosure provides methods and compositions for administering intrathecally to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within an LNP described herein, such that the administering of the composition results in the intracellular delivery of mRNA in neurons in the brain and/or spinal cord. The present disclosure is particularly useful for the treatment of CNS diseases, disorders or conditions, such as spinal muscular atrophy. [001047] The present disclosure can be used to deliver any mRNA to the central nervous system. In particular, the present disclosure is useful to deliver mRNA that encodes a protein associated with or implicated in a CNS disease, disorder or condition. As used herein, a "CNS disease, disorder or condition" refers to a disease, disorder or condition affecting one or more neuronal functions of the central nervous system (i.e., the brain and/or spinal cord). In some embodiments, a CNS disease, disorder or condition may be caused by a protein deficiency or dysfunction in neurons of the CNS (i.e., the brain and/or spinal cord). [001048] Exemplary CNS diseases, disorders or conditions include, but are not limited to, Acid Lipase Disease, Acid Maltase Deficiency, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, ADHD, Adie's Pupil, Adie's Syndrome, Adrenoleukodystrophy, Agnosia, Aicardi Syndrome, Aicardi-Goutieres Syndrome Disorder, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Antiphospholipid Syndrome, Aphasia, Apraxia, Arachnoiditis, Arnold-Chiari Malformation, Asperger Syndrome, Ataxia, Ataxia Telangiectasia, Ataxias and Cerebellar or Spinocerebellar Degeneration, Attention Deficit-Hyperactivity Disorder, Autism, Autonomic Dysfunction, Barth Syndrome, Batten Disease, Becker's Myotonia, Behcet's Disease, Bell's Palsy, Bernhardt-Roth Syndrome, Binswanger's Disease, Bloch-Sulzberger Syndrome, Bradbury-Eggleston Syndrome, Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, CADASIL, Canavan Disease, Causalgia, Cavernomas, Cavernous Angioma, Central Cervical Cord Syndrome, Central Cord Syndrome, Central Pontine Myelinolysis, Ceramidase Deficiency, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Beriberi, Cerebral Gigantism, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome (COFS), Cholesterol Ester Storage Disease, Chorea, Choreoacanthocytosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance, Cockayne Syndrome Type II, Coffin Lowry Syndrome, Colpocephaly, Congenital Myasthenia, Corticobasal Degeneration, Cranial Arteritis, Cree encephalitis, Creutzfeldt- Jakob Disease, Cushing's Syndrome, Cytomegalic Inclusion Body Disease, Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, Dawson Disease, De Morsier's Syndrome, Dejerine- Klumpke Palsy, Dentate Cerebellar Ataxia, Dentatorubral Atrophy, Dermatomyositis, Developmental Dyspraxia, Devic's Syndrome, Diffuse Sclerosis, Dravet Syndrome, Dysautonomia, Dysgraphia, Dyslexia, Dysphagia, Dyspraxia, Dyssynergia Cerebellaris Myoclonica, Dyssynergia Cerebellaris Progressiva, Fabry Disease, Fahr's Syndrome, Familial Dysautonomia, Familial Hemangioma, Familial Idiopathic Basal Ganglia Calcification, Familial Periodic Paralyses, Familial Spastic Paralysis, Farber's Disease, Fibromuscular Dysplasia, Fisher Syndrome, Floppy Infant Syndrome, Friedreich's Ataxia, Gaucher Disease, Generalized Gangliosidoses, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker Disease, Giant Axonal Neuropathy, Giant Cell Arteritis, Giant Cell Inclusion Disease, Globoid Cell Leukodystrophy, Glossopharyngeal Neuralgia, Glycogen Storage Disease, Guillain-Barré Syndrome, Hallervorden-Spatz Disease, Hemicrania Continua, Hemiplegia Alterans, Hereditary Spastic Paraplegia, Heredopathia Atactica Polyneuritiformis, Holmes-Adie syndrome, Holoprosencephaly, Hughes Syndrome, Huntington's Disease, Hydranencephaly, Hydromyelia, Hypercortisolism, Immune-Mediated, Encephalomyelitis, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile Hypotonia, Infantile Neuroaxonal Dystrophy, Acid Storage Disease, Iniencephaly, Isaac's Syndrome, Joubert Syndrome, Kearns-Sayre Syndrome, Kennedy's Disease, Kinsbourne syndrome, Kleine-Levin Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay Syndrome (KTS), Klüver-Bucy Syndrome, Korsakoffs Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Lateral, Femoral Cutaneous Nerve Entrapment, Lateral Medullary Syndrome, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Levine-Critchley Syndrome, Lewy Body Dementia, Lipoid Proteinosis, Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, Lupus - Neurological Sequelae, Lyme Disease, Machado-Joseph Disease, Macrencephaly, Melkersson- Rosenthal Syndrome, Menkes Disease, Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Miller Fisher Syndrome, Moebius Syndrome, Multiple Sclerosis, Muscular Dystrophy, Myasthenia Gravis, Myelinoclastic Diffuse Sclerosis, Narcolepsy, Neuroacanthocytosis, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurosarcoidosis, Niemann-Pick Disease, Ohtahara Syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, O'Sullivan-McLeod Syndrome, Pantothenate Kinase-Associated Neurodegeneration, Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Hemicrania, Parry- Romberg, Pelizaeus-Merzbacher Disease, Pena Shokeir II Syndrome, Periventricular Leukomalacia, Phytanic Acid Storage Disease, Pick's Disease, Piriformis Syndrome, Polymyositis, Pompe Disease, Post-Polio Syndrome, Primary Dentatum Atrophy, Primary Lateral Sclerosis, Primary Progressive Aphasia, Prion Diseases, Progressive Hemifacial Atrophy, Progressive Locomotor Ataxia, Progressive Multifocal Leukoencephalopathy, Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy, Prosopagnosia, Ramsay Hunt Syndrome I, Ramsay Hunt Syndrome II, Rasmussen's Encephalitis, Refsum Disease, Rett Syndrome, Reye's Syndrome, Riley-Day Syndrome, Sandhoff Disease, Schilder's Disease, Seitelberger Disease, Severe Myoclonic Epilepsy of Infancy (SMEI), Shy-Drager Syndrome, Sjögren's Syndrome, Spasticity, Spina Bifida, Spinal Muscular Atrophy, Spinocerebellar Atrophy, Spinocerebellar Degeneration, Steele-Richardson-Olszewski Syndrome, Striatonigral Degeneration, Sturge-Weber Syndrome, Tardive Dyskinesia, Tay-Sachs Disease, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Tic Douloureux, Todd's Paralysis, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Troyer Syndrome, Von Economo's Disease, Von Hippel-Lindau Disease (VHL), Von Recklinghausen's Disease, Wallenberg's Syndrome, Werdnig- Hoffman Disease, Wemicke-Korsakoff Syndrome, West Syndrome, Whipple's Disease, Williams Syndrome, Wilson Disease, Wolman's Disease, X-Linked Spinal and Bulbar Muscular Atrophy and Zellweger Syndrome. Motor Neuron Diseases [001049] In some embodiments, a CNS disease, disorder or condition is a disease, disorder or condition that affects one or more functions of motor neurons, which is also referred to as a motor neuron disease. In some embodiments, a motor neuron disease may be caused by a protein deficiency or dysfunction in motor neurons of the CNS (i.e., the brain and/or spinal cord). As used herein, the term "motor neurons" refer to those neurons that control voluntary muscle activity. Typically, motor neurons include upper motor neurons and lower motor neurons. As used herein, the term "upper motor neuron" refers to motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway. Upper motor neurons also referred to as "corticospinal neurons". Typically, upper motor neurons refer to any motor neurons that are not directly responsible for stimulating the target muscle. As used herein, the term "lower motor neuron" refers to the motor neurons connecting the brainstem and spinal cord to muscle fibers. In other words, lower motor neurons bring the nerve impulses from the upper motor neurons out to the muscles. Typically, a lower motor neuron's axon terminates on an effector (muscle). Lower motor neurons include "spinal neuron" and "Anterior horn cells". [001050] Exemplary motor neuron diseases, disorders or conditions include, but are limited to, Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Pseudobulbar Pasly, Hereditary Spastic Paraplegia, Progressive Muscular Atrophy (PMA), Progressive Bulbar Palsy (PBP), Distal Hereditary Motor Neuropathies, and Spinal Muscular Atrophies. [001051] In some embodiments, a motor neuron disease, disorder or condition is a form of spinal muscular atrophy. The family of spinal muscular atrophies are a genetically and clinically heterogeneous group of rare debilitating disorders characterized by degeneration of the lower motor neurons. Degeneration of the cells within the lower motor neurons, which are also known as the anterior horn cells of the spinal cord, leads to a loss of motor function resulting in atrophy and excessive wasting of various muscle groups within the body. Diseases that comprise the family can be divided into Proximal, Distal, Autosomal Recessive Proximal and Localized spinal muscular atrophies. However, given that protein deficiencies are the major cause of the various forms of spinal muscular atrophy, each disease member is usually classified according to the gene associated with the condition. [001052] Diseases with a CNS component [001053] In some embodiments, a CNS disease, disorder or condition is a disease with a CNS component. Typically, a disease with a CNS component is caused by a protein deficiency in one or more tissues, including both CNS and peripheral tissues, of the body, resulting in one or more CNS etiology and/or symptoms. For example, in some embodiments, a protein deficiency may result in the excess accumulation of an intracellular and/or extracellular component such as: glucosaminoglycans (GAGs), lipids, plaque (i.e.; Beta-amyloid) or protein. Thus, in some embodiments, a disease with a CNS component is a lysosomal storage disease caused by a deficiency in a lysosomal enzyme, which results in the excess accumulation of glucosaminoglycans (GAGs) in both the CNS and peripheral tissues. [001054] In some embodiments, lysosomal storage diseases can be treated having CNS etiology and/or symptoms include, but are not limited to, aspartylglucosaminuria, cholesterol ester storage disease, Wolman disease, cystinosis, Danon disease, Fabry disease, Farber lipogranulomatosis, Farber disease, fucosidosis, galactosialidosis types I/II, Gaucher disease types I/II/III, globoid cell leukodystrophy, Krabbe disease, glycogen storage disease II, Pompe disease, GM1-gangliosidosis types I/II/III, GM2-gangliosidosis type I, Tay Sachs disease, GM2-gangliosidosis type II, Sandhoff disease, GM2-gangliosidosis, α-mannosidosis types I/II, beta-mannosidosis, metachromatic leukodystrophy, mucolipidosis type I, sialidosis types I/II, mucolipidosis types II /III, I-cell disease, mucolipidosis type IIIC pseudo-Hurler polydystrophy, mucopolysaccharidosis type I, mucopolysaccharidosis type II, mucopolysaccharidosis type IIIA, Sanfilippo syndrome, mucopolysaccharidosis type IIIB, mucopolysaccharidosis type IIIC, mucopolysaccharidosis type IIID, mucopolysaccharidosis type IVA, Morquio syndrome, mucopolysaccharidosis type IVB, mucopolysaccharidosis type VI, mucopolysaccharidosis type VII, Sly syndrome, mucopolysaccharidosis type IX, multiple sulfatase deficiency, neuronal ceroid lipofuscinosis, CLN1 Batten disease, CLN2 Batten diseae, Niemann-Pick disease types A/B, Niemann-Pick disease type C1, Niemann-Pick disease type C2, pycnodysostosis, Schindler disease types I/II, Gaucher disease and sialic acid storage disease. [001055] A detailed review of the genetic etiology, clinical manifestations, and molecular biology of the lysosomal storage diseases are detailed in Scriver et al., eds., The Metabolic and Molecular Basis of Inherited Disease, 7.sup.th Ed., Vol. II, McGraw Hill, (1995). [001056] In various embodiments, the present disclosure may be used to deliver an mRNA encoding a protein that is deficient in any of the CNS diseases, disorders or conditions described herein. In some embodiments, the present disclosure may be used to deliver an mRNA encoding a protein that is deficient in a motor neuron disease. In particular embodiments, the present disclosure may be used to deliver an mRNA encoding a protein that is deficient in Spinal muscular atrophy (SMA), e.g., SMN1, which is described in detail below. In some embodiments, the present disclosure may be used to deliver an mRNA encoding a lysosomal enzyme that is deficient in a lysosomal storage disease with a CNS component. disclosureIn some embodiments, an mRNA suitable for the disclosure may encoded a wild-type or naturally occurring amino acid sequence. In some embodiments, an mRNA suitable for the disclosure may be a wild-type or naturally occurring sequence. In some embodiments, an mRNA suitable for the disclosure may be a codon-optimized sequence. In some embodiments, an mRNA suitable for the disclosure may encode an amino acid sequence having substantial homology or identify to the wild-type or naturally-occurring amino acid protein sequence (e.g., having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% sequence identity to the wild-type or naturally-occurring sequence). Survival of Motor Neuron [001057] In some embodiments, the methods and compositions provided by the present disclosure are used to deliver an mRNA encoding a Survival of Motor Neuron protein to the CNS for treatment of spinal muscular atrophy (SMA). [001058] A suitable SMN mRNA encodes any full length, fragment or portion of a SMN protein which can be substituted for naturally-occurring SMN protein activity or rescue one or more phenotypes or symptoms associated with spinal muscular atrophy. The mRNA sequence for human Survival of Motor Neuron-1 (hSMN-1) and corresponding amino acid sequence of a typical wild-type or naturally occurring hSMN-1 protein are known in the art. [001059] Thus, in some embodiments, a suitable mRNA for the present disclosure is a wild- type hSMN-2 mRNA sequence. In some embodiments, a suitable mRNA may be a codon optimized hSMN-1 mRNA sequence. [001060] Human SMN-1 gene may undergo alternative processing and transcriptional modification to produce alternative splice isoforms. For example, there are five known hSMN-1 splice isoforms: hSMN-1 isoform b, c, e, f and g. Human SMN-2 gene can also undergo alternative processing and transcriptional modification to produce alternative splice isoforms. There are four known hSMN-2 splice isoforms: hSMN-2 isoform a, b, c and d. In some embodiments, the present disclosure is used to deliver an mRNA encoding an hSMN-1 isoform (e.g., isoform b, c, e, f, or g). In some embodiments, the present disclosure is used to deliver an mRNA encoding an hSMN-2 isoform (e.g., isoform a, b, c or d). The nucleotide and amino acid sequence of the hSMN-1 and hSMN-2 isoforms are known in the art. Thus, in some embodiments, the present disclosure can be used to deliver an mRNA encoding an hSMN-1 isoform or an hSMN-2 protein or an isoform thereof. In some embodiments, an mRNA suitable for the disclosure may be a wild-type or naturally occurring hSMN- 1 or hSMN-2 isoform sequence. In some embodiments, an mRNA suitable for the disclosure may be a codon-optimized hSMN-1 or hSMN-2 isoform sequence. In some embodiments, an mRNA suitable for the disclosure may encode an amino acid sequence having substantial homology or identify to the wild-type or naturally-occurring hSMN-1 or hSMN-2 isoform sequence (e.g., having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% sequence identity to the wild-type or naturally-occurring hSMN-1 or hSMN-2 isoform sequence). Intrathecal delivery [001061] In some embodiments, mRNA loaded LNPs are delivered to the CNS by injecting into the cerebrospinal fluid (CSF) of a subject in need of treatment. In some embodiments, intrathecal administration is used for injecting mRNA or mRNA loaded nanoparticles to the CSF. As used herein, intrathecal administration (also referred to as intrathecal injection) refers to an injection into the spinal canal (intrathecal space surrounding the spinal cord). Various techniques may be used including, without limitation, lateral cerebroventricular injection through a burrhole or cistemal or lumbar puncture or the like. Exemplary methods are described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169- 179, the contents of which are incorporated herein by reference. [001062] According to the present disclosure, mRNA or mRNA loaded nanoparticles may be injected at any region surrounding the spinal canal. In some embodiments, mRNA or mRNA loaded nanoparticles are injected into the lumbar area or the cisterna magna or intraventricularly into a cerebral ventricle space. As used herein, the term "lumbar region" or "lumbar area" refers to the area between the third and fourth lumbar (lower back) vertebrae and, more inclusively, the L2-S1 region of the spine. Typically, intrathecal injection via the lumbar region or lumber area is also referred to as "lumbar IT delivery" or "lumbar IT administration." The term "cisterna magna" refers to the space around and below the cerebellum via the opening between the skull and the top of the spine. Typically, intrathecal injection via cisterna magna is also referred to as "cisterna magna delivery." The term "cerebral ventricle" refers to the cavities in the brain that are continuous with the central canal of the spinal cord. Typically, injections via the cerebral ventricle cavities are referred to as intravetricular Cerebral (ICV) delivery. Delivery to neurons and other cell types in the brain and/or spinal cord [001063] The disclosure provides methods and compositions for the delivery of mRNA to various neurons and other cell types in the brain and/or spinal cord. In some embodiments, mRNA encoding a therapeutic protein is delivered to various cells in the brain including, but not limited to, neurons, glial cells, perivascular cells and/or meningeal cells. In particular, the methods and compositions for delivery to neurons results in delivery of mRNA in various neurons and other cell types affected by a CNS disease and/or deficiency, or various neurons and other cell types in which the deficient protein associated with the CNS disease is normally expressed. In some embodiments, the herein described methods result in delivery of mRNA in various neurons and other cell types in the CNS in which there is a detectable or abnormally high amount of enzyme substrate, for example stored in the cellular lysosomes of the tissue, in patients suffering from or susceptible to the lysosomal storage disease. In some embodiments, the methods disclosed herein result in delivery of mRNA in various neurons and other cell types that display disease-associated pathology, symptom, or feature. For example, mRNA may be delivered to neurons or other cell types that are deteriorating, degenerating or undergoing apoptosis such as those neurons or non-neuronal cells associated with neurodenegrative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Huntington's disease) or motor neurons associated with motor neuron diseases (e.g., Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Pseudobulbar Pasly, Hereditary Spastic Paraplegia, Progressive Muscular Atrophy (PMA), Progressive Bulbar Palsy (PBP), Distal Hereditary Motor Neuropathies, and Spinal Muscular Atrophies). [001064] In some embodiments, mRNA is delivered to neurons and/or non-neuronal cells located within the brain. In some embodiments, mRNA is delivered to neurons and/or non-neuronal cells located within the spinal cord. In some embodiments, mRNA is delivered to motor neurons. In some embodiments, the mRNA is delivered to upper motor neurons and/or lower motor neurons. In some embodiments, the motor neurons are located within the anterior horn and/or dorsal root ganglia of the spinal cord. [001065] In some embodiments, mRNA is delivered intracellularly in various neurons and other cell types in the brain and/or spinal cord. In some embodiments, mRNA is delivered to the axons of neurons. In some embodiments, mRNA delivery according to the present disclosure results in intracellular expression of the protein encoded by the mRNA within cytosol of the neurons. In some embodiments, mRNA delivery according to the present disclosure results in expression of the protein encoded by the mRNA in subcellular compartment of the neurons, e.g., lysosomes, mitochondria, transmembrane, and the like. In some embodiments, mRNA delivery according to the present disclosure results in expression of the protein encoded by the mRNA and secretion extracellularly from the neurons. Brain [001066] In general, methods according to the present disclosure can be used to deliver mRNA and encoded protein to neurons and other cell types in various regions of the brain. Typically, brain can be divided into different regions, layers and tissues. For example, meningeal tissue is a system of membranes which envelops the central nervous system, including the brain. The meninges contain three layers, including dura mater, arachnoid mater, and pia mater. In general, the primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system. In some embodiments, mRNA and the encoded protein is delivered to neurons or non-neuronal cells in one or more layers of the meninges. [001067] The brain has three primary subdivisions, including the cerebrum, cerebellum, and brain stem. The cerebral hemispheres, which are situated above most other brain structures, are covered with a cortical layer. Underneath the cerebrum lies the brainstem, which resembles a stalk on which the cerebrum is attached. At the rear of the brain, beneath the cerebrum and behind the brainstem, is the cerebellum. [001068] The diencephalon, which is located near the midline of the brain and above the mesencephalon, contains the thalamus, metathalamus, hypothalamus, epithalamus, prethalamus, and pretectum. The mesencephalon, also called the midbrain, contains the tectum, tegumentum, ventricular mesocoelia, and cerebral peduncels, the red nucleus, and the cranial nerve III nucleus. The mesencephalon is associated with vision, hearing, motor control, sleep/wake, alertness, and temperature regulation. [001069] In some embodiments, mRNA and the encoded protein is delivered to neurons and/or non-neuronal cells of one or more tissues of the cerebellum. In certain embodiments, the targeted one or more tissues of the cerebellum are selected from the group consisting of tissues of the molecular layer, tissues of the Purkinje cell layer, tissues of the Granular cell layer, cerebellar peduncles, and combination thereof. In some embodiments, mRNA and the encoded protein is delivered to one or more deep tissues of the cerebellum including, but not limited to, tissues of the Purkinje cell layer, tissues of the Granular cell layer, deep cerebellar white matter tissue (e.g., deep relative to the Granular cell layer), and deep cerebellar nuclei tissue. [001070] In some embodiments, mRNA and the encoded protein is delivered to one or more tissues of the brainstem. In some embodiments, mRNA and encoded protein is delivered to various brain tissues including, but not limited to, gray matter, white matter, periventricular areas, piaarachnoid, meninges, neocortex, cerebellum, deep tissues in cerebral cortex, molecular layer, caudate/putamen region, midbrain, deep regions of the pons or medulla, and combinations thereof. In some embodiments, mRNA and encoded protein is delivered to oligodendrocytes of deep white matter. Spinal Cord [001071] In some embodiments, the methods according to the present disclosure can be used to deliver mRNA and encoded protein to neurons and other cell types in various regions of the spinal cord. In general, regions or tissues of the spinal cord can be characterized based on the depth of the tissues. For example, spinal cord tissues can be characterized as surface or shallow tissues, mid-depth tissues, and/or deep tissues. [001072] In some embodiments, mRNA and the encoded protein is delivered to one or more surface or shallow tissues of the spinal cord. In some embodiments, a targeted surface or shallow tissue of the spinal cord contains pia mater and/or the tracts of white matter. [001073] In some embodiments, mRNA and the encoded protein is delivered to one or more deep tissues of the spinal cord. In some embodiments, a targeted deep tissue of the spinal cord contains spinal cord grey matter and/or ependymal cells. [001074] The disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the disclosure. All literature citations are incorporated by reference. Treatment of muscle disorders [001075] Provided herein are therapeutic methods for treating muscle diseases or disorders by using the LNP-based RNA compositions described herein to deliver one or more therapeutic agents encoded on a payload RNA (e.g., linear or circular mRNA payload) to a cell, tissue, or organ having muscle. Delivery may be in vitro or ex vivo to cells, or to a cell, tissue, or organ in vivo. [001076] The mRNA payloads of the herein disclosed LNP-based RNA therapeutics may delivery one or more therapeutic proteins for treating a muscle condition, which may include the following diseases: (A) Muscular dystrophies; (B) Myopathies; (C) Motor neuron diseases; (D) Ion channel diseases; (E) Mitochondrial diseases; (F) Neuromuscular junction diseases; and (G) Peripheral nerve diseases. [001077] With regard to (A) muscular dystrophies, this category of muscular diseases can encompass the following specific disorders: Becker muscular dystrophy (BMD); Congenital muscular dystrophies (CMD); Bethlem CMD; Fukuyama CMD; Muscle-eye-brain diseases (MEBs); Rigid spine syndromes; Ullrich CMD; Walker-Warburg syndromes (WWS); Duchenne muscular dystrophy (DMD); Emery-Dreifuss muscular dystrophy (EDMD); Facioscapulohumeral muscular dystrophy (FSHD); Limb-girdle muscular dystrophies (LGMD); Myotonic dystrophy (DM); or Oculopharyngeal muscular dystrophy (OPMD). [001078] With regard to (B) myopathies, this category of muscular diseases can encompass the following specific disorders: Congenital myopathies; Cap myopathies; Centronuclear myopathies; Congenital myopathies with fiber type disproportion; Core myopathies; Central core disease; Multiminicore myopathies; Myosin storage myopathies; Myotubular myopathy; Nemaline myopathies; Distal myopathies; GNE myopathy/Nonaka myopathy/hereditary inclusion-body myopathy (HIBM); Laing distal myopathy; Markesbery-Griggs late-onset distal myopathy; Miyoshi myopathy; Udd myopathy/tibial muscular dystrophy; VCP Myopathy / IBMPFD; Vocal cord and pharyngeal distal myopathy; Welander distal myopathy; Endocrine myopathies; Hyperthyroid myopathy; Hypothyroid myopathy; Inflammatory myopathies; Dermatomyositis; Inclusion-body myositis; Polymyositis; Metabolic myopathies; Acid maltase deficiency (AMD, Pompe disease); Carnitine deficiency; Carnitine palmitoyltransferase deficiency; Debrancher enzyme deficiency (Cori disease, Forbes disease); Lactate dehydrogenase deficiency; Myoadenylate deaminase deficiency; Phosphofructokinase deficiency (Tarui disease); Phosphoglycerate kinase deficiency; Phosphoglycerate mutase deficiency; Phosphorylase deficiency (McArdle disease); Myofibrillar myopathies (MFM); or Scapuloperoneal myopathy. [001079] With regard to (C) motor neuron diseases, this category of muscular diseases can encompass the following specific disorders: ALS (amyotrophic lateral sclerosis); Spinal-bulbar muscular atrophy (SBMA); or Spinal muscular atrophy (SMA). [001080] With regard to (D) ion channel diseases, this category of muscular diseases can encompass the following specific disorder: Andersen-Tawil syndrome; Hyperkalemic periodic paralysis; Hypokalemic periodic paralysis; Myotonia congenita; Becker myotonia; Thomsen myotonia; Paramyotonia congenita; or Potassium- aggravated myotonia. [001081] With regard to (E) mitochondrial diseases, this category of muscular diseases can encompass the following specific disorder: Friedreich’s ataxia (FA); Mitochondrial myopathies; Kearns-Sayre syndrome (KSS); Leigh syndrome (subacute necrotizing encephalomyopathy); Mitochondrial DNA depletion syndromes; Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS); Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); Myoclonus epilepsy with ragged red fibers (MERRF); Neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; or Progressive external opthalmoplegia (PEO). [001082] With regard to (F) neuromuscular junction diseases, this category of muscular diseases can encompass the following specific disorder: Congenital myasthenic syndromes (CMS); Lambert-Eaton myasthenic syndrome (LEMS); or Myasthenia gravis (MG). [001083] With regard to (G) peripheral nerve diseases, this category of muscular diseases can encompass the following specific disorder: Charcot-Marie-Tooth disease (CMT); or Giant axonal neuropathy (GAN). [001084] In some embodiments, the compositions may be used to treat a range of muscle- related disorders, including, but not limited to, Duchenne muscular dystrophy, limb girdle muscle disease, and spinal muscular atrophy, as well as other muscle tissue related diseases. Exemplary muscle tissue related diseases include but are not limited to Acid Maltase Deficiency (AMD), Amyotrophic Lateral Sclerosis (ALS), Andersen-Tawil Syndrome, Becker Muscular Dystrophy (BMD), Becker Myotonia Congenita, Bethlem Myopathy, Bulbospinal Muscular Atrophy (Spinal- Bulbar Muscular Atrophy), Carnitine Deficiency, Carnitine Palmityl Transferase Deficiency (CPT Deficiency), Central Core Disease (CCD), Centronuclear Myopathy, Charcot-Marie-Tooth Disease (CMT), Congenital Muscular Dystrophy (CMD), Congenital Myasthenic Syndromes (CMS), Congenital Myotonic Dystrophy, Cori Disease (Debrancher Enzyme Deficiency), Debrancher Enzyme Deficiency, Dejerine-Sottas Disease (DSD), Dermatomyositis (DM), Distal Muscular Dystrophy (DD), Duchenne Muscular Dystrophy (DMD), Dystrophia Myotonica (Myotonic Muscular Dystrophy), Emery-Dreifuss Muscular Dystrophy (EDMD), Endocrine Myopathies, Eulenberg Disease (Paramyotonia Congenita), Facioscapulohumeral Muscular Dystrophy (FSH or FSHD), Finnish (Tibial) Distal Myopathy, Forbes Disease (Debrancher Enzyme Deficiency), Friedreich's Ataxia (FA), Fukuyama Congenital Muscular Dystrophy, Glycogenosis Type 10, Glycogenosis Type 11, Glycogenosis Type 2, Glycogenosis Type 3, Glycogenosis Type 5, Glycogenosis Type 7, Glycogenosis Type 9, Gowers-Laing Distal Myopathy, Hauptmann-Thanheuser MD (Emery-Dreifuss Muscular Dystrophy), Hereditary Inclusion-Body Myositis, Hereditary Motor and Sensory Neuropathy (Charcot-Marie-Tooth Disease), Hyperthyroid Myopathy, Hypothyroid Myopathy, Inclusion-Body Myositis (IBM), Inherited Myopathies, Integrin-Deficient Congenital Muscular Dystrophy, Kennedy Disease (Spinal-Bulbar Muscular Atrophy), Kugelberg-Welander Disease (Spinal Muscular Atrophy), Lactate Dehydrogenase Deficiency, Lambert-Eaton Myasthenic Syndrome (LEMS), Limb-Girdle Muscular Dystrophy (LGMD), Lou Gehrig's Disease (Amyotrophic Lateral Sclerosis), McArdle Disease (Phosphorylase Deficiency), Merosin-Deficient Congenital Muscular Dystrophy, Metabolic Diseases of Muscle, Mitochondrial Myopathy, Miyoshi Distal Myopathy, Motor Neurone Disease, Muscle-Eye-Brain Disease, Myasthenia Gravis (MG), Myoadenylate Deaminase Deficiency, Myofibrillar Myopathy, Myophosphorylase Deficiency, Myotonia Congenita (MC), Myotonic Muscular Dystrophy (MMD), Myotubular Myopathy (MTM or MM), Nemaline Myopathy, Nonaka Distal Myopathy, Oculopharyngeal Muscular Dystrophy (OPMD), Paramyotonia Congenita, Pearson Syndrome, Periodic Paralysis, Peroneal Muscular Atrophy (Charcot-Marie-Tooth Disease), Phosphofructokinase Deficiency, Phosphoglycerate Kinase Deficiency, Phosphoglycerate Mutase Deficiency, Phosphorylase Deficiency, Phosphorylase Deficiency, Polymyositis (PM), Pompe Disease (Acid Maltase Deficiency), Progressive External Ophthalmoplegia (PEO), Rod Body Disease (Nemaline Myopathy), Spinal Muscular Atrophy (SMA), Spinal-Bulbar Muscular Atrophy (SBMA), Steinert Disease (Myotonic Muscular Dystrophy), Tarui Disease (Phosphofructokinase Deficiency), Thomsen Disease (Myotonia Congenita), Ullrich Congenital Muscular Dystrophy, Walker-Warburg Syndrome (Congenital Muscular Dystrophy), Welander Distal Myopathy, Werdnig-Hoffmann Disease (Spinal Muscular Atrophy), and ZASP- Related Myopathy. [001085] The present disclosure provides, among other things, improved methods and compositions for efficient LNP delivery of mRNA payloads (e.g., circular mRNA and/or linear mRNA), encoding a therapeutic protein, to muscles. In various embodiments, the mRNA- encapsulated nanoparticles (e.g., LNPs) can be administered directly into a muscle (e.g., via intramuscular administration) and effectively penetrate muscle cell membrane, resulting in intracellular delivery of mRNA in muscle cells. Other delivery modes are also contemplated. [001086] Further, the present disclosure provides methods for treating one more or muscle diseases or conditions by administering an effective amount of the LNP-based RNA therapeutics described herein. In various embodiments, the RNA payload of the LNP-based RNA therapeutics may encode one more therapeutic polypeptides. [001087] For example, the LNP-based RNA therapeutics and pharmaceutical compositions thereof described herein may be used to treat muscle atrophy, which is both a disease state and an aging process condition that diminishes the quality of life. There has been a high demand for therapeutics that increase lean mass while abrogating the need for special dietary and exercise requirements that are usually unattainable in people with active muscle wasting. Therefore, in some embodiments, a nanomedicine approach capable of increasing skeletal muscle mass and restricting body fat accumulation is disclosed herein. The therapeutic modality is based on LNP-based nanoparticles that deliver mRNA payloads (e.g., linear or circular mRNA) that encode a therapeutic protein for treating muscle wasting, such as follistatin. [001088] By “muscle cell” or “muscle tissue” is meant a cell or group of cells derived from muscle of any kind (for example, skeletal muscle and smooth muscle, e.g. from the digestive tract, urinary bladder, blood vessels or cardiac tissue). Such muscle cells may be differentiated or undifferentiated, such as myoblasts, myocytes, myotubes, cardiomyocytes and cardiomyoblasts. Since muscle tissue is readily accessible to the circulatory system, a protein produced and secreted by muscle cells and tissue in vivo will logically enter the bloodstream for systemic delivery, thereby providing sustained, therapeutic levels of protein secretion from muscle. [001089] In some embodiments, exemplary polypeptides include neuroprotective polypeptides and anti-angiogenic polypeptides. Suitable polypeptides include, but are not limited to, glial derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF-2), nurturin, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF; e.g., nerve growth factor-.beta.), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-6 (NT-6), epidermal growth factor (EGF), pigment epithelium derived factor (PEDF), a Wnt polypeptide, soluble Flt-1, angiostatin, endostatin, VEGF, an anti-VEGF antibody, a soluble VEGFR, Factor VIII (FVIII), Factor IX (FIX), and a member of the hedgehog family (sonic hedgehog, Indian hedgehog, and desert hedgehog, etc.). [001090] The delivered RNA payload directs the body (e.g., hepatic cellular machinery) to produce the protein encoded in the delivered linear or circular mRNA. [001091] The disclosure further relates to methods of treating muscle disease, and/or modulating muscle mass in a subject by administering an effective amount of the LNP-based RNA therapeutics and/or pharmaceutical compositions thereof described herein to a subject in need. In various embodiments, the RNA payloads of the LNP-based RNA therapeutics and/or pharmaceutical compositions thereof may encode one or more the therapeutic polypeptides disclosed herein. [001092] In embodiments, the LNP-based methods include slowing the loss of, increasing, and/or maintaining lean muscle mass in a subject (e.g., a human and/or mammalian subject). In some examples, the LNP-based methods include treating a subject with a muscle-wasting disease and/or muscle atrophy. In embodiments, the LNP-based methods include administering to a subject an effective amount (e.g., a therapeutically effective amount) of any LNP-based composition disclosed herein. In embodiments, administering to the subject the mRNA polymer complex or the drug delivery system slows the loss of, increases, and/or maintains lean muscle mass in a subject and/or treats acute or chronic muscle atrophy and/or a muscle-wasting disease. The methods can include selecting a subject in need of augmented or maintained muscle growth, such as a subject with a muscle-wasting disease or muscle atrophy or a healthy subject, for example, to enhance athletic performance. Any type of subject can be selected, including human or mammalian subjects. [001093] In some examples, the subject can have a muscle-wasting disease and/or acute or chronic muscle atrophy. The subject can have any muscle-wasting disease and/or any condition associated with acute or chronic muscle atrophy. In some examples, the subject can have sarcopenia, cachexia, cancer, congestive heart failure, renal failure, chronic obstructive pulmonary disease, severe burns, an inflammatory muscle disease, myasthenia gravis, neuropathy, polio, multiple sclerosis, anorexia nervosa, human immunodeficiency virus, acquired immune deficiency syndrome, osteomalacia, herniated disk, hypercalicemia, kwashiorkor, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, diabetes, amyotrophic lateral sclerosis, necrotizing vasculitis, abetalipoproteinemia, malabsorption syndrome, Legg Calvé-Perthes disease, muscular dystrophy, polymyositis, Guillain-Barre syndrome, and/or osteoarthritis. [001094] In some particular embodiments, the LNP-based compositions may comprise an RNA payload that encodes one or more polypeptides that may be delivered as a substitute for a defective endogenous muscle related protein that is associated with a particular muscle disorder. For example, the composition herein may be used to deliver a gene responsible for one of the neuromuscular diseases listed herein, preferably selected from the group comprising Duchenne muscular dystrophy and Becker muscular dystrophy (DMD gene), Limb-girdle muscular dystrophies (LGMDs) (CAPN3, DYSF, FKRP, AN05 genes and others), Spinal muscular atrophy (SMN1 , ASAH1 genes) and Amyotrophic lateral sclerosis (SOD1, ALS2, SETX, FUS, ANG, TARDBP, FIG4, OPTN and others), Myotubular myopathy (MTM1 gene), Centronuclear myopathies (MTM1, DNM2, BIN1 genes), Nemaline myopathies (ACTA1, KLHL40, KLHL41, KBTBD13 genes), Selenoprotein N-related myopathy (SEPN1 gene), Congenital myasthenia (ColQ, CHRNE , RAPSN, DOK7, MUSK genes), Pompe disease ( GAA gene), Glycogen storage disease III (GSD3) ( AGL gene), Myotonic dystrophy type 1 ( DMPK gene) and type 2 ( CNBP/ZNF9 gene ); Hereditary paraplegia (SPAST) and Charcot-Marie-Tooth, Type 4B1 ( MTMR2 ). In some more preferred embodiments, the target gene is selected from the group consisting of : DMD, CAPN3, DYSF, FKRP, AN05, MTM1, DNM2, BIN1, ACTA1, KLHL40, KLHL41, KBTBD13, TPM3, TPM2, TNNT1, CFL2, LMOD3, SEPN1, GAA, AGL , SMN1, and ASAH1 genes. [001095] The LNP compositions described may be used to treat (i) myopathies, such as muscular dystrophies, including congenital muscular dystrophies; (ii) spinal muscular atrophies (SMAs) and motor neuron diseases ; (iii) Myotonic syndrome, in particular myotonic dystrophy type 1 and type 2; (iv) Hereditary motor and sensory neuropathies; (v) Hereditary paraplegia and Hereditary ataxia; (vi) Congenital myasthenic syndromes, in particular muscular dystrophies including congenital muscular dystrophies, congenital myasthenic syndromes , and spinal muscular atrophies (SMAs) and motor neuron diseases. [001096] In some embodiments, the LNP-based RNA payload compositions may be used to deliver a desired polynucleotide that will restore the function of a protein that is associated with a muscle disease, muscular dystrophy, including congenital muscular dystrophy affecting at least the nervous system, selected from the group consisting of: FKTN, POMT1, POMT2, POMGNT1, POMGNT2, LMNA, ISPD, GMPPB, LARGE, LAMA2, TRIM 32, and B3GALNT2. [001097] The compositions may also used to treat dystrophinopathies, which are a spectrum of X-linked muscle diseases caused by pathogenic variants in DMD gene, which encodes the protein dystrophin. Dystrophinopathies comprises Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy. [001098] The compositions may also be used to treat the Limb-girdle muscular dystrophies (LGMDs), which are a group of disorders that are clinically similar to DMD but occur in both sexes as a result of autosomal recessive and autosomal dominant inheritance. Limb-girdle dystrophies are caused by mutation of genes that encode sarcoglycans and other proteins associated with the muscle cell membrane, which interact with dystrophin. The term LGMD1 refers to genetic types showing dominant inheritance (autosomal dominant), whereas LGMD2 refers to types with autosomal recessive inheritance. Pathogenic variants at more than 50 loci have been reported (LGMD1A to LGMD1G; LGMD2A to LGMD2W). Calpainopathy (LGMD2A) is caused by mutation of the gene CAPN3 with more than 450 pathogenic variants described. Contributing genes to LGMD phenotype include: anoctamin 5 (. AN05 ), blood vessel epicardial substance (BYES), calpain 3 ( CAPN3 ), caveolin 3 ( CAV3 ), CDP-L-ribitol pyrophosphorylase A ( CRPPA ), dystroglycan 1 ( DAG1 ), desmin ( DES ), DnaJ heat shock protein family (Hsp40) homolog, subfamily B, member 6 ( DNAJB6 ), dysferlin ( DYSF ), fukutin related protein ( FKRP ), fukutin ( FKT ), GDP-mannose pyrophosphorylase B ( GMPPB ), heterogeneous nuclear ribonucleoprotein D like ( HNRNPDL ), LIM zinc finger domain containing 2 ( LIMS2 ), lain A:C ( LMNA ), myotilin ( MYOT ), plectin ( PLEC ), protein O- glucosyltransferase 1 ( PLOGLUT1 ), protein O-linked mannose N- acetylglucosaminyltransferase 1 (beta 1,2-) ( POMGNT1 ), protein O-mannose kinase ( POMK ), protein O-mannosyltransferase 1 ( POMT1 ), protein O-mannosyltransferase 2 ( POMT2 ), sarcoglycan alpha (SGCA), sarcoglycan beta ( SGCB ), sarcoglycan delta ( SGCD ), sarcoglycan gamma ( SGCG ), titin-cap ( TCAP ), transportin 3 ( TNP03 ), torsin 1A interacting protein ( TOR1AIP1 ), trafficking protein particle complex 11 ( TRAPPC11 ), tripartite motif containing 32 (TRIM 32) and titin (TTN). Major contributing genes to LGMD phenotype include CAPN3, DYSF, FKRP and AN 05 (Babi Ramesh Reddy Nallamilli et ah, Annals of Clinical and Translational Neurology, 2018, 5, 1574-1587. [001099] The compositions may also be used to treat certain neurological disorders caused by Dysferlin, which is involved in neurological disorders including multiple sclerosis (Hochmeister et ah, J. Neuropathol. Exp. Neurol., 2006 Sep;65(9):855-65); Alzheimer (Galvin et ah, Acta Neuropathol., 2006 Dec;112(6):665-71 and choreic movement (Takahashi T, et al„ Mov. Disord., 2006, Sep;21(9): 1513-5). [001100] Spinal muscular atrophy is a genetic disorder caused by mutations in the Survival Motor Neuron 1 (SMN1 ) gene which is characterized by weakness and wasting (atrophy) in muscles used for movement. Mutations in ASAH1 gene lead to SMA-PME (spinal muscular atrophy with progressive myoclonic epilepsy). Compositions may be used to deliver replacement SMN1 protein. [001101] The composition disclosed here may also be used to treat X-linked X-linked myotubular myopathy is a genetic disorder caused by mutations in the myotubularin (MTM1) gene which affects muscles used for movement (skeletal muscles) and occurs almost exclusively in males. This condition is characterized by muscle weakness (myopathy) and decreased muscle tone (hypotonia). [001102] Pompe disease is a genetic disorder caused by mutations in the acid alpha- glucosidase (GAA) gene. Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen effectively, which allows this sugar to build up to toxic levels in lysosomes. This buildup damages organs and tissues throughout the body, particularly the muscles, leading to the progressive signs and symptoms of Pompe disease. [001103] Glycogen storage disease III (GSD3) is an autosomal recessive metabolic disorder caused by homozygous or compound heterozygous mutation in the Amylo-Alpha-1, 6- Glucosidase, 4-Alpha-Glucanotransferase (AGL) gene which encodes the glycogen debrancher enzyme and associated with an accumulation of abnormal glycogen with short outer chains. Clinically, patients with GSD III present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in those with Ilia is minimal in childhood but can become more severe in adults; some patients develop cardiomyopathy. The compositions of the disclosure can be used to supplement with a healthy version of AGS. [001104] The methods can include administering an LNP-based composition described herein in any amount (e.g., any concentration and/or dose). The administered amount (e.g., concentration and/or dose) of the LNP-based compositions described herein will depend on the subject being treated, the severity of the affliction, and the manner of administration and is best left to the judgment of the prescribing clinician. The herein described compositions can be administered at any concentration. Exemplary concentrations include at least about 10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 ng/ml or about 10-1000, 25-500, 50-250, 100-500, 300-700, 400-800, 600-1000, 10-50, 50-100, 100-150, 150-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, or 950-1000 ng/ml or about 250 or 500 ng/ml. The herein described compositions can be administered at any dose. Exemplary doses include at least about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, or 5 mg/kg or about 0.05-1, 0.1-2, 0.5-5, 1-5, 2-4, 3-5, 0.05-0.1, 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, or 2-5 mg/kg or about 0.5 mg/kg. [001105] The methods can include administering a herein described composition for treating a muscle disease over any timeframe. The timeframe of administration will depend on the subject being treated, the severity of the affliction, and the manner of administration and is best left to the judgment of the prescribing clinician. For example, the herein described compositions can be injected or infused over any length of time and/or the herein described compositions can be administered (e.g., by injection or infusion) in any amount of doses over any amount of time. In some examples, the herein disclosed LNP compositions are infused, such as at least over about 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, or 8 hours or about 1-15 minutes, 2-30 minutes, 5-60 minutes, 15-90 minutes, 30-120 minutes, 5-10 minutes, 10-15 minutes, 15-30 minutes, 30-45 minutes, 45 minutes-1 hour, 1-1.5 hours, 1.5-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, or 7-8 hours. In some examples, multiple doses of the herein disclosed LNP compositions can be administered (e.g., by injection or infusion, such as by subcutaneous injection), for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 20, 25, 30, 35, 40, 45, or 50 doses or about 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-12, 12-15, 15-18, 18-20, 20-25, 25-30, 30-35, 35-40, 40-45, or 45-50 doses or about 1 dose, 16 doses, or 18 doses. Exemplary frequencies for administering one or more doses of the LNP compositions described herein include administration (e.g., injection or infusions, such as subcutaneous injection) at least about every day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 30 days, 60 days, or 180 days or about every 1-7 days, 3-10 days, 5-14 days, 21-42 days, 28-60 days, 1 day-2 days, 2-3 days, 3-4 days, 4-5 days, 5-6 days, 6-7 days, 7-8 days, 8-9 days, 9-10 days, 10-30 days, 30-60 days, or 60-180 days or about every 3 days. Exemplary timespans for administering herein disclosed compositions include administering the doses over at least about 1 day, 3 days, 9 days, 18 days, 30 days, 60 days, 180 days, 1 year, 2 years, 3 years, or 4 years or about 1 day-3 days, 3-9 days, 9-18 days, 18-30 days, 30-60 days, 60-180 days, 180 days-1 year, 1-2 years, 2-3 years, or 3-4 years or about 1 days or 60 days. In some examples, the mRNA polymer complex or drug delivery system can be administered (e.g., by subcutaneous injection, such as every 3 days) indefinitely, such as to a subject with chronic muscle atrophy and/or a chronic muscle-wasting disease. [001106] In embodiments, the methods include assessing biocompatibility (e.g., efficacy, therapeutic response, toxicity, inflammation, side effects, and/or elimination), such as before, with, and/or after administration of a composition disclosed herein. In some examples, efficacy and/or therapeutic response is assessed. Assays for efficacy and/or therapeutic response are known in the art. Any efficacy and/or therapeutic response assay can be used. Exemplary efficacy and/or therapeutic response assays include measuring levels of molecules involved in forming muscle mass, such as follistatin, myostatin, and/or activin A levels. Levels of molecules involved in forming muscle mass can be measured in any fluid or tissue, such as in a urine or blood sample (e.g., whole blood, serum, and/or plasma). Any method of measuring such molecules can be used (e.g., immunohistochemistry, IHC). In some examples, efficacy and/or therapeutic response is assessed by measuring physiological changes, such as changes in body fat and/or muscle mass. Any method of measuring physiological changes can be used (e.g., Correa-de-Araujo, Front Physiol., 8:87, 2017, incorporated herein by reference). In some examples, measurements in an efficacy and/or therapeutic response assay can be compared to measurements and/or expected measurements in a control subject (e.g., a subject that was not administered a herein disclosed LNP composition). [001107] In some examples, the methods herein include delivery a composition described herein to a muscle in order to increase in the levels (e.g., blood levels, such as blood serum levels) of a therapeutic protein (e.g., follistatin - an endogenous glycoprotein that promotes growth and repair of skeletal muscle by sequestering inhibitory ligands of the transforming growth factor-β superfamily and may therefore have therapeutic potential for neuromuscular diseases) of a subject by at least about 0.5-, 1-, 1.5-, 2-, 2.5-, 3-, 3.5-, 4-, 4.5-, 5-, 5.5-, 6-, 6.5-, 7- , 7.5-, or 8-fold or about 0.5- to 1-fold, 1- to 1.5-fold, 1.5- to 2-fold, 2- to 2.5-fold, 2.5- to 3-fold, 3- to 3.5-fold, 3.5- to 4-fold, 4- to 4.5-fold, 4.5- to 5-fold, 5- to 5.5-fold, 5.5- to 6-fold, 6- to 6.5- fold, 6.5- to 7-fold, 7- to 7.5-fold, or 7.5- to 8-fold or about 1.8-, 2.1-, or 2.4-fold (e.g., after administration of a composition described herein, such as at least about 2, 4, 8, 12, 24, 48, 72, 96, or 120 hours or about 2-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96, or 96-120 hours or about 8 or 24 hours after administration). In some examples, the methods herein include increasing the blood levels (e.g., blood serum levels) of fola therapeutic protein (e.g. follistatin) for at least about 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days or about 1 hour-2 hours, 2-4 hours, 4-8 hours, 8-12 hours, 12 hours-1 day, 1-2 days, 2-3 days, 3-4 days, 4-5 days, 5-6 days, or 6-7 days or at least about 3 days after administration of an effective dose of an LNP composition described herein. [001108] In some examples, the methods herein include decreasing in the blood levels (e.g., blood serum levels) a muscle protein (e.g., myostatin and/or activin A) by at least about 0.5-, 1-, 1.5-, 2-, 2.5-, 3-, 3.5-, 4-, 4.5-, 5-, 5.5-, 6-, 6.5-, 7-, 7.5-, or 8-fold or about 0.5- to 1-fold, 1- to 1.5-fold, 1.5- to 2-fold, 2- to 2.5-fold, 2.5- to 3-fold, 3- to 3.5-fold, 3.5- to 4-fold, 4- to 4.5- fold, 4.5- to 5-fold, 5- to 5.5-fold, 5.5- to 6-fold, 6- to 6.5-fold, 6.5- to 7-fold, 7- to 7.5-fold, or 7.5- to 8-fold or about 1.8-fold (e.g., after administration of a composition described herein an mRNA polymer complex or a drug delivery system disclosed herein, such as at least about 2, 4, 8, 12, 24, 48, 72, 96, or 120 hours or about 2-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96, or 96-120 hours after administration of a disclosed mRNA polymer complex or drug delivery system, for example, about 0.5 mg/kg thereof). [001109] In some examples, the methods herein include inducing physiological changes in a muscle, such as changes in body fat and/or muscle mass, in a subject, following the administration of an effective amount of an LNP composition described herein. [001110] In some examples, side effects and/or toxicity is assessed. Side effect and toxicity assays are known in the art (see, e.g., Mendell et al., Mol Ther., 23(1):192-201, 2015; Haidet et al., Proc Natl Acad Sci USA, 105(11):4318-22, 2008; Rodina-Klapac et al., Muscle Nerve., 39(3):283-96, 2009). Any assays for side effects and toxicity can be used. Exemplary toxicity assays include measuring molecules associated with toxicity (e.g., toxicity-associated biomarkers), such as molecules associated with liver, kidney, muscle, heart, and/or major organ toxicity, in a subject and comparing the measured values to those expected from a control subject without toxicity. [001111] In some examples, toxicity assays can include liver toxicity assays, such as measuring alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transferase (AST), gamma-glutamyl transferase (GGT), and/or bilirubin levels (see, e.g., Giannini et al., CMAJ, 172(3): 367-379, 2005, incorporated herein by reference). Levels of ALP, ALT, AST, GGT, and bilirubin typically increase under conditions of liver toxicity. In some examples, the methods include administration of an mRNA polymer complex or a drug delivery system disclosed herein without an increase (such as without a statistically significant increase) in ALP, ALT, AST, GGT, and/or bilirubin (e.g., the disclosed mRNA polymer complex or drug delivery system is non-toxic). In other examples, an increase in ALP, ALT, AST, GGT, and/or bilirubin is within clinically acceptable limits. [001112] In some examples, toxicity assays can include kidney toxicity assays, such as measuring blood urea nitrogen (BUN), creatinine levels, urinary proteins with enzymatic activity, proteinuria, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cytokines, clusterin, osteopontin, and/or type IV collagen (see, e.g., Kim and Moon, Biomol Ther (Seoul), 20(3): 268-272, 2012, incorporated herein by reference). Levels of BUN, creatinine, urinary proteins with enzymatic activity, proteinuria, KIM-1, NGAL, cytokines, clusterin, oseopontin, and/or type IV collagen typically increase under conditions of kidney toxicity. In some examples, the methods include administration of an mRNA polymer complex or a drug delivery system disclosed herein without an increase (such as without a statistically significant increase) in BUN, creatinine, urinary proteins with enzymatic activity, proteinuria, KIM-1, NGAL, cytokines, clusterin, oseopontin, and/or type IV collagen (e.g., the disclosed mRNA polymer complex or drug delivery system is non-toxic). In other examples, an increase in BUN, creatinine, urinary proteins with enzymatic activity, proteinuria, KIM-1, NGAL, cytokines, clusterin, oseopontin, and/or type IV collagen is within clinically acceptable limits. [001113] In some examples, toxicity assays can include muscle and/or heart toxicity assays, such as measuring creatine kinase (CK), AST, skeletal troponin I (Tnni1, Tnni2), skeletal troponin T (Tnnt1, Tnnt3), creatinine kinase protein M, parvalbumin (Pvalb), myosin light chain 3 (My13), fatty acid-binding protein 3 (Fabp3), aldolase A (Aldoa), and/or myoglobin, including myoglobinuria (see, e.g., Campion et al., Expert Opin Drug Metab Toxicol, 9(11), doi:10.1517/17425255.2013.827170, 2013, incorporated herein by reference). Levels of CK, AST, Tnni1 (or Tnni2), Tnnt1 (or Tnnt3), creatinine kinase protein M, Pvalb, My13, Fabp3, Aldoa, and/or myoglobin typically increase under conditions of muscle or heart toxicity. In some examples, the methods include administration of an mRNA polymer complex or a drug delivery system disclosed herein without an increase (such as without a statistically significant increase) in CK, AST, Tnni1 (or Tnni2), Tnnt1 (or Tnnt3), creatinine kinase protein M, Pvalb, My13, Fabp3, Aldoa, and/or myoglobin (e.g., the disclosed mRNA polymer complex or drug delivery system is non-toxic). In other examples, an increase in CK, AST, Tnni1 (or Tnni2), Tnnt1 (or Tnnt3), creatinine kinase protein M, Pvalb, My13, Fabp3, Aldoa, and/or myoglobin is within clinically acceptable limits. [001114] In some examples, toxicity assays can include major organ toxicity assays, such as measuring blood protein and/or electrolyte levels (e.g., in whole blood, serum, and/or plasma). In general, changes in electrolyte levels and increases in protein levels are associated with major organ toxicity. In some examples, the methods include administration of an mRNA polymer complex or a drug delivery system disclosed herein without a change in electrolyte levels and/or an increase in protein levels (such as without a statistically significant increase) (e.g., the disclosed mRNA polymer complex or drug delivery system is non-toxic). Other indicia of toxicity (e.g., toxicity-associated biomarkers) are possible (see, e.g., Campion et al., Expert Opin Drug Metab Toxicol, 9(11), doi:10.1517/17425255.2013.827170, 2013; Anadón et al., Chapter 34. Biomarkers of drug toxicity. Biomarkers in Toxicology, 593-607, 2014, both of which are incorporated herein by reference). In other examples, changes in electrolyte levels and/or protein levels is within clinically acceptable limits. [001115] In some examples, inflammation is assessed. Inflammation assays are known in the art. Any inflammation assay can be used. Exemplary inflammation assays include measuring molecules associated with inflammation (e.g., inflammation-associated molecules), such as expression of inflammatory genes, in a subject and comparing the measured values to those expected from a control subject without inflammation. In some examples, inflammation assays include measuring expression of tumor necrosis factor (TNF), interleukin (IL)-6, IL-1b, C- reactive protein (CRP), and/or adenomatous polyposis coli (APC) genes. In some examples, the methods include administration of an mRNA polymer complex or a drug delivery system disclosed herein without a change (such as without a statistically significant change) in TNF, IL- 6, IL-1b, CRP, and/or APC gene expression (e.g., the disclosed mRNA polymer complex or drug delivery system is non-inflammatory). Expression levels of other inflammatory genes can also be assessed (see, e.g., Cooper et al., Genome Biol., 6(1): R5, 2005; Newton and Dixit, Cold Spring Harb Perspect Biol, 4(3):pii: a006049, 2012, both of which are incorporated herein by reference). C. Vaccination methods using LNPs described herein [001116] The compositions described herein may also be used as immunogenic compositions and/or vaccines. For example, an LNP composition described here is capable of delivering an RNA payload that encodes one or more vaccine antigens and/or immunogenic polypeptides to a subject which generate an antigen-specific immune response. [001117] In some embodiments, the antigen-specific immune response is characterized by measuring an anti-viral antigenic polypeptide antibody titer produced in a subject administered an influenza RNA (e.g., mRNA) vaccine as provided herein. An antibody titer is a measurement of the amount of antibodies within a subject, for example, antibodies that are specific to a particular antigen (e.g., an anti-influenza antigenic polypeptide) or epitope of an antigen. Antibody titer is typically expressed as the inverse of the greatest dilution that provides a positive result. Enzyme-linked immunosorbent assay (ELISA) is a common assay for determining antibody titers, for example. [001118] In some embodiments, an antibody titer is used to assess whether a subject has had an infection or to determine whether immunizations are required. In other embodiments an antibody titer is used to assess the effectiveness of a vaccine after administering same to a subject. In some embodiments, an antibody titer is used to determine the strength of an autoimmune response, to determine whether a booster immunization is needed, to determine whether a previous vaccine was effective, and to identify any recent or prior infections. In accordance with the present disclosure, an antibody titer may be used to determine the strength of an immune response induced in a subject by an LNP composition described herein. [001119] In some embodiments, when using the LNP compositions described herein, the anti- antigen antibody titer produced in a subject is increased by at least 1 log relative to a control. For example, anti-antigen antibody titer produced in a subject after having been administered an LNP composition described herein may be increased by at least 1.5, at least 2, at least 2.5, or at least 3 log relative to a control. In some embodiments, the anti-antigen antibody titer produced in the subject is increased by 1, 1.5, 2, 2.5 or 3 log relative to a control. In some embodiments, the anti-antigen antibody titer produced in the subject is increased by 1-3 log relative to a control. For example, the anti-antigen antibody titer produced in a subject may be increased by 1-1.5, 1-2, 1-2.5, 1-3, 1.5-2, 1.5- 2.5, 1.5-3, 2-2.5, 2-3, or 2.5-3 log relative to a control. [001120] In some embodiments, an effective amount of an LNP-based RNA (e.g., mRNA) vaccine disclosed herein is a dose that is reduced compared to the standard of care dose of a recombinant protein vaccine. A “standard of care,” as provided herein, refers to a medical or psychological treatment guideline and can be general or specific. “Standard of care” specifies appropriate treatment based on scientific evidence and collaboration between medical professionals involved in the treatment of a given condition. It is the diagnostic and treatment process that a physician/clinician should follow for a certain type of patient, illness or clinical circumstance. A “standard of care dose,” as provided herein, refers to the dose of a recombinant or purified virus protein vaccine, or a live attenuated or inactivated virus vaccine, that a physician/clinician or other medical professional would administer to a subject to treat or prevent a virus infection, while following the standard of care guideline for treating or preventing influenza, or an influenza-related condition. [001121] In some embodiments, an effective amount of an LNP-based RNA vaccine composition described herein is a dose equivalent to an at least 2-fold reduction in a standard of care dose of a recombinant or purified influenza protein vaccine. For example, an effective amount of an LNP-based RNA vaccine composition described herein may be a dose equivalent to an at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold reduction in a standard of care dose of a recombinant or purified influenza protein vaccine. In some embodiments, an effective amount of an LNP-based RNA vaccine composition described herein is a dose equivalent to an at least at least 100-fold, at least 500-fold, or at least 1000-fold reduction in a standard of care dose of a recombinant or purified influenza protein vaccine. In some embodiments, an effective amount of an LNP-based RNA vaccine composition described herein is a dose equivalent to a 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 20-, 50-, 100-, 250-, 500-, or 1000-fold reduction in a standard of care dose of a recombinant or purified influenza protein vaccine. In some embodiments, an effective amount of an LNP-based RNA vaccine composition described herein is a dose equivalent to a 2-fold to 1000-fold (e.g., 2-fold to 100-fold, 10-fold to 1000-fold) reduction in the standard of care dose of a recombinant or purified influenza protein vaccine. [001122] In some embodiments, the effective amount of an LNP-based RNA vaccine composition described herein is a dose equivalent to a 2 to 1000-, 2 to 900-, 2 to 800-, 2 to 700-, 2 to 600-, 2 to 500-, 2 to 400-, 2 to 300-, 2 to 200-, 2 to 100-, 2 to 90-, 2 to 80-, 2 to 70-, 2 to 60-, 2 to 50-, 2 to 40-, 2 to 30-, 2 to 20-, 2 to 10-, 2 to 9-, 2 to 8-, 2 to 7-, 2 to 6-, 2 to 5-, 2 to 4-, 2 to 3-, 3 to 1000-, 3 to 900-, 3 to 800-, 3 to 700-, 3 to 600-, 3 to 500-, 3 to 400-, 3 to 3 to 00-, 3 to 200-, 3 to 100-, 3 to 90-, 3 to 80-, 3 to 70-, 3 to 60-, 3 to 50-, 3 to 40-, 3 to 30-, 3 to 20-, 3 to 10-, 3 to 9-, 3 to 8-, 3 to 7-, 3 to 6-, 3 to 5-, 3 to 4-, 4 to 1000-, 4 to 900-, 4 to 800-, 4 to 700-, 4 to 600-, 4 to 500-, 4 to 400-, 4 to 4 to 00-, 4 to 200-, 4 to 100-, 4 to 90-, 4 to 80-, 4 to 70-, 4 to 60-, 4 to 50-, 4 to 40-, 4 to 30-, 4 to 20-, 4 to 10-, 4 to 9-, 4 to 8-, 4 to 7-, 4 to 6-, 4 to 5-, 4 to 4-, 5 to 1000-, 5 to 900-, 5 to 800-, 5 to 700-, 5 to 600-, 5 to 500-, 5 to 400-, 5 to 300-, 5 to 200-, 5 to 100-, 5 to 90-, 5 to 80-, 5 to 70-, 5 to 60-, 5 to 50-, 5 to 40-, 5 to 30-, 5 to 20-, 5 to 10-, 5 to 9-, 5 to 8-, 5 to 7-, 5 to 6-, 6 to 1000-, 6 to 900-, 6 to 800-, 6 to 700-, 6 to 600-, 6 to 500-, 6 to 400-, 6 to 300-, 6 to 200-, 6 to 100-, 6 to 90-, 6 to 80-, 6 to 70-, 6 to 60-, 6 to 50-, 6 to 40-, 6 to 30-, 6 to 20-, 6 to 10-, 6 to 9-, 6 to 8-, 6 to 7-, 7 to 1000-, 7 to 900-, 7 to 800-, 7 to 700-, 7 to 600-, 7 to 500-, 7 to 400-, 7 to 300-, 7 to 200-, 7 to 100-, 7 to 90-, 7 to 80-, 7 to 70-, 7 to 60-, 7 to 50-, 7 to 40-, 7 to 30-, 7 to 20-, 7 to 10-, 7 to 9-, 7 to 8-, 8 to 1000-, 8 to 900-, 8 to 800-, 8 to 700-, 8 to 600-, 8 to 500-, 8 to 400-, 8 to 300-, 8 to 200-, 8 to 100-, 8 to 90-, 8 to 80-, 8 to 70-, 8 to 60-, 8 to 50-, 8 to 40-, 8 to 30-, 8 to 20-, 8 to 10-, 8 to 9-, 9 to 1000-, 9 to 900-, 9 to 800-, 9 to 700-, 9 to 600-, 9 to 500-, 9 to 400-, 9 to 300-, 9 to 200-, 9 to 100-, 9 to 90-, 9 to 80-, 9 to 70-, 9 to 60- , 9 to 50-, 9 to 40-, 9 to 30-, 9 to 20-, 9 to 10-, 10 to 1000-, 10 to 900-, 10 to 800-, 10 to 700-, 10 to 600-, 10 to 500-, 10 to 400-, 10 to 300-, 10 to 200-, 10 to 100-, 10 to 90-, 10 to 80-, 10 to 70-, 10 to 60-, 10 to 50-, 10 to 40-, 10 to 30-, 10 to 20-, 20 to 1000-, 20 to 900-, 20 to 800-, 20 to 700-, 20 to 600-, 20 to 500-, 20 to 400-, 20 to 300-, 20 to 200-, 20 to 100-, 20 to 90-, 20 to 80-, 20 to 70-, 20 to 60-, 20 to 50-, 20 to 40-, 20 to 30-, 30 to 1000-, 30 to 900-, 30 to 800-, 30 to 700-, 30 to 600-, 30 to 500-, 30 to 400-, 30 to 300-, 30 to 200-, 30 to 100-, 30 to 90-, 30 to 80-, 30 to 70-, 30 to 60-, 30 to 50- , 30 to 40-, 40 to 1000-, 40 to 900-, 40 to 800-, 40 to 700-, 40 to 600-, 40 to 500-, 40 to 400-, 40 to 300-, 40 to 200-, 40 to 100-, 40 to 90-, 40 to 80-, 40 to 70-, 40 to 60-, 40 to 50-, 50 to 1000-, 50 to 900-, 50 to 800-, 50 to 700-, 50 to 600-, 50 to 500-, 50 to 400-, 50 to 300-, 50 to 200-, 50 to 100-, 50 to 90-, 50 to 80-, 50 to 70-, 50 to 60-, 60 to 1000-, 60 to 900-, 60 to 800-, 60 to 700-, 60 to 600-, 60 to 500-, 60 to 400-, 60 to 300-, 60 to 200-, 60 to 100-, 60 to 90-, 60 to 80-, 60 to 70-, 70 to 1000-, 70 to 900-, 70 to 800-, 70 to 700-, 70 to 600-, 70 to 500-, 70 to 400-, 70 to 300-, 70 to 200-, 70 to 100-, 70 to 90-, 70 to 80-, 80 to 1000-, 80 to 900-, 80 to 800-, 80 to 700-, 80 to 600-, 80 to 500-, 80 to 400-, 80 to 300-, 80 to 200-, 80 to 100-, 80 to 90-, 90 to 1000-, 90 to 900-, 90 to 800-, 90 to 700-, 90 to 600-, 90 to 500-, 90 to 400-, 90 to 300-, 90 to 200-, 90 to 100-, 100 to 1000-, 100 to 900-, 100 to 800-, 100 to 700-, 100 to 600-, 100 to 500-, 100 to 400-, 100 to 300-, 100 to 200-, 200 to 1000-, 200 to 900-, 200 to 800-, 200 to 700-, 200 to 600-, 200 to 500-, 200 to 400-, 200 to 300-, 300 to 1000-, 300 to 900- , 300 to 800-, 300 to 700-, 300 to 600-, 300 to 500-, 300 to 400-, 400 to 1000-, 400 to 900-, 400 to 800-, 400 to 700-, 400 to 600-, 400 to 500-, 500 to 1000-, 500 to 900-, 500 to 800-, 500 to 700-, 500 to 600-, 600 to 1000-, 600 to 900-, 600 to 800-, 600 to 700-, 700 to 1000-, 700 to 900-, 700 to 800-, 800 to 1000-, 800 to 900-, or 900 to 1000-fold reduction in the standard of care dose of a recombinant protein vaccine. [001123] In some embodiments, the effective amount is a dose equivalent to (or equivalent to an at least) 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 20-, 30-, 40-, 50-, 60-, 70-, 80-, 90-, 100-, 110-, 120-, 130-, 140-, 150-, 160-, 170-, 1280-, 190-, 200-, 210-, 220-, 230-, 240-, 250-, 260-, 270-, 280-, 290-, 300-, 310-, 320-, 330-, 340-, 350-, 360-, 370-, 380-, 390-, 400-, 410-, 420-, 430-, 440-, 450-, 4360-, 470-, 480-, 490-, 500-, 510-, 520-, 530-, 540-, 550-, 560-, 5760-, 580-, 590-, 600-, 610-, 620-, 630-, 640-, 650-, 660-, 670-, 680-, 690-, 700-, 710-, 720-, 730-, 740-, 750-, 760-, 770-, 780-, 790-, 800-, 810-, 820-, 830-, 840-, 850-, 860-, 870-, 880-, 890-, 900-, 910-, 920-, 930-, 940-, 950-, 960-, 970-, 980-, 990-, or 1000-fold reduction in the standard of care dose of a recombinant influenza protein vaccine [001124] In some embodiments, the effective amount of an LNP-based RNA vaccine composition described herein is a total dose of 50-1000 μg. In some embodiments, the effective amount of an i LNP-based RNA vaccine composition described herein is a total dose of 50-1000, 50- 900, 50-800, 50-700, 50-600, 50-500, 50-400, 50-300, 50-200, 50-100, 50-90, 50-80, 50-70, 50-60, 60-1000, 60-900, 60-800, 60-700, 60-600, 60-500, 60-400, 60-300, 60-200, 60-100, 60-90, 60-80, 60- 70, 70-1000, 70-900, 70-800, 70-700, 70-600, 70-500, 70-400, 70-300, 70-200, 70-100, 70-90, 70-80, 80-1000, 80-900, 80-800, 80-700, 80-600, 80-500, 80-400, 80-300, 80-200, 80-100, 80-90, 90-1000, 90-900, 90-800, 90-700, 90-600, 90-500, 90-400, 90-300, 90-200, 90-100, 100-1000, 100-900, 100- 800, 100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1000, 200-900, 200-800, 200-700, 200-600, 200-500, 200-400, 200-300, 300-1000, 300-900, 300-800, 300-700, 300-600, 300-500, 300- 400, 400-1000, 400-900, 400-800, 400-700, 400-600, 400-500, 500-1000, 500-900, 500-800, 500- 700, 500-600, 600-1000, 600-900, 600-900, 600-700, 700-1000, 700-900, 700-800, 800-1000, 800- 900, or 900-1000 μg. In some embodiments, the effective amount of an LNP-based RNA vaccine composition described herein is a total dose of 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 μg. In some embodiments, the effective amount is a dose of 25-500 μg administered to the subject a total of two times. In some embodiments, the effective amount of an LNP-based RNA vaccine composition described herein is a dose of 25-500, 25-400, 25-300, 25-200, 25-100, 25-50, 50-500, 50-400, 50-300, 50-200, 50-100, 100-500, 100-400, 100-300, 100-200, 150-500, 150-400, 150-300, 150-200, 200-500, 200-400, 200-300, 250-500, 250- 400, 250-300, 300-500, 300-400, 350-500, 350-400, 400-500 or 450-500 μg administered to the subject a total of two times. In some embodiments, the effective amount of an LNP-based RNA vaccine composition described herein is a total dose of 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 μg administered to the subject a total of two times. [001125] In some embodiments, the antigen specific immune response induced by the LNP- based RNA vaccine composition described herein in a subject is the production of antibodies specific to an expressed antigen. In some embodiments, such antibodies are capable of neutralizing the corresponding virus of the antigen in an infected host. In some embodiments, the antigen specific immune response induced by the LNP-based RNA vaccine composition described herein in a subject is antigen-specific T-cell response. Such T-cell response may provide immunity to the immunized animal (e.g., mice or human) against future infections by the virus of the expressed antigen. [001126] The LNP-based vaccines disclosed herein may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited, to intradermal, intramuscular, and/or subcutaneous administration. The present disclosure provides methods comprising administering RNA vaccines to a subject in need thereof. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. influenza RNA vaccines compositions are typically formulated in dosage unit form for ease of administration and uniformity of dosage. [001127] It will be understood, however, that the total daily usage of influenza RNA vaccines compositions may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. [001128] In some embodiments, the LNP-based vaccines disclosed compositions may be administered at dosage levels sufficient to deliver 0.0001 mg/kg to 100 mg/kg, 0.001 mg/kg to 0.05 mg/kg, 0.005 mg/kg to 0.05 mg/kg, 0.001 mg/kg to 0.005 mg/kg, 0.05 mg/kg to 0.5 mg/kg, 0.01 mg/kg to 50 mg/kg, 0.1 mg/kg to 40 mg/kg, 0.5 mg/kg to 30 mg/kg, 0.01 mg/kg to 10 mg/kg, 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 25 mg/kg, of subject body weight per day, one or more times a day, per week, per month, etc. to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect (see e.g., the range of unit doses described in International Publication No WO2013078199, herein incorporated by reference in its entirety). The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, every four weeks, every 2 months, every three months, every 6 months, etc. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). When multiple administrations are employed, split dosing regimens such as those described herein may be used. In exemplary embodiments, influenza RNA vaccines compositions may be administered at dosage levels sufficient to deliver 0.0005 mg/kg to 0.01 mg/kg, e.g., about 0.0005 mg/kg to about 0.0075 mg/kg, e.g., about 0.0005 mg/kg, about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg or about 0.005 mg/kg. [001129] In some embodiments, the LNP-based vaccine compositions may be administered once or twice (or more) at dosage levels sufficient to deliver 0.025 mg/kg to 0.250 mg/kg, 0.025 mg/kg to 0.500 mg/kg, 0.025 mg/kg to 0.750 mg/kg, or 0.025 mg/kg to 1.0 mg/kg. [001130] In some embodiments, the LNP-based vaccine compositions may be administered twice (e.g., Day 0 and Day 7, Day 0 and Day 14, Day 0 and Day 21, Day 0 and Day 28, Day 0 and Day 60, Day 0 and Day 90, Day 0 and Day 120, Day 0 and Day 150, Day 0 and Day 180, Day 0 and 3 months later, Day 0 and 6 months later, Day 0 and 9 months later, Day 0 and 12 months later, Day 0 and 18 months later, Day 0 and 2 years later, Day 0 and 5 years later, or Day 0 and 10 years later) at a total dose of or at dosage levels sufficient to deliver a total dose of 0.0100 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.100 mg, 0.125 mg, 0.150 mg, 0.175 mg, 0.200 mg, 0.225 mg, 0.250 mg, 0.275 mg, 0.300 mg, 0.325 mg, 0.350 mg, 0.375 mg, 0.400 mg, 0.425 mg, 0.450 mg, 0.475 mg, 0.500 mg, 0.525 mg, 0.550 mg, 0.575 mg, 0.600 mg, 0.625 mg, 0.650 mg, 0.675 mg, 0.700 mg, 0.725 mg, 0.750 mg, 0.775 mg, 0.800 mg, 0.825 mg, 0.850 mg, 0.875 mg, 0.900 mg, 0.925 mg, 0.950 mg, 0.975 mg, or 1.0 mg. Higher and lower dosages and frequency of administration are encompassed by the present disclosure. For example, an influenza RNA vaccine composition may be administered three or four times. [001131] In some embodiments, the LNP-based vaccine compositions may be administered twice (e.g., Day 0 and Day 7, Day 0 and Day 14, Day 0 and Day 21, Day 0 and Day 28, Day 0 and Day 60, Day 0 and Day 90, Day 0 and Day 120, Day 0 and Day 150, Day 0 and Day 180, Day 0 and 3 months later, Day 0 and 6 months later, Day 0 and 9 months later, Day 0 and 12 months later, Day 0 and 18 months later, Day 0 and 2 years later, Day 0 and 5 years later, or Day 0 and 10 years later) at a total dose of or at dosage levels sufficient to deliver a total dose of 0.010 mg, 0.025 mg, 0.100 mg or 0.400 mg. [001132] In some embodiments, the LNP-based vaccines for use in a method of vaccinating a subject is administered to the subject in a single dosage of between 10 μg/kg and 400 μg/kg of the nucleic acid vaccine in an effective amount to vaccinate the subject. In some embodiments the RNA vaccine for use in a method of vaccinating a subject is administered to the subject in a single dosage of between 10 μg and 400 μg of the nucleic acid vaccine in an effective amount to vaccinate the subject. In some embodiments, an influenza RNA (e.g., mRNA) vaccine for use in a method of vaccinating a subject is administered to the subject in a single dosage of 10 μg. In some embodiments, an influenza RNA vaccine for use in a method of vaccinating a subject is administered to the subject in a single dosage of 2 μg. In some embodiments, an influenza RNA vaccine for use in a method of vaccinating a subject is administered to the subject in two dosages of 10 μg. In some embodiments, an influenza RNA vaccine for use in a method of vaccinating a subject is administered the subject two dosages of 2 μg. [001133] An the LNP-based vaccine pharmaceutical compositions described herein can be formulated into a dosage form described herein, such as an intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intradermal, intracardiac, intraperitoneal, and subcutaneous). [001134] The LNP delivery systems described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non- limiting example, the LNP delivery systems disclosed herein may be utilized to treat and/or prevent influenza infection, i.e. diseases and conditions related to influenza virus infection (seasonal and pandemic). [001135] The LNP delivery systems described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non- limiting example, the LNP delivery systems disclosed herein may be utilized to treat and/or prevent coronavirus infection, i.e. diseases and conditions related to coronavirus virus infection (seasonal and pandemic). [001136] The LNP delivery systems described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non- limiting example, the LNP delivery systems disclosed herein may be utilized to treat and/or prevent SARS-CoV-2 infection, i.e. diseases and conditions related to SARS-CoV-2 virus infection (seasonal and pandemic), e.g., Covid-19. D. Treating/preventing infections and/or their associated conditions [001137] In other embodiments, the LNP-based RNA compositions described herein may be used to protect, treat, or cure infections arising from contact with an infectious agent, which can include bacteria, viruses, fungi, protozoa, and parasites. [001138] In one embodiment, provided are the LNP-based RNA compositions described herein and their use for treating or preventing a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial or viral infection, or a symptom thereof, in a subject, by administering an LNP-based RNA composition described herein one or more polynucleotide encoding an anti-microbial polypeptide. The administration may be in combination with an anti-microbial agent (e.g., an anti-bacterial agent), e.g., an anti-microbial polypeptide or a small molecule anti-microbial compound described herein. The anti-microbial agents include, but are not limited to, anti-bacterial agents, anti-viral agents, anti-fungal agents, anti-protozoal agents, anti- parasitic agents, and anti-prion agents. Treating conditions associated with bacterial infections [001139] Diseases, disorders, or conditions which may be associated with bacterial infections which may be treated using the LNP-based RNA compositions described herein include, but are not limited to one or more of the following: abscesses, actinomycosis, acute prostatitis, Aeromonas hydrophila, annual ryegrass toxicity, anthrax, bacillary peliosis, bacteremia, bacterial gastroenteritis, bacterial meningitis, bacterial pneumonia, bacterial vaginosis, bacterium-related cutaneous conditions, bartonellosis, BCG-oma, botryomycosis, botulism, Brazilian purpuric fever, Brodie abscess, brucellosis, Buruli ulcer, campylobacteriosis, caries, Carrion's disease, cat scratch disease, cellulitis, chlamydia infection, cholera, chronic bacterial pro statitis, chronic recurrent multifocal osteomyelitis, clostridial necrotizing enteritis, combined periodontic-endodontic lesions, contagious bovine pleuropneumonia, diphtheria, diphtheritic stomatitis, ehrlichiosis, erysipelas, piglottitis, erysipelas, Fitz-Hugh-urtis syndrome, flea-borne spotted fever, foot rot (infectious pododermatitis), Garre's sclerosing osteomyelitis, Gonorrhea, Granuloma inguinale, human granulocytic anaplasmosis, human monocytotropic ehrlichiosis, hundred days' cough, impetigo, late congenital syphilitic oculopathy, legionellosis, Lemierre's syndrome, leprosy (Hansen's Disease), leptospirosis, listeriosis, Lyme disease, lymphadenitis, melioidosis, meningococcal disease, meningococcal septicaemia, methicillin- resistant Staphylococcus aureus (MRSA) infection, Mycobacterium avium-intracellulare (MAI), mycoplasma pneumonia, necrotizing fasciitis, nocardiosis, noma (cancrum oris or gangrenous stomatitis), omphalitis, orbital cellulitis, osteomyelitis, overwhelming post-splenectomy infection (OPSI), ovine brucellosis, pasteurellosis, periorbital cellulitis, pertussis (whooping cough), plague, pneumococcal pneumonia, Pott disease, proctitis, pseudomonas infection, psittacosis, pyaemia, pyomyositis, Q fever, relapsing fever (typhinia), rheumatic fever, Rocky Mountain spotted fever (RMSF), rickettsiosis, salmonellosis, scarlet fever, sepsis, serratia infection, shigellosis, southern tick- associated rash illness, staphylococcal scalded skin syndrome, streptococcal pharyngitis, swimming pool granuloma, swine brucellosis, syphilis, syphilitic aortitis, tetanus, toxic shock syndrome (TSS), trachoma, trench fever, tropical ulcer, tuberculosis, tularemia, typhoid fever, typhus, urogenital tuberculosis, urinary tract infections, vancomycin-resistant Staphylococcus aureus infection, Waterhouse-Friderichsen syndrome, pseudotuberculosis (Yersinia) disease, and yersiniosis. Treating bacterial pathogens [001140] The LNP-based RNA compositions described herein may be administered to treat infections by bacterial pathogens. [001141] The bacterium described herein can be a Gram-positive bacterium or a Gram-negative bacterium. Bacterial pathogens include, but are not limited to, Acinetobacter baumannii, Bacillus anthracis, Bacillus subtilis, Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, coagulase Negative Staphylococcus, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli, E. coli O157:H7, Enterobacter sp., Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes, Moraxella catarralis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitides, Preteus mirabilis, Proteus sps., Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneri, Shigella sonnei, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum, Vibrio cholerae, and Yersinia pestis. [001142] Bacterial pathogens may also include bacteria that cause resistant bacterial infections, for example, clindamycin-resistant Clostridium difficile, fluoroquinolon-resistant Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Enterococcus faecalis, multidrug-resistant Enterococcus faecium, multidrug-resistance Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and vancomycin-resistant Staphylococcus aureus (VRSA). Co-administered antibiotic combinations [001143] The LNP-based RNA compositions described herein may be co-administered with one or more antibiotics and/or antibacterial agents. Antibacterial Agents [001144] Anti-bacterial agents that may be co-administered with LNP-based RNA compositions include, but are not limited to, aminoglycosides (e.g., amikacin (AMIKIN®), gentamicin (GARAMYCIN®), kanamycin (KANTREX®), neomycin (MYCIFRADIN®), netilmicin (NETROMYCIN®), tobramycin (NEBCIN®), Paromomycin (HUMATIN®)), ansamycins (e.g., geldanamycin, herbimycin), carbacephem (e.g., loracarbef (LORABID®), Carbapenems (e.g., ertapenem (INVANZ®), doripenem (DORIBAX®), imipenem/cilastatin (PRIMAXIN®), meropenem (MERREM®), cephalosporins (first generation) (e.g., cefadroxil (DURICEF®), cefazolin (ANCEF®), cefalotin or cefalothin (KEFLIN®), cefalexin (KEFLEX®), cephalosporins (second generation) (e.g., cefaclor (CECLOR®), cefamandole (MANDOL®), cefoxitin (MEFOXIN®), cefprozil (CEFZIL®), cefuroxime (CEFTIN®, ZINNAT®)), cephalosporins (third generation) (e.g., cefixime (SUPRAX®), cefdinir (OMNICEF®, CEFDIEL®), cefditoren (SPECTRACEF®), cefoperazone (CEFOBID®), cefotaxime (CLAFORAN®), cefpodoxime (VANTIN®), ceftazidime (FORTAZ®), ceftibuten (CEDAX®), ceftizoxime (CEFIZOX®), ceftriaxone (ROCEPHIN®)), cephalosporins (fourth generation) (e.g., cefepime (MAXIPIME®)), cephalosporins (fifth generation) (e.g., ceftobiprole (ZEFTERA®)), glycopeptides (e.g., teicoplanin (TARGOCID®), vancomycin (VANCOCIN®), telavancin (VIBATIV®)), lincosamides (e.g., clindamycin (CLEOCIN®), lincomycin (LINCOCIN®)), lipopeptide (e.g., daptomycin (CUBICIN®)), macrolides (e.g., azithromycin (ZITHROMAX®, SUMAMED®, ZITROCIN®), clarithromycin (BIAXIN®), dirithromycin (DYNABAC®), erythromycin (ERYTHOCIN®, ERYTHROPED®), roxithromycin, troleandomycin (TAO®), telithromycin (KETEK®), spectinomycin (TROBICIN®)), monobactams (e.g., aztreonam (AZACTAM®)), nitrofurans (e.g., furazolidone (FUROXONE®), nitrofurantoin (MACRODANTIN®, MACROBID®)), penicillins (e.g., amoxicillin (NOVAMOX®, AMOXIL®), ampicillin (PRINCIPEN®), azlocillin, carbenicillin (GEOCILLIN®), cloxacillin (TEGOPEN®), dicloxacillin (DYNAPEN®), flucloxacillin (FLOXAPEN®), mezlocillin (MEZLIN®), methicillin (STAPHCILLIN®), nafcillin (UNIPEN®), oxacillin (PROSTAPHLIN®), penicillin G (PENTIDS®), penicillin V (PEN-VEE-K®), piperacillin (PIPRACIL®), temocillin (NEGABAN®), ticarcillin (TICAR®)), penicillin combinations (e.g., amoxicillin/clavulanate (AUGMENTIN®), ampicillin/sulbactam (UNASYN®), piperacillin/tazobactam (ZOSYN®), ticarcillin/clavulanate (TIMENTIN®)), polypeptides (e.g., bacitracin, colistin (COLY-MYCIN-S®), polymyxin B, quinolones (e.g., ciprofloxacin (CIPRO®, CIPROXIN®, CIPROBAY®), enoxacin (PENETREX®), gatifloxacin (TEQUIN®), levofloxacin (LEVAQUIN®), lomefloxacin (MAXAQUIN®), moxifloxacin (AVELOX®), nalidixic acid (NEGGRAM®), norfloxacin (NOROXIN®), ofloxacin (FLOXIN®, OCUFLOX®), trovafloxacin (TROVAN®), grepafloxacin (RAXAR®), sparfloxacin (ZAGAM®), temafloxacin (OMNIFLOX®)), sulfonamides (e.g., mafenide (SULFAMYLON®), sulfonamidochrysoidine (PRONTOSIL®), sulfacetamide (SULAMYD®, BLEPH-10®), sulfadiazine (MICRO-SULFON®), silver sulfadiazine (SILVADENE®), sulfamethizole (THIOSULFIL FORTE®), sulfamethoxazole (GANTANOL®), sulfanilimide, sulfasalazine (AZULFIDINE®), sulfisoxazole (GANTRISIN®), trimethoprim (PROLOPRIM®), TRIMPEX®), trimethoprim- sulfamethoxazole (co-trimoxazole) (TMP-SMX) (BACTRIM®, SEPTRA®)), tetracyclines (e.g., demeclocycline (DECLOMYCIN®), doxycycline (VIBRAMYCIN®), minocycline (MINOCIN®), oxytetracycline (TERRAMYCIN®), tetracycline (SUMYCIN®, ACHROMYCIN® V, STECLIN®)), drugs against mycobacteria (e.g., clofazimine (LAMPRENE®), dapsone (AVLOSULFON®), capreomycin (CAPASTAT®), cycloserine (SEROMYCIN®), ethambutol (MYAMBUTOL®), ethionamide (TRECATOR®), isoniazid (I.N.H.®), pyrazinamide (ALDINAMIDE®), rifampin (RIFADIN®, RIMACTANE®), rifabutin (MYCOBUTIN®), rifapentine (PRIFTIN®), streptomycin), and others (e.g., arsphenamine (SALVARSAN®), chloramphenicol (CHLOROMYCETIN®), fosfomycin (MONUROL®), fusidic acid (FUCIDIN®), linezolid (ZYVOX®), metronidazole (FLAGYL®), mupirocin (BACTROBAN®), platensimycin, quinupristin/dalfopristin (SYNERCID®), rifaximin (XIFAXAN®), thiamphenicol, tigecycline (TIGACYL®), tinidazole (TINDAMAX®, FASIGYN®)). Treating conditions associated with viral infection [001145] In another embodiment, provided are methods for treating or preventing a viral infection and/or a disease, disorder, or condition associated with a viral infection, or a symptom thereof, in a subject, by administering an LNP-based RNA composition to a subject infected with or who is suspected of being infected with a virus. [001146] In various other embodiments, a LNP-based RNA composition may be co- administered with one or more polynucleotides encoding an anti-viral polypeptide, e.g., an LNP-based RNA composition described herein in combination with an anti-viral agent, e.g., an anti-viral polypeptide or a small molecule anti-viral agent described herein. [001147] Diseases, disorders, or conditions associated with viral infections which may be treated using the LNP-based RNA compositions disclosed herein, but are not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, bronchiolitis, pneumonia, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes zoster. Viral infections treatable by the LNP compositions [001148] In another embodiment, provided are methods for treating or preventing a viral infection and/or a disease, disorder, or condition associated with a viral infection, or a symptom thereof, in a subject, by administering an LNP-based RNA composition to a subject infected with or who is suspected of being infected with a virus. The viral pathogen can be any viral infectious agent. [001149] Examples of viral infectious agents include, but are not limited to, adenovirus; Herpes simplex, type 1; Herpes simplex, type 2; encephalitis virus, papillomavirus, Varicella-zoster virus; Epstein-barr virus; Human cytomegalovirus; Human herpesvirus, type 8; Human papillomavirus; BK virus; JC virus; Smallpox; polio virus, Hepatitis B virus; Human bocavirus; Parvovirus B19; Human astrovirus; Norwalk virus; coxsackievirus; hepatitis A virus; poliovirus; rhinovirus; Severe acute respiratory syndrome virus; Hepatitis C virus; yellow fever virus; dengue virus; West Nile virus; Rubella virus; Hepatitis E virus; Human immunodeficiency virus (HIV); Influenza virus, type A or B; Guanarito virus; Junin virus; Lassa virus; Machupo virus; Sabia virus; Crimean-Congo hemorrhagic fever virus; Ebola virus; Marburg virus; Measles virus; Mumps virus; Parainfluenza virus; Respiratory syncytial virus; Human metapneumovirus; Hendra virus; Nipah virus; Rabies virus; Hepatitis D; Rotavirus; Orbivirus; Coltivirus; Hantavirus, Middle East Respiratory Coronavirus; Chikungunya virus or Banna virus. Antiviral agents [001150] Exemplary anti-viral agents include, but are not limited to, abacavir (ZIAGEN®), abacavir/lamivudine/zidovudine (Trizivir®), aciclovir or acyclovir (CYCLOVIR®, HERPEX®, ACIVIR®, ACIVIRAX®, ZOVIRAX®, ZOVIR®), adefovir (Preveon®, Hepsera®), amantadine (SYMMETREL®), amprenavir (AGENERASE®), ampligen, arbidol, atazanavir (REYATAZ®), boceprevir, cidofovir, darunavir (PREZISTA®), delavirdine (RESCRIPTOR®), didanosine (VIDEX®), docosanol (ABREVA®), edoxudine, efavirenz (SUSTIVA®, STOCRIN®), emtricitabine (EMTRIVA®), emtricitabine/tenofovir/efavirenz (ATRIPLA®), enfuvirtide (FUZEON®), entecavir (BARACLUDE®, ENNAVIR®), famciclovir (FAMVIR®), fomivirsen (VITRAVENE®), fosamprenavir (LEXIVA®, TELZIR®), foscarnet (FOSCAVIR®), fosfonet, ganciclovir (CYTOVENE®, CYMEVENE®, VITRASERT®), GS 9137 (ELVITEGRAVIR®), imiquimod (ALDARA®, ZYCLARA®, BESELNA®), indinavir (CRIXIVAN®), inosine, inosine pranobex (IMUNOVIR®), interferon type I, interferon type II, interferon type III, kutapressin (NEXAVIR®), lamivudine (ZEFFIX®, HEPTOVIR®, EPIVIR®), lamivudine/zidovudine (COMBIVIR®), lopinavir, loviride, maraviroc (SELZENTRY®, CELSENTRI®), methisazone, MK-2048, moroxydine, nelfinavir (VIRACEPT®), nevirapine (VIRAMUNE®), oseltamivir (TAMIFLU®), peginterferon alfa-2a (PEGASYS®), penciclovir (DENAVIR®), peramivir, pleconaril, podophyllotoxin (CONDYLOX®), raltegravir (ISENTRESS®), ribavirin (COPEGUs®, REBETOL®, RIBASPHERE®, VILONA® AND VIRAZOLE®), rimantadine (FLUMADINE®), ritonavir (NORVIR®), pyramidine, saquinavir (INVIRASE®, FORTOVASE®), stavudine, tea tree oil (melaleuca oil), tenofovir (VIREAD®), tenofovir/emtricitabine (TRUVADA®), tipranavir (APTIVUS®), trifluridine (VIROPTIC®), tromantadine (VIRU-MERZ®), valaciclovir (VALTREX®), valganciclovir (VALCYTE®), vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (RELENZA®), and zidovudine (azidothymidine (AZT), RETROVIR®, RETROVIS®). Conditions Associated with Fungal Infections [001151] Diseases, disorders, or conditions associated with fungal infections which may be treated using the LNP-based RNA compositions described herein include, but are not limited to, aspergilloses, blastomycosis, candidasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mycetomas, paracoccidioidomycosis, and tinea pedis. Furthermore, persons with immuno-deficiencies are particularly susceptible to disease by fungal genera such as Aspergillus, Candida, Cryptoccocus, Histoplasma, and Pneumocystis. Other fungi can attack eyes, nails, hair, and especially skin, the so- called dermatophytic fungi and keratinophilic fungi, and cause a variety of conditions, of which ringworms such as athlete's foot are common. Fungal spores are also a major cause of allergies, and a wide range of fungi from different taxonomic groups can evoke allergic reactions in some people. Fungal pathogens [001152] Fungal pathogens include, but are not limited to, Ascomycota (e.g., Fusarium oxysporum, Pneumocystis jirovecii, Aspergillus spp., Coccidioides immitis/posadasii, Candida albicans), Basidiomycota (e.g., Filobasidiella neoformans, Trichosporon), Microsporidia (e.g., Encephalitozoon cuniculi, Enterocytozoon bieneusi), and Mucoromycotina (e.g., Mucor circinelloides, Rhizopus oryzae, Lichtheimia corymbifera). Anti fungal agents [001153] The LNP-based RNA compositions described herein may be co-administered with one or more anti-fungal agents. [001154] Exemplary anti-fungal agents include, but are not limited to, polyene antifungals (e.g., natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF, CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), sulconazole, tioconazole), triazole antifungals (e.g., albaconazole fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole), thiazole antifungals (e.g., abafungin), allylamines (e.g., terbinafine (LAMISIL®), naftifine (NAFTIN®), butenafine (LOTRIMIN® Ultra)), echinocandins (e.g., anidulafungin, caspofungin, micafungin), and others (e.g., polygodial, benzoic acid, ciclopirox, tolnaftate (TINACTIN®, DESENEX®, AFTATE®), undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, sodium bicarbonate, allicin). Conditions associated with protozoal infection [001155] Diseases, disorders, or conditions associated with protozoal infections which may be treated using the LNP-based RNA compositions of the disclosure include, but are not limited to, amoebiasis, giardiasis, trichomoniasis, African Sleeping Sickness, American Sleeping Sickness, leishmaniasis (Kala-Azar), balantidiasis, toxoplasmosis, malaria, acanthamoeba keratitis, and babesiosis. Protozoan Pathogens [001156] Protozoal pathogens include, but are not limited to, Entamoeba histolytica, Giardia lambila, Trichomonas vaginalis, Trypanosoma brucei, T. cruzi, Leishmania donovani, Balantidium coli, Toxoplasma gondii, Plasmodium spp., and Babesia microti. These protozoal pathogens may be treatable with the LNP-based RNA compositions. Anti-Protozoan Agents [001157] Exemplary anti-protozoal agents include, but are not limited to, eflornithine, furazolidone (FUROXONE®, DEPENDAL-M®), melarsoprol, metronidazole (FLAGYL®), ornidazole, paromomycin sulfate (HUMATIN®), pentamidine, pyrimethamine (DARAPRIM®), and tinidazole (TINDAMAX®, FASIGYN®). Conditions associated with parasitic infection [001158] Diseases, disorders, or conditions associated with parasitic infections which may be treated using the LNP-based RNA compositions of the disclosure include, but are not limited to, acanthamoeba keratitis, amoebiasis, ascariasis, babesiosis, balantidiasis, baylisascariasis, chagas disease, clonorchiasis, cochliomyia, cryptosporidiosis, diphyllobothriasis, dracunculiasis, echinococcosis, elephantiasis, enterobiasis, fascioliasis, fasciolopsiasis, filariasis, giardiasis, gnathostomiasis, hymenolepiasis, isosporiasis, katayama fever, leishmaniasis, lyme disease, malaria, metagonimiasis, myiasis, onchocerciasis, pediculosis, scabies, schistosomiasis, sleeping sickness, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis, and trichuriasis. Parasitic Pathogens [001159] Parasitic pathogens include, but are not limited to, Acanthamoeba, Anisakis, Ascaris lumbricoides, botfly, Balantidium coli, bedbug, Cestoda, chiggers, Cochliomyia hominivorax, Entamoeba histolytica, Fasciola hepatica, Giardia lamblia, hookworm, Leishmania, Linguatula serrata, liver fluke, Loa boa, Paragonimus, pinworm, Plasmodium falciparum, Schistosoma, Strongyloides stercoralis, mite, tapeworm, Toxoplasma gondii, Trypanosoma, whipworm, Wuchereria bancrofti. Anti-Parasitic Agents [001160] Exemplary anti-parasitic agents include, but are not limited to, antinematodes (e.g., mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin), anticestodes (e.g., niclosamide, praziquantel, albendazole), antitrematodes (e.g., praziquantel), antiamoebics (e.g., rifampin, amphotericin B), and antiprotozoals (e.g., melarsoprol, eflornithine, metronidazole, tinidazole). E. Cancer [001161] In various embodiments, the LNP-based RNA therapeutics and pharmaceutical compositions thereof described herein may be used to treat cancer. [001162] A “cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and may also metastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” may include a tumor. Examples of cancers that may be treated by the methods disclosed herein include, but are not limited to, cancers of the immune system including lymphoma, leukemia, myeloma, and other leukocyte malignancies. In some embodiments, the methods disclosed herein may be used to reduce the tumor size of a tumor derived from, for example, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, squamous cell cancer, T cell lymphoma, environmentally induced cancers including those induced by asbestos, other B cell malignancies, and combinations of said cancers. In some embodiments, the methods disclosed herein may be used to reduce the tumor size of a tumor derived from, for example, sarcomas and carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, Kaposi's sarcoma, sarcoma of soft tissue, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, hepatocellular carcinomna, lung cancer, colorectal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (for example adenocarcinoma of the pancreas, colon, ovary, lung, breast, stomach, prostate, cervix, or esophagus), sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumor, cervical cancer, testicular tumor, bladder carcinoma, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, carcinoma of the renal pelvis, CNS tumors (such as a glioma, astrocytoma, medulloblastoma, craniopharyogioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma and retinoblastoma). The particular cancer may be responsive to chemo- or radiation therapy or the cancer may be refractory. A refractor cancer refers to a cancer that is not amendable to surgical intervention and the cancer is either initially unresponsive to chemo- or radiation therapy or the cancer becomes unresponsive over time. F. Co-therapy with another therapeutic agent [001163] In other embodiments, LNP-based RNA therapeutics and pharmaceutical compositions thereof described herein may be co-administered in conjunction with another agent for treating a disease (e.g., muscle atrophy and/or muscle-wasting disease, disease of the CNS, or cancer). Such additional agents are as follows: agents that treat conditions related to acute or chronic muscle atrophy and/or a muscle-wasting disease, such as sarcopenia, cachexia (e.g., megestrol, Megace®, Megace ES®, somatropin, Serostim®, and Norditropin FlexPro Pen®), cancer (e.g., carboplatin, Adriamycin®, Adrucil®, etoposide, fluorouracil, doxorubicin, Paraplatin®, Cosmegen®, cyclophosphamide, Ethyol®, Leukeran®, Vincasar PFS®, vincristine, Etopophos®, Oncovin®, Toposar®, Hycamtin®, Ifex®, ifosfamide, Mustargen®, Velban®, VePesid®, vinblastine, amifostine, chlorambucil, dactinomycin, mechlorethamine, Tepadina®, thiotepa, topotecan, and fludarabine), congestive heart failure (e.g., Furosemide®, Lasix®, carvedilol, Coreg®, spironolactone, Lisinopril®, digoxin, Metoprolol Succinate ER®, Aldactone®, Accupril®, metoprolol, isosorbide mononitrate, Coumadin®, Cardizem®, warfarin, Altace®, amlodipine, Lanoxin®, Norvasc®, Toprol-XL®, Nitrostat®, Diovan®, Prinivil®, Zestril®, diltiazem, hydralazine, nitroglycerin, Ramipril®, Apresoline®, bisoprolol, enalapril, torsemide, Vasotec®, isosorbide dinitrate, Lotensin®, allopurinol, Atacand®, Coreg®, valsartan, benazepril, Cardizem CD®, Cartia XT®, Digox®, Entresto®, Qbrelis®, quinapril, Cardizem LA®, CaroSpir®, Demadex®, Digitek®, Dilacor®, Dilt-XR®, Diltia XT®, Diltzac®, eplerenone, Jantoven®, Matzim LA®, nifedipine, Nitrolingual Pumpspray®, NitroQuick®, Taztia XT®, Tiadylt ER®, Tiazac®, candesartan, captopril, Clinacort®, dobutamine, hydrochlorothiazide/lisinopril, Isordil, Kenalog-40®, Lanoxicaps®, milrinone, Minitran®, Monoket®, Nitrek®, Nitro-Bid®, Nitro-Dur®, Nitro-Time®, Nitrocot®, Nitrol Appli-Kit®, NitroMist®, Nitro TD Patch-A®, Prexxartan®, Transderm-Nitro®, triamcinolone, amiloride, BiDil®, Capoten®, Corlanor®, Dobutrex®, hydrochlorothiazide/spironolactone, Inspra®, ivabradine, Midamor®, Minipress®, perindopril, prazosin, Prinzide®, sacubitril/valsartan, trandolapril, Zestoretic®, Aceon®, Aldactazide®, amiloride/hydrochlorothiazide, Capozide®, Capozide®, Capozide 25/25®, Capozide 50/15®, Capozide 50/25®, captopril/hydrochlorothiazide, Cardene®, Cardene IV®, Cardene SR®, Dilatrate-SR®, enalapril/hydrochlorothiazide, fosinopril, hydralazine/isosorbide dinitrate, Isochron®, IsoDitrate®, Isordil Titradose®, Mavik®, Moduretic 5- 50®, moexipril, Monopril®, Natrecor®, nesiritide, nicardipine, Nipride RTU®, Nitropress®, nitroprusside, Primacor®, Univasc®, and Vaseretic®), renal failure (e.g., furosemide, Lasix®, Demadex®, Edecrin®, torsemide, Sodium Edecrin®, and ethacrynic acid), chronic obstructive pulmonary disease (e.g., Symbicort®, prednisone, montelukast, Breo Ellipta®, Daliresp®, Anoro Ellipta®, budesonide/formoterol, Tudorza Pressair®, Rayos®, aclidinium, fluticasone/vilanterol, Incruse Ellipta®, umeclidinium/vilanterol, roflumilast, Stiolto Respimat®, guaifenesin/theophylline, levalbuterol, olodaterol/tiotropium, dyphylline, olodaterol, Striverdi Respimat®, umeclidinium, Xopenex HFA®, Xopenex®, fluticasone/umeclidinium/vilanterol, Trelegy Ellipta®, and Xopenex Concentrate®), severe burns (e.g., silver sulfadiazine, Silvadene®, lidocaine, Xylocaine Jelly®, Bactine®, Dermoplast®, AneCream®, Solarcaine Burn Relief®, Albuminar-25®, Aloe Vera Burn Relief Spray with Lidocaine®, Lidocream®, Nupercainal®, SSD®, Xylocaine Topical®, Garamycin®, Thermazene®, Albutein®, AneCream with Tegaderm®, benzocaine, CidalEaze®, DermacinRx Lido V Pak®, Eha Lotion®, LidaMantle®, Lidopac®, Lidopin®, LidoRx®, LidoRxKit®, Lidotrans®, Lidovex®, Lidozion®, Lidozol®, Medi-Quik Spray®, RadiaGuard®, Regenecare HA Spray®, Senatec®, Sulfamylon®, Topicaine®, Vancocin®, Bionect®, gentamicin, vancomycin, mafenide, albumin human, dibucaine, Flexbumin®, Human Albumin Grifols®, Nebcin®, sodium hyaluronate, Tobi®, Tobramycin®, Vancocin HCl®, Vancocin HCl Pulvules®, Albuminar-5®, Albuminar-20®, SSD AF®, Albuked®, Albuked 5®, Albuked 25®, Albumin-ZLB®, Alburx®, Buminate®, Hylira®, IPM Wound®, Kedbumin®, Plasbumin®, Plasbumin-5®, Plasbumin-25®, RadiaPlex®, Solarcaine First Aid Medicated Spray®, and Xclair®), an inflammatory muscle disease, myasthenia gravis (e.g., Mestinon®, pyridostigmine, Mestinon Timespan®, azathioprine, mycophenolate mofetil, Prostigmin®, neostigmine, Prostigmin Bromide®, Regonol®, immune globulin intravenous, Soliris®, ephedrine, and eculizumab), neuropathy, polio (e.g., amantadine), multiple sclerosis (e.g., Copaxone®, Gilenya®, Ampyra®, Tysabri®, Tecfidera®, Aubagio®, Rebif®, Avonex®, Betaseron®, Decadron®, Prednisone®, Avonex Pen®, glatiramer, interferon beta-1a, fingolimod, dalfampridine, Novantrone®, dimethyl fumarate, teriflunomide, Acthar®, dexamethasone, Extavia®, natalizumab, Imuran®, Dexamethasone Intensol®, interferon beta-1b, prednisolone, Plegridy®, Prelone®, Rebif Rebidose®, valacyclovir, azathioprine, Lemtrada®, ocrelizumab, alemtuzumab, corticotropin, cyclophosphamide, Glatopa®, H.P. Acthar Gel®, mitoxantrone, peginterferon beta-1a, Azasan®, cladribine, daclizumab, De-Sone LA®, Dexpak Taperpak®, Millipred®, Millipred DP®, mycophenolate mofetil, Ocrevus®, Orapred®, PediaPred®, Veripred 20®, and Zinbryta®), anorexia nervosa (e.g., olanzapine and cyproheptadine), human immunodeficiency virus/acquired immune deficiency syndrome (e.g., non-nucleoside reverse transcriptase inhibitors, nucleoside analog reverse transcriptase inhibitors, and protease inhibitors), osteomalacia (e.g., vitamin D2, Drisdol®, ergocalciferol, Calciferol®, Calcidol®, Posture®, Ridactate®, calcium lactate, and calcium phosphate, tribasic), herniated disk, hypercalcemia, kwashiorkor, Creutzfeldt-Jakob disease or bovine spongiform encephalopathy (e.g., methylene blue, cefotaxime, and Claforan®), diabetes (e.g., Tresiba®, insulin degludec, insulin aspart/insulin degludec, and Ryzodeg 70/30®), amyotrophic lateral sclerosis (e.g., Rilutek®, riluzole, edaravone, and Radicava®), necrotizing vasculitis, abetalipoproteinemia, malabsorption syndrome, Legg-Calvé- Perthes disease, polymyositis (e.g., prednisone), Guillain-Barre syndrome, osteoarthritis (e.g., paracetamol, nonsteroidal anti-inflammatory drugs, antacid, COX-2 selective inhibitors, and glucocorticoids), and/or muscular dystrophy (e.g., deflazacort, eteplirsen, Emflaza®, Exondys 51®, mexiletine, phenytoin, procainamide, and nusinersen), such as Duchenne, Becker congenital, distal, myotonic, oculopharyngeal, Limb-Girdle, facioscapulohumeral, and/or Emery-Dreifuss muscular dystrophy. [001164] In other embodiments, the LNP-based RNA therapeutics and pharmaceutical compositions thereof described herein may be co-administered with a co-stimulatory molecule in order to achieve an immune response. An “immune response” refers to the action of a cell of the immune system (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including Abs, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from a vertebrate's body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues. [001165] A “costimulatory signal,” as used herein, refers to a signal, which in combination with a primary signal, such as TCR/CD3 ligation, leads to a T cell response, such as, but not limited to, proliferation and/or upregulation or down regulation of key molecules. [001166] A “costimulatory ligand,” as used herein, includes a molecule on an antigen presenting cell that specifically binds a cognate co-stimulatory molecule on a T cell. Binding of the costimulatory ligand provides a signal that mediates a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A costimulatory ligand induces a signal that is in addition to the primary signal provided by a stimulatory molecule, for instance, by binding of a T cell receptor (TCR)/CD3 complex with a major histocompatibility complex (MHC) molecule loaded with peptide. A co-stimulatory ligand may include, but is not limited to, 3/TR6, 4-IBB ligand, agonist or antibody that binds Toll ligand receptor, B7-1 (CD80), B7-2 (CD86), CD30 ligand, CD40, CD7, CD70, CD83, herpes virus entry mediator (HVEM), human leukocyte antigen G (HLA-G), ILT4, immunoglobulin-like transcript (ILT) 3, inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), ligand that specifically binds with B7-H3, lymphotoxin beta receptor, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), 0X40 ligand, PD-L2, or programmed death (PD) LI. A co-stimulatory ligand includes, without limitation, an antibody that specifically binds with a co-stimulatory molecule present on a T cell, such as, but not limited to, 4-1BB, B7-H3, CD2, CD27, CD28, CD30, CD40, CD7, ICOS, ligand that specifically binds with CD83, lymphocyte function-associated antigen-1 (LFA-1), natural killer cell receptor C (NKG2C), OX40, PD-1, or tumor necrosis factor superfamily member 14 (TNFSF14 or LIGHT). [001167] A “costimulatory molecule” is a cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules include, but are not limited to, A “costimulatory molecule” is a cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules include, but are not limited to, 4-1BB/CD137, B7- H3, BAFFR, BLAME (SLAMF8), BTLA, CD 33, CD 45, CD100 (SEMA4D), CD103, CD134, CD137, CD154, CD16, CD160 (BY55), CD 18, CD19, CD19a, CD2, CD22, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 (alpha; beta; delta; epsilon; gamma; zeta), CD30, CD37, CD4, CD4, CD40, CD49a, CD49D, CD49f, CD5, CD64, CD69, CD7, CD80, CD83 ligand, CD84, CD86, CD8alpha, CD8beta, CD9, CD96 (Tactile), CD1-1a, CD1-1b, CD1-1c, CD1-1d, CDS, CEACAM1, CRT AM, DAP-10, DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, ICOS, Ig alpha (CD79a), IL2R beta, IL2R gamma, IL7R alpha, integrin, ITGA4, ITGA4, ITGA6, IT GAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, LFA-1, LIGHT, LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), LTBR, Ly9 (CD229), lymphocyte function-associated antigen-1 (LFA-1 (CD1 la/CD18), MHC class I molecule, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), 0X40, PAG/Cbp, PD-1, PSGL1, SELPLG (CD162), signaling lymphocytic activation molecule, SLAM (SLAMF1; CD150; IPO-3), SLAMF4 (CD244; 2B4), SLAMF6 (NTB-A; Ly108), SLAMF7, SLP-76, TNF, TNFr, TNFR2, Toll ligand receptor, TRANCE/RANKL, VLA1, or VLA-6, or fragments, truncations, or combinations thereof. DEFINITIONS [001168] For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [001169] As used herein, the following terms and phrases are intended to have the following meanings: A / an [001170] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. About [001171] As used herein, the term “about” means acceptable variations within 20%, within 10% and within 5% of the stated value. In certain embodiments, "about" can mean a variation of +/- 1%, 2%, 3%, 4%, 5%, 10% or 20%. Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [001172] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. [001173] It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects. Adjuvant [001174] As used herein, “adjuvant” means an agent that does not constitute a specific antigen, but modifies (Th1/Th2), boosts the strength and longevity of an immune response, and/or broadens the immune response to a concomitantly administered antigen. Administration [001175] The term “administration” or “administering” as used herein includes all means of introducing the compounds or the pharmaceutical compositions to the subject in need thereof, including but not limited to, oral, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal and the like. Administration of the compound or the composition is suitably parenteral. For example, the compounds or the composition can be preferentially administered intravenously, but can also be administered intraperitoneally or via inhalation like is currently used in the clinic for liposomal amikacin in the treatment of mycobacterium avium (see Shirley et al., Amikacin Liposome Inhalation Suspension: A Review in Mycobacterium avium Complex Lung Disease. Drugs.2019 Apr; 79(5):555-562). Aliphatic [001176] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule or multiple points of attachment to the rest of the molecule, as would be readily apparent to a person of ordinary skill in the art based on the context of the described molecule. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic, bicyclic, or polycyclic C3-C14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Exemplary aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Examples of bicyclic and polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls. Alkenyl [001177] As used herein, “alkenyl” means a straight chain, cyclic or branched aliphatic hydrocarbon having the specified number of carbon atoms and one or more double bonds including but not limited to diene, triene and tetraene unsaturated aliphatic hydrocarbons. The terms "alkenyl" and "alkynyl", refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. In one embodiment, the alkenyl contains one double bond. In another embodiment, the alkenyl contains two double bonds. In another embodiment, the alkenyl contains three double bonds. Alkenylenyl [001178] The term "alkenylenyl" as used herein refers to a divalent radical of an alkenyl group. In one embodiment, the alkenylenyl is a divalent form of a C_2-12 alkenyl, i.e., a C₂-C₁₂ alkenylenyl. In one embodiment, the alkenylenyl is a divalent form of a C_2-6 alkenyl, i.e., a C₂-C₁₀ alkenylenyl. In one embodiment, the alkenylenyl is a divalent form of a C2-14 alkenyl, i.e., a C2-C8 alkenylenyl. In one embodiment, the alkylenyl is a divalent form of an unsubstituted C2-6 alkenyl, i.e., a C2-C6 alkenylenyl. In another embodiment, the alkylenyl is a divalent form of an unsubstituted C2-4 alkyl, i.e., a C₂-C₄ alkenylenyl. Nonlimiting exemplary alkenylenyl groups include CH=CH-, CH₂CH=CH-, CH₂CH₂CH=CHCH₂-, and CH₂CH=CHCH₂CH=CHCH₂CH₂-. Alkoxyl [001179] The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. Aroxy can be represented by –O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined below. The alkoxy and aroxy groups can be substituted as described above for alkyl. Alkyl [001180] As used herein, “alkyl” means a straight chain, cyclic or branched saturated aliphatic hydrocarbon having the specified number of carbon atoms. Alkylenyl [001181] The term "alkylenyl" as used herein refers to a divalent radical of a straight-chain or branched-chain alkyl group. In one embodiment, the alkylenyl is a divalent form of a C1-12 alkyl, i.e., a C1-C12 alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C2-6 alkyl, i.e., a C1-C10 alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C_2-14 alkyl, i.e., a C₁-C₈ alkylenyl. In one embodiment, the alkylenyl is a divalent form of an unsubstituted C_1-6 alkyl, i.e., a C₁-C₆ alkylenyl. In another embodiment, the alkylenyl is a divalent form of an unsubstituted C_1-4 alkyl, i.e., a C₁-C₄ alkylenyl. Nonlimiting exemplary alkylenyl groups include CH₂-, CH₂CH₂-, CH₂CH₂CH₂-, CH₂CH(CH3)CH₂-, -CH₂(CH₂)2CH₂-, CH(CH₂)3CH₂-, and CH₂(CH₂)4CH₂-. The term "alkylenyl" may be used interchangeably with the term “alkylene.” Alkylthio [001182] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In some embodiments, the "alkylthio" moiety is represented by one of -S- alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, and ethylthio. The term "alkylthio" also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. "Arylthio" refers to aryl or heteroaryl groups. Alkylthio groups can be substituted as defined above for alkyl groups. Aralkyl [001183] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). Aryl [001184] "Aryl", as used herein, refers to C5-C10-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems. Broadly defined, "aryl", as used herein, includes 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF₃, -CN; and combinations thereof. [001185] The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined above for "aryl". Analogs [001186] As used herein, “analogs” is meant to include polypeptide variants which differ by one or more amino acid alterations, for example, substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting polypeptide. Antibodies [001187] As used herein, the term "antibody" is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., "functional"). Antibodies are primarily amino-acid based molecules but may also comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.). Non-limiting examples of antibodies or fragments thereof include VH and VL domains, scFvs, Fab, Fab', F(ab')2, Fv fragment, diabodies, linear antibodies, single chain antibody molecules, multispecific antibodies, bispecific antibodies, intrabodies, monoclonal antibodies, polyclonal antibodies, humanized antibodies, codon-optimized antibodies, tandem scFv antibodies, bispecific T-cell engagers, mAb2 antibodies, chimeric antigen receptors (CAR), tetravalent bispecific antibodies, biosynthetic antibodies, native antibodies, miniaturized antibodies, unibodies, maxibodies, antibodies to senescent cells, antibodies to conformers, antibodies to disease specific epitopes, or antibodies to innate defense molecules. Antigen [001188] As defined herein, the term “antigen” or “antibody generator” (“Ag”) refers to a composition, for example, a substance or agent which causes an immune response in an organism, e.g., causes the immune response of the organism to produce antibodies against the substance or agent, in particular, which provokes an adaptive immune response in an organism. Antigens can be any immunogenic substance including, in particular, proteins, polypeptides, polysaccharides, nucleic acids, lipids and the like. Exemplary antigens are derived from infectious agents. Such agents can include parts or subunits of infectious agents, for example, coats, coat components, e.g., coat protein or polypeptides, surface components, e.g., surface proteins or polypeptides, capsule components, cell wall components, flagella, fimbrae, and/or toxins or toxoids) of infectious agents, for example, bacteria, viruses, and other microorganisms. Certain antigens, for example, lipids and/or nucleic acids are antigenic, preferably, when combined with proteins and/or polysaccharides. Approximately [001189] As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Associated with [001190] As used herein, the terms “associated with,” “conjugated,” “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization based connectivity sufficiently stable such that the “associated” entities remain physically associated. Associated [001191] As used herein, the terms "associated with," "conjugated," "linked," "attached," and "tethered," when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An "association" need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization based connectivity sufficiently stable such that the "associated" entities remain physically associated. Bicyclic Ring [001192] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [001193] Exemplary bridged bicyclics include:

Biologically active [001194] As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, a polynucleotide of the present disclosure may be considered biologically active if even a portion of the polynucleotides is biologically active or mimics an activity considered biologically relevant. Binding domain [001195] By "binding domain" it is meant a protein domain that is able to bind non-covalently to another molecule. A binding domain can bind to, for example, a DNA molecule (a DNA-binding domain), an RNA molecule (an RNA-binding domain) and/or a protein molecule (a protein-binding domain). In the case of a protein having a protein-binding domain, it can in some cases bind to itself (to form homodimers, homotrimers, etc.) and/or it can bind to one or more regions of a different protein or proteins. Bulge [001196] As used herein, the term “bulge” refers to a small region of unpaired base(s) that interrupts a “stem” of base-paired nucleotides. The bulge may comprise one or two single-stranded or unbase-paired nucleotides joined at both ends by base-paired nucleotides of the stem. The bulge can be symmetrical (viz., the two unbase-paired single-stranded regions have the same number of nucleotides), or asymmetrical (viz., the unbase-paired single stranded region(s) have different or unequal numbers of nucleotides), or there is only one unbase-paired nucleotide on one strand. A bulge can be described as A/B (such as a “2/2 bulge,” or a “1/0 bulge”) wherein A represents the number of unpaired nucleotides on the upstream strand of the stem, and B represents the number of unpaired nucleotides on the downstream strand of the stem. An upstream strand of a bulge is more 5’ to a downstream strand of the bulge in the primary nucleotide sequence. CARs [001197] As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificial chimeric protein comprising at least one antigen specific targeting region (ASTR), a transmembrane domain and an intracellular signaling domain, wherein the antigen specific targeting region comprises a full-length antibody or a fragment thereof. Any molecule that is capable of binding a target antigen with high affinity can be used in the ASTR of a CAR. The CAR may optionally have an extracellular spacer domain and/or a co-stimulatory domain. A CAR may also be used to generate a cytotoxic cell carrying the CAR. Carbocycle [001198] The term "carbocycle," as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon. Carbonyl [001199] The term "carbonyl" is art-recognized and includes such moieties as can be represented by the general formula: [001200] wherein X is a bond or represents an oxygen or a sulfur, and R11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl, R'11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl. Where X is an oxygen and R11 or R'11 is not hydrogen, the formula represents an "ester". Where X is an oxygen and R11 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R₁₁ is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen and R'₁₁ is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. Where X is a sulfur and R11 or R'11 is not hydrogen, the formula represents a "thioester." Where X is a sulfur and R11 is hydrogen, the formula represents a "thiocarboxylic acid." Where X is a sulfur and R'11 is hydrogen, the formula represents a "thioformate." On the other hand, where X is a bond, and R₁₁ is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R₁₁ is hydrogen, the above formula represents an "aldehyde" group. Cargo or payload [001201] As used herein, the term "cargo" or "payload" can refer to one or more molecules or structures encompassed in a delivery vehicle for delivery to or into a cell or tissue. Non-limiting examples of cargo can include a nucleic acid (e.g., mRNA, such as a linear or a circular mRNA), a polypeptide, a peptide, a protein, a liposome, a label, a tag, a small chemical molecule, a large biological molecule, and any combinations thereof. Cationic lipid [001202] As used herein, “cationic lipid” refers to any of a number of lipid species which carry a net positive charge at a selective pH, such as physiological pH. cDNA [001203] As used herein, the term “cDNA” refers to a strand of DNA copied from an RNA template, e.g., by a reverse transcriptase. Circular RNA [001204] As used herein, the terms "circular RNA" or "circRNA" or “oRNA” equivalently refer to a RNA that forms a circular structure through covalent or non-covalent bonds. Co-administration [001205] As used herein the term “co-administration” or “co-administering” refers to administration of the LNP adjuvant and an agonist or antigen concurrently, i.e., simultaneously in time, or sequentially, i.e., administration of an LNP adjuvant, followed by administration of the agonist or antigen. That is, after administration of the LNP adjuvant, the agonist or antigen can be administered substantially immediately after the LNP adjuvant or the agonist or antigen can be administered after an effective time period after the LNP adjuvant; the effective time period is the amount of time given for realization of maximum benefit from the administration of the LNP adjuvant. An effective time period can be determined experimentally and can be generally within 1, 2, 3, 5, 10, 15, 20, 25, 30, 45 or 60 minutes. Complementary [001206] As used herein, the term "complementary" refers to the ability of polynucleotides to form base pairs with one another. Base pairs are typically formed by hydrogen bonds between nucleotide units in antiparallel polynucleotide strands. Complementary polynucleotide strands can form base pair in the Watson-Crick manner (e.g., A to T, A to U, C to G), or in any other manner that allows for the formation of duplexes. As persons skilled in the art are aware, when using RNA as opposed to DNA, uracil rather than thymine is the base that is considered to be complementary to adenosine. However, when a U is denoted in the context of the present disclosure, the ability to substitute a T is implied, unless otherwise stated. Perfect complementarity or 100% complementarity refers to the situation in which each nucleotide unit of one polynucleotide strand can form hydrogen bond with a nucleotide unit of a second polynucleotide strand. Less than perfect complementarity refers to the situation in which some, but not all, nucleotide units of two strands can form hydrogen bond with each other. For example, for two 20-mers, if only two base pairs on each strand can form hydrogen bond with each other, the polynucleotide strands exhibit 10% complementarity. In the same example, if 18 base pairs on each strand can form hydrogen bonds with each other, the polynucleotide strands exhibit 90% complementarity. As used herein, the term "substantially complementary" means that the siRNA has a sequence (e.g., in the antisense strand) which is sufficient to bind the desired target mRNA, and to trigger the RNA silencing of the target mRNA. Compound or structure [001207] The term "compound" or "structure," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. The compounds or structures described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. [001208] Compounds or structures of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. [001209] Compounds or structures of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. "Isotopes" refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. [001210] In some embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer. Likewise, in some embodiments cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g., have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. [001211] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, or from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In some embodiments, alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl. Comprising / comprises [001212] As used herein the term "comprising" or "comprises" is used in reference to compositions, methods, and respective component(s) thereof, that are present in a given embodiment, yet open to the inclusion of unspecified elements. Conservative amino acid substitution [001213] As used herein the term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions. Examples of non- conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue. Consisting essentially of [001214] As used herein the term “consisting essentially of” refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the disclosure. Consisting of [001215] The term "consisting of” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment. Cycloalkylenyl [001216] The term "cycloalkylenyl" as used herein refers to a divalent radical of a cycloalkyl group. In one embodiment, the cycloalkylenyl is a divalent form of a C_3-8 cycloalkyl, i.e., a C₃-C₈ cycloalkylenyl. Nonlimiting exemplary cycloalkylenyl groups include: [001217] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF₃, -CN and the like. Cycloalkyls can be substituted in the same manner. Delivery [001218] As used herein, "delivery" refers to the act or manner of delivering a compound, substance, entity, moiety, cargo or payload. Derivative [001219] The present disclosure provides several types of compositions that are polynucleotide or polypeptide based, including variants and derivatives. These include, for example, substitutional, insertional, deletion and covalent variants and derivatives. The term “derivative” is used synonymously with the term “variant” but generally refers to a molecule that has been modified and/or changed in any way relative to a reference molecule or starting molecule. [001220] As such, polynucleotides encoding peptides or polypeptides containing substitutions, insertions and/or additions, deletions and covalent modifications with respect to reference sequences, in particular the polypeptide sequences disclosed herein, are included within the scope of this disclosure. For example, sequence tags or amino acids, such as one or more lysines, can be added to peptide sequences (e.g., at the N-terminal or C-terminal ends). Sequence tags can be used for peptide detection, purification or localization. Lysines can be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support. DNA/RNA [001221] As used herein, the term "RNA" or "RNA molecule" or "ribonucleic acid molecule" refers to a polymer of ribonucleotides; the term "DNA" or "DNA molecule" or "deoxyribonucleic acid molecule" refers to a polymer of deoxyribonucleotides. DNA and RNA can be synthesized naturally, e.g., by DNA replication and transcription of DNA, respectively; or be chemically synthesized. DNA and RNA can be single-stranded (i.e., ssRNA or ssDNA, respectively) or multi-stranded (e.g., double stranded, i.e., dsRNA and dsDNA, respectively). The term "mRNA" or "messenger RNA", as used herein, refers to a single stranded RNA that encodes the amino acid sequence of one or more polypeptide chains. DNA-guided nuclease or nucleic acid programmable nuclease [001222] As used herein, an “DNA-guided nuclease” is a type of “programmable nuclease,” and a specific type of “nucleic acid-guided nuclease.” Equivalent terms for purposes of this disclosure include “nucleic acid programmable nuclease.” An example of a DNA-guided nuclease is reported in Varshney et al., DNA-guided genome editing using structure-guided endonucleases, Genome Biology, 2016, 17(1), 187, which may be used in the context of the present disclosure and is incorporated herein by reference. As used herein, the term “DNA-guided nuclease” or “DNA-guided endonuclease” refers to a nuclease that associates covalently or non-covalently with a guide RNA thereby forming a complex between the guide RNA and the DNA-guided nuclease. The guide RNA comprises a spacer sequence which comprises a nucleotide sequence having complementarity with a strand of a target DNA sequence. Thus, the DNA-guided nuclease is indirectly guided or programmed to localize to a specific site in a DNA molecule through its association with the guide RNA, which directly binds or anneals to a strand of the target DNA through its complementarity region via Watson-Crick base-pairing. A “nucleic acid programmable DNA-guided DNA binding protein or nucleic acid programmable DNA binding protein [001223] As used herein, an “DNA-guided DNA binding protein” or “nucleic acid programmable DNA binding protein” has a similar meaning as a “DNA-guided nuclease” except that a “DNA binding protein” may include a nuclease but is not required to have a nuclease activity. By contrast to a nuclease, a nuclease domain (e.g., FokI) could be fused to a DNA binding protein top give rise to a DNA-guided nuclease as a fusion protein. DNA regulatory sequences [001224] As used herein, the terms “DNA regulatory sequences,” “control elements,” and “regulatory elements,” can be used interchangeably herein to refer to transcriptional and translational control sequences, such as promoters, enhancers, polyadenylation signals, terminators, protein degradation signals, and the like, that provide for and/or regulate transcription of a non-coding sequence (e.g., guide RNA) or a coding sequence and/or regulate translation of a mRNA into an encoded polypeptide. Domain [001225] As used herein when referring to polypeptides the term “domain” refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions). Donor template DNA or template DNA [001226] By a “donor template DNA” or “donor DNA” or “template DNA” it is meant a single-stranded or double-stranded DNA to be incorporated at a site cleaved by a programmable nuclease (e.g., a CRISPR/Cas effector protein; a TALEN; a ZFN; a meganuclease) (e.g., after dsDNA cleavage, after nicking a target DNA, after dual nicking a target DNA, and the like). The donor DNA can contain sufficient homology to a genomic sequence at the target site, e.g.70%, 80%, 85%, 90%, 95%, or 100% homology with the nucleotide sequences flanking the target site, e.g., within about 200 bases or less of the target site, e.g., within about 190 bases or less of the target site, e.g., within about 180 bases or less of the target site, e.g., within about 170 bases or less of the target site, e.g., within about 160 bases or less of the target site, e.g., within about 150 bases or less of the target site, e.g., within about 140 bases or less of the target site, e.g., within about 130 bases or less of the target site, e.g., within about 120 bases or less of the target site, e.g., within about 110 bases or less of the target site, e.g., within about 100 bases or less of the target site, e.g., within about 90 bases or less of the target site, e.g., within about 80 bases or less of the target site, e.g., within about 70 bases or less of the target site, e.g., within about 60 bases or less of the target site, e.g., 50 bases or less of the target site, e.g., within about 30 bases, within about 15 bases, within about 10 bases, within about 5 bases, or immediately flanking the target site, to support integration into the cut site. In certain embodiments, integration of the donor template DNA occurs by way of homology-directed repair between the donor and the genomic sequence to which it bears homology. Encapsulate [001227] The terms “encapsulation” and “entrapped,” as used herein, refer to the incorporation or association of the mRNA, DNA, siRNA or other nucleic acid pharmaceutical agent in or with a lipidic nanoparticle. As used herein, the term “encapsulated” refers to complete encapsulation or partial encapsulation. A siRNA may be capable of selectively knocking down or down regulating expression of a gene of interest. For example, an siRNA could be selected to silence a gene associated with a particular disease, disorder, or condition upon administration to a subject in need thereof of a nanoparticle composition including the siRNA. A siRNA may comprise a sequence that is complementary to an mRNA sequence that encodes a gene or protein of interest. Encapsulation efficiency [001228] As used herein, “encapsulation efficiency” refers to the amount of a therapeutic and/or prophylactic that becomes part of a nanoparticle composition, relative to theinitial total amount of therapeutic and/or prophylactic used in the preparation of a nanoparticle composition. For example, if 97 mg of a polynucleotide are encapsulated in a nanoparticle composition out of a total 100 mg of therapeutic and/or prophylactic initially provided to the composition, the encapsulation efficiency may be given as 97%. As used herein, “encapsulation” may refer to complete, substantial, or partial enclosure, confinement, surrounding, or encasement. [001229] Throughout the disclosure, chemical substituents described in Markush structures are represented by variables. Where a variable is given multiple definitions as applied to different Markush formulas in different sections of the disclosure, it is to be understood that each definition should only apply to the applicable formula in the appropriate section of the disclosure. Encode [001230] As used herein the term "encode" refers broadly to any process whereby the information in a polymeric macromolecule is used to direct the production of a second molecule that is different from the first. The second molecule may have a chemical structure that is different from the chemical nature of the first molecule. Exosome [001231] As used herein, the term “exosomes” refer to small membrane bound vesicles with an endocytic origin. Without wishing to be bound by theory, exosomes are generally released into an extracellular environment from host/progenitor cells post fusion of multivesicular bodies the cellular plasma membrane. As such, exosomes can include components of the progenitor membrane in addition to designed components (e.g. engineered TnpB editing system). Exosome membranes are generally lamellar, composed of a bilayer of lipids, with an aqueous inter-nanoparticle space. Features [001232] “Features” when referring to polypeptide or polynucleotide are defined as distinct amino acid sequence-based or nucleotide-based components of a molecule respectively. Features of the polypeptides encoded by the polynucleotides include surface manifestations, local conformational shape, folds, loops, half-loops, domains, half-domains, sites, termini or any combination thereof. Fusion [001233] The term “fusion” as used herein as applied to a nucleic acid or polypeptide refers to two components that are defined by structures derived from different sources. For example, where "fusion" is used in the context of a fusion polypeptide (e.g., a fusion Cas9-RT protein), the fusion polypeptide includes amino acid sequences that are derived from different polypeptides. A fusion polypeptide may comprise either modified or naturally-occurring polypeptide sequences (e.g., a first amino acid sequence from a modified or unmodified Cas9-RT protein; and a second amino acid sequence from a modified or unmodified protein other than a Cas9-RT protein, etc.). Similarly, "fusion" in the context of a polynucleotide encoding a fusion polypeptide includes nucleotide sequences derived from different coding regions (e.g., a first nucleotide sequence encoding a modified or unmodified Cas9-RT protein; and a second nucleotide sequence encoding a polypeptide other than a Cas9-RT protein). Fusion Polypeptide [001234] The term “fusion polypeptide” refers to a polypeptide which is made by the combination (i.e., “fusion”) of two otherwise separated segments of amino acid sequence, usually through human intervention. Formulation [001235] As used herein, a "formulation" includes at least one compound, substance, entity, moiety, cargo or payload and a delivery agent. Fragment [001236] A "fragment," as used herein, refers to a portion. For example, fragments of proteins may comprise polypeptides obtained by digesting full-length protein isolated from cultured cells. Halogen [001237] As used herein, “halogen” means Br, Cl, F and I. Heteroalkyl [001238] The term "heteroalkyl", as used herein, refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups. Heteroatom [001239] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Examples of heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Other useful heteroatoms include silicon and arsenic. Heterocyclyl [001240] As used herein, “heterocyclyl” or “heterocycle” means a 4- to 14-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. “Heterocyclyl” therefore includes, the following: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof all of which are optionally substituted with one to three substituents selected from R″. Heterocycle [001241] "Heterocycle" or "heterocyclic," as used herein, refers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic, bicyclic, or polycyclic ring containing 3-14 ring atoms, for example, from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C₁- C10) alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4- piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. Heterocyclic groups can optionally be substituted with one or more substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, and -CN. Examples of bicyclic or polycyclic heterocycles include bridged, fused, and spirocyclic heterocycles. Homology [001242] As used herein, the term "homology" refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be "homologous" to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term "homologous" necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). In accordance with the disclosure, two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least about 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4–5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4–5 uniquely specified amino acids. In accordance with the disclosure, two protein sequences are considered to be homologous if the proteins are at least about 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least about 20 amino acids. Homology implies that the compared sequences diverged in evolution from a common origin. The term “homolog” refers to a first amino acid sequence or nucleic acid sequence (e.g., gene (DNA or RNA) or protein sequence) that is related to a second amino acid sequence or nucleic acid sequence by descent from a common ancestral sequence. The term “homolog” may apply to the relationship between genes and/or proteins separated by the event of speciation or to the relationship between genes and/or proteins separated by the event of genetic duplication. “Orthologs” are genes (or proteins) in different species that evolved from a common ancestral gene (or protein) by speciation. Typically, orthologs retain the same function in the course of evolution. “Paralogs” are genes (or proteins) related by duplication within a genome. Orthologs retain the same function in the course of evolution, whereas paralogs evolve new functions, even if these are related to the original one. [001243] Homology implies that the compared sequences diverged in evolution from a common origin. The term “homolog” refers to a first amino acid sequence or nucleic acid sequence (e.g., gene (DNA or RNA) or protein sequence) that is related to a second amino acid sequence or nucleic acid sequence by descent from a common ancestral sequence. The term “homolog” may apply to the relationship between genes and/or proteins separated by the event of speciation or to the relationship between genes and/or proteins separated by the event of genetic duplication. “Orthologs” are genes (or proteins) in different species that evolved from a common ancestral gene (or protein) by speciation. Typically, orthologs retain the same function in the course of evolution. “Paralogs” are genes (or proteins) related by duplication within a genome. Orthologs retain the same function in the course of evolution, whereas paralogs evolve new functions, even if these are related to the original one. Homology-directed repair [001244] As used herein, “homology-directed repair (HDR)” refers to the specialized form DNA repair that takes place, for example, during repair of double-strand breaks in cells. This process requires nucleotide sequence homology, uses a “donor” molecule to template repair of a “target” molecule (i.e., the one that experienced the double-strand break), and leads to the transfer of genetic information from the donor to the target. Homology-directed repair may result in an alteration of the sequence of the target molecule (e.g., insertion, deletion, mutation), if the donor polynucleotide differs from the target molecule and part or all of the sequence of the donor polynucleotide is incorporated into the targeted polynucleotide sequence. Identity [001245] The term “identity” refers to the overall relatedness between polymeric molecules, for example, between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleic acid sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleic acid sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleic acid sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)). Immunogenic [001246] As used herein, the term “immunogenic” refers to a potential to induce an immune response to a substance. An immune response may be induced when an immune system of an organism or a certain type of immune cell is exposed to an immunogenic substance. The term “non- immunogenic” refers to a lack of or absence of an immune response above a detectable threshold to a substance. No immune response is detected when an immune system of an organism or a certain type of immune cell is exposed to a non-immunogenic substance. In some embodiments, a non- immunogenic circular polyribonucleotide as provided herein, does not induce an immune response above a pre-determined threshold when measured by an immunogenicity assay. In some embodiments, no innate immune response is detected when an immune system of an organism or a certain type of immune cell is exposed to a non-immunogenic circular polyribonucleotide as provided herein. In some embodiments, no adaptive immune response is detected when an immune system of an organism or a certain type of immune cell is exposed to a non-immunogenic circular polyribonucleotide as provided herein. Ionizable lipid [001247] As used herein "ionizable lipid" refers to any of a number of lipid species that carry a net positive charge at a selected pH. IRES [001248] As used herein, the term "internal ribosome entry site" or "IRES" refers to an RNA sequence or structural element ranging in size form 10 nucleotides to 1,000 nucleotides or more which is capable of initiating translation of a polypeptide in the absence of a normal RNA cap structure. In other words, IRES are sequences that can recruit ribosomes and allow cap-independent translation, which can link two coding sequences in one bicistronic vector and allow the translation of both proteins. See Kozak M, “A second look at cellular mRNA sequences said to function as internal ribosome entry sites,” Nucleic Acids Research, 2005, Vol.33: pp.6593–6602 (incorporated herein by reference). Linker [001249] As used herein, the term“linker” refers to a molecule linking or joining two other molecules or moieties. The linker can be an amino acid sequence in the case of a linker joining two fusion proteins. For example, a TnpB protein can be fused to an accessory protein (e.g., a deaminase, nuclease, ligase, reverse transcriptase, recombinase, etc.) by an amino acid linker sequence. The linker can also be a nucleotide sequence in the case of joining two nucleotide sequences together. For example, in the instant case, a reRNA at its 5ʹ and/or 3ʹ ends may be linked by a nucleotide sequence linker to one or more other functional nucleic acid molecules, such as guide RNAs or HDR donor molecules. In other embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker is 5-100 amino acids in length, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 30-35, 35-40, 40- 45, 45- 50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-150, or 150-200 amino acids in length. Longer or shorter linkers are also contemplated. Lipid conjugate [001250] The term “lipid conjugate” refers to a conjugated lipid that inhibits aggregation of lipid particles. Such lipid conjugates include, but are not limited to, polysarcosine (see e.g. WO2021191265A1 which is herein incorporated by reference in its entirety for all purposes), polyamide oligomers (e.g., ATTA-lipid conjugates), PEG-lipid conjugates, such as PEG coupled to di alkyl oxy propyls, PEG coupled to diacylglycerols, PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, PEG conjugated to ceramides (see, e.g., U.S. Pat. No.5,885,613, the disclosure of which is herein incorporated by reference in its entirety for all purposes), cationic PEG lipids, and mixtures thereof. PEG can be conjugated directly to the lipid or may be linked to the lipid via a linker moiety. Any linker moiety suitable for coupling the PEG to a lipid can be used including, e.g., non-ester containing linker moieties and ester-containing linker moieties. In preferred embodiments, non-ester containing linker moieties are used. Lipid nanoparticle (LNP) [001251] The term “lipid nanoparticle”, or “LNP”, refers to particles having a diameter of from about 5 to 500 nm. In some embodiments, lipid nanoparticle refers to any lipid composition that can be used to deliver a prophylactic product, preferably vaccine antigens, including, but not limited to, liposomes or vesicles, wherein an aqueous volume is encapsulated by amphipathic lipid bilayers (e.g., single; unilamellar or multiple; multilamellar), or, in other embodiments, wherein the lipids coat an interior comprising a prophylactic product, or lipid aggregates or micelles, wherein the lipid encapsulated therapeutic product is contained within a relatively disordered lipid mixture. Except where noted, the lipid nanoparticle does not need to have antigen incorporated therein and may be used to deliver a prophylactic product when in the same formulation. [001252] In some embodiments, the active agent (e.g., RNA payload encoding a polypeptide, such as an antigen or therapeutic protein) is encapsulated into the LNP. In some embodiments, the active agent can be an anionic compound, for example, but not limited to DNA, RNA, natural and synthetic oligonucleotides (including antisense oligonucleotides, interfering RNA and small interfering RNA), nucleoprotein, peptide, nucleic acid, ribozyme, DNA- containing nucleoprotein, such as an intact or partially deproteinated viral particles (virions), oligomeric and polymeric anionic compounds other than DNA (for example, acid polysaccharides and glycoproteins)). In some embodiments, the active agent can be intermixed with an adjuvant. [001253] In a LNP vaccine product described herein, the active agent is generally contained in the interior of the LNP. In some embodiments, the active agent comprises a nucleic acid (e.g., a circular or linear mRNA). Typically, water soluble nucleic acids are condensed with cationic lipids or polycationic polymers in the interior of the particle and the surface of the particle is enriched in neutral lipids or PEG-lipid derivatives. Additional ionizable cationic lipid may also be at the surface and respond to acidification in the environment by becoming positively charged, facilitating endosomal escape. Lipid components of the herein disclosed LNPs are described herein. [001254] Release of nucleic acids from LNP formulations, among other characteristics such as liposomal clearance and circulation half-life, can be modified by the presence of polyethylene glycol and/or sterols (e.g., cholesterol) or other potential additives in the LNP, as well as the overall chemical structure, including pKa of any ionizable cationic lipid included as part of the formulation. Liposome [001255] As used herein "liposome" generally refers to a vesicle composed of lipids (e.g., amphiphilic lipids) arranged in one or more spherical bilayers or bilayers. Modified [001256] As used herein "modified" refers to a changed state or structure of a molecule. Molecules may be modified in many ways including chemically, structurally, and functionally. Modulating [001257] By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated subject. The term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human. Naturally-occurring [001258] The term "naturally-occurring" or “unmodified” or “wild type” as used herein as applied to a nucleic acid, a polypeptide, a cell, or an organism, refers to a nucleic acid, polypeptide, cell, or organism that is found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism that can be isolated from a source in nature is naturally occurring. Non-homologous end joining [001259] As used herein, “non-homologous end joining (NHEJ)” refers to the repair of double- strand breaks in DNA by direct ligation of the break ends to one another without the need for a homologous template (in contrast to homology-directed repair, which requires a homologous sequence to guide repair). NHEJ often results in the loss (deletion) of nucleotide sequence near the site of the double-strand break. Nuclear localization sequence (NLS) [001260] As used herein, the term“nuclear localization sequence” or“NLS” refers to an amino acid sequence that promotes import of a protein (e.g., a RNA-guided nuclease) into the cell nucleus, for example, by nuclear transport. Nuclear localization sequences are known in the art. For example, NLS sequences are described in Plank et al., international PCT application, PCT/EP2000/011690, filed November 23, 2000, published as WO/2001/038547 on May 31, 2001, the contents of which are incorporated herein by reference for its disclosure of exemplary nuclear localization sequences. Nuclease [001261] “Nuclease” and “endonuclease” are used interchangeably herein to mean an enzyme which possesses catalytic activity for nucleic acid cleavage (e.g., ribonuclease activity (ribonucleic acid cleavage), deoxyribonuclease activity (deoxyribonucleic acid cleavage), etc.). Nucleic acid [001262] As used herein, the term “nucleic acid” or “nucleic acid molecule” or “nucleic acid sequence” or “polynucleotide” generally refer to deoxyribonucleic or ribonucleic oligonucleotides in either single- or double-stranded form. The term may (or may not) encompass oligonucleotides containing known analogues of natural nucleotides. The term also may (or may not) encompass nucleic acid-like structures with synthetic backbones, see, e.g., Eckstein, 1991; Baserga et ah, 1992; Milligan, 1993; WO 97/03211; WO 96/39154; Mata, 1997; Strauss-Soukup, 1997; and Samstag, 1996. The term encompasses both ribonucleic acid (RNA) and DNA, including cDNA, genomic DNA, synthetic, synthesized (e.g., chemically synthesized) DNA, and/or DNA (or RNA) containing nucleic acid analogs. The nucleotides Adenine (A), Thymine (T), Guanine (G) and Cytosine (C) also may (or may not) encompass nucleotide modifications, e.g., methylated and/or hydroxylated nucleotides, e.g., Cytosine (C) encompasses 5-methylcytosine and 5- hydroxymethylcytosine. Nucleic acid loop [001263] As used herein, the term “loop” in the polynucleotide refers to a single stranded stretch of one or more nucleotides, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, wherein the most 5’ nucleotide and the most 3’ nucleotide of the loop are each linked to a base-paired nucleotide in a stem. Nucleic acid stem [001264] As used herein, the term “stem” refers to two or more base pairs, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more base pairs, formed by inverted repeat sequences connected at a “tip,” where the more 5’ or “upstream” strand of the stem bends to allows the more 3’ or “downstream”strand to base-pair with the upstream strand. The number of base pairs in a stem is the “length” of the stem. The tip of the stem is typically at least 3 nucleotides, but can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more nucleotides. Larger tips with more than 5 nucleotides are also referred to as a “loop.” An otherwise continuous stem may be interrupted by one or more bulges as defined herein. The number of unpaired nucleotides in the bulge(s) are not included in the length of the stem. The position of a bulge closest to the tip can be described by the number of base pairs between the bulge and the tip (e.g., the bulge is 4 bps from the tip). The position of the other bulges (if any) further away from the tip can be described by the number of base pairs in the stem between the bulge in question and the tip, excluding any unpaired bases of other bulges in between. Nitro _[001265] As used herein, the term "nitro" means -NO₂; the term "halogen" designates -F, -Cl, - Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO₂-. Non-cationic lipid [001266] As used herein "non-cationic lipid" refers to any neutral, zwitterionic or anionic lipid. Open reading frame [001267] An “open reading frame” is a continuous stretch of DNA beginning with a start codon (e.g., methionine (ATG)), and ending with a stop codon (e.g., TAA, TAG or TGA) and encodes a polypeptide. Orthologs [001268] As used herein, “orthologs” refers to genes in different species that evolved from a common ancestral gene by speciation. Normally, orthologs retain the same function in the course of evolution. Identification of orthologs is critical for reliable prediction of gene function in newly sequenced genomes. pegRNA [001269] As used herein, the terms “prime editing guide RNA” or “pegRNA” or “PEgRNA” or “extended guide RNA” refer to a specialized form of a guide RNA that has been modified to include one or more additional sequences for implementing the prime editing methods and compositions described herein. As described herein, the prime editing guide RNA comprise one or more “extended regions” of nucleic acid sequence. The extended region comprises a “DNA synthesis template” which encodes (by the polymerase of the prime editor) a single-stranded DNA which, in turn, has been designed to be (a) homologous with the endogenous target DNA to be edited, and (b) which comprises at least one desired nucleotide change (e.g., a transition, a transversion, a deletion, or an insertion) to be introduced or integrated into the endogenous target DNA. The extended region may also comprise other functional sequence elements, such as, but not limited to, a “primer binding site” and a “spacer or linker” sequence, or other structural elements, such as, but not limited to aptamers, stem loops, hairpins, toe loops (e.g., a 3′ toeloop), or an RNA-protein recruitment domain (e.g., MS2 hairpin). As used herein the “primer binding site” comprises a sequence that hybridizes to a single- strand DNA sequence having a 3´ end generated from the nicked DNA of the R-loop. PE1 [001270] As used herein, “PE1” refers to a PE complex comprising a fusion protein comprising Cas9(H840A) and a wild type MMLV RT having the following structure: [NLS]-[Cas9(H840A)]- [linker]-[MMLV_RT(wt)] + a desired pegRNA, wherein the PE fusion has the amino acid sequence of SEQ ID NO: 33. PE2 [001271] As used herein, “PE2” refers to a PE complex comprising a fusion protein comprising Cas9(H840A) and a variant MMLV RT having the following structure: [NLS]-[Cas9(H840A)]- [linker]-[MMLV_RT(D200N)(T330P)(L603W)(T306K)(W313F)] + a desired pegRNA, wherein the PE fusion has the amino acid sequence of SEQ ID NO: 34. Pharmaceutically acceptable salt [001272] The term “pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present disclosure which salt possesses the desired pharmacological activity. Pharmaceutically acceptable carrier, diluent, or excipient [001273] As used herein, the term “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. Various aspects and embodiments are described in further detail in the following subsections. Pharmaceutical composition [001274] As used herein the term "pharmaceutical composition" refers to compositions comprising at least one active ingredient (e.g., an LNP encapsulated with a mRNA payload) and optionally one or more pharmaceutically acceptable excipients. PEG [001275] As used herein "PEG" means any polyethylene glycol or other polyalkylene ether polymer. Peptide [001276] As used herein, "peptide" is less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long. PolyA tail [001277] A “polyA tail” is a region of mRNA that is downstream, e.g., directly downstream (i.e., 3′), from the 3′ UTR that contains multiple, consecutive adenosine monophosphates. A polyA tail may contain 10 to 300 adenosine monophosphates. For example, a polyA tail may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 adenosine monophosphates. In some embodiments, a polyA tail contains 50 to 250 adenosine monophosphates. In a relevant biological setting (e.g., in cells, in vivo) the poly(A) tail functions to protect mRNA from enzymatic degradation, e.g., in the cytoplasm, and aids in transcription termination, export of the mRNA from the nucleus and translation. Polyamine [001278] As used herein, “polyamine” means compounds having two or more amino groups. Examples include putrescine, cadaverine, spermidine, and spermine. Polypeptide variant [001279] The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. The amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. Ordinarily, variants possess at least 50% identity to a native or reference sequence. In some embodiments, variants share at least 80%, or at least 90% identity with a native or reference sequence. Prime editor [001280] The term “prime editor (PE)” refers to the polypeptide or polypeptide components involved in prime editing, or any polynucleotide(s) encoding the polypeptide or polypeptide components. In various embodiments, a prime editor includes a polypeptide domain having DNA binding activity and a polypeptide domain having DNA polymerase activity. Protein fragment, function protein domains, homologous proteins [001281] As recognized by those skilled in the art, protein fragments, functional protein domains, and homologous proteins are also considered to be within the scope of polypeptides of interest. For example, provided herein is any protein fragment (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) of a reference protein 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or greater than 100 amino acids in length. In another example, any protein that includes a stretch of 20, 30, 40, 50, or 100 amino acids which are 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% identical to any of the sequences described herein can be utilized in accordance with the disclosure. In some embodiments, a polypeptide includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein. RNA [001282] The term “RNA” is a well-known term of art that refers to ribonucleic acid. RNA-guided nuclease [001283] As used herein, an “RNA-guided nuclease” is a type of “programmable nuclease,” and a specific type of “nucleic acid-guided nuclease.” As used herein, the term “RNA-guided nuclease” or “RNA-guided endonuclease” refers to a nuclease that associates covalently or non- covalently with a guide RNA thereby forming a complex between the guide RNA and the RNA- guided nuclease. The guide RNA comprises a spacer sequence which comprises a nucleotide sequence having complementarity with a strand of a target DNA sequence. Thus, the RNA-guided nuclease is indirectly guided or programmed to localize to a specific site in a DNA molecule through its association with the guide RNA, which directly binds or anneals to a strand of the target DNA through its complementarity region via Watson-Crick base-pairing. Sequence identity [001284] As used herein, the term “sequence identity” refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). For example, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna. CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H. and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990). Spacer [001285] As used herein the term "spacer" refers to a region of a polynucleotide or polypeptide ranging from 1 residue to hundreds or thousands of residues separating two other elements in a sequence. The sequence of the spacer can be defined or random. A spacer sequence is typically non- coding but may be a coding sequence. Stereoisomers [001286] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. These compounds may also be designated by “(+)” and “(-)” based on their optical rotation properties. The presently described compounds encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the symbol “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. Structural lipid [001287] As used herein "structural lipid" refers to sterols and lipids containing sterol moieties. Subject [001288] As used herein, the term“subject” refers to an individual organism, for example, an individual mammal or plant. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a rodent. In some embodiments, the subject is a sheep, a goat, a cattle, a cat, or a dog. In some embodiments, the subject is a vertebrate, an amphibian, a reptile, a fish, an insect, a fly, or a nematode. In some embodiments, the subject is a research animal. In some embodiments, the subject is genetically engineered, e.g., a genetically engineered non-human subject. The subject may be of either sex and at any stage of development. The terms “individual,” “subject,” “host,” and “patient,” used interchangeably herein. Substituted [001289] The term "substituted" as used herein, refers to all permissible substituents of the compounds described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, for example, 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups. [001290] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [001291] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; —(CH₂)_0-4R^∘; —(CH₂)_0-4OR^∘; —O(CH₂)_0-4R^∘, —O— (CH₂)_0-4C(O)OR^∘; —(CH₂)_0-4CH(OR^∘)2; —(CH₂)_0-4SR^∘; —(CH₂)_0-4Ph, which may be substituted with R^∘; —(CH₂)_0-4O(CH₂)_0-1Ph which may be substituted with R^∘; —CH═CHPh, which may be substituted with R^∘; —(CH₂)_0-4O(CH₂)_0-1-pyridyl which may be substituted with R^∘; —NO₂; —CN; — N3; —(CH₂)_0-4N(R^∘)2; —(CH₂)_0-4N(R^∘)C(O)R^∘; —N(R^∘)C(S)R^∘; —(CH₂)_0-4N(R^∘)C(O)NR^∘2; — N(R^∘)C(S)NR^∘2; —(CH₂)_0-4N(R^∘)C(O)OR^∘; —N(R^∘)N(R^∘)C(O)R^∘; —N(R^∘)N(R^∘)C(O)NR^∘2; — N(R^∘)N(R^∘)C(O)OR^∘; —(CH₂)_0-4C(O)R^∘; —C(S)R^∘; —(CH₂)_0-4C(O)OR^∘; —(CH₂)_0-4C(O)SR^∘; — (CH₂)_0-4C(O)OSiR^∘ ₃; —(CH₂)_0-4OC(O)R^∘; —OC(O)(CH₂)_0-4SR^∘, SC(S)SR^∘; —(CH₂)_0-4SC(O)R^∘; — (CH₂)_0-4C(O)NR^∘ ₂; —C(S)NR^∘ ₂; —C(S)SR^∘; —SC(S)SR^∘, —(CH₂)_0-4OC(O)NR^∘ ₂; —C(O)N(OR^∘)R^∘; —C(O)C(O)R^∘; —C(O)CH₂C(O)R^∘; —C(NOR^∘)R^∘; —(CH₂)_0-4SSR^∘; —(CH₂)_0-4S(O)2R^∘; —(CH₂)0- 4S(O)2OR^∘; —(CH₂)_0-4OS(O)2R^∘; —S(O)2NR^∘2; —(CH₂)_0-4S(O)R^∘; —N(R^∘)S(O)2NR^∘2; — N(R^∘)S(O)2R^∘; —N(OR^∘)R^∘; —C(NH)NR^∘2; —P(O)2R^∘; —P(O)R^∘2; —OP(O)R^∘2; —OP(O)(OR^∘)2; SiR^∘ ₃; —(C_1-4 straight or branched alkylene)O—N(R^∘)₂; or —(C_1-4 straight or branched alkylene)C(O)O—N(R^∘)₂, wherein each R^∘ may be substituted as defined below and is independently hydrogen, C_1-6 aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [001292] Suitable monovalent substituents on R^∘ (or the ring formed by taking two independent occurrences of R^∘ together with their intervening atoms), are independently halogen, —(CH₂)0-2R^●, - (haloR^●), —(CH₂)0-2OH, —(CH₂)0-2OR^●, —(CH₂)0-2CH(OR^●)2; —O(haloR^●), —CN, —N3, —(CH₂)0- 2C(O)R^●, —(CH₂)0-2C(O)OH, —(CH₂)0-2C(O)OR^●, —(CH₂)0-2SR^●, —(CH₂)0-2SH, —(CH₂)0-2NH2, — (CH₂)0-2NHR^●, —(CH₂)0-2NR^●2, —NO2, —SiR^● 3, —OSiR^● 3, —C(O)SR^●, —(C1-4 straight or branched alkylene)C(O)OR^●, or —SSR^● wherein each R^● is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from C_1- ₄ aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^∘ include ═O and ═S. [001293] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1- 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [001294] Suitable substituents on the aliphatic group of R* include halogen, —R^●, -(haloR^●), —OH, —OR^●, —O(haloR^●), —CN, —C(O)OH, —C(O)OR^●, —NH₂, —NHR^●, —NR^● ₂, or —NO₂, wherein each R^● is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C_1-4 aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [001295] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include —R^†, —NR^† ₂, —C(O)R^†, —C(O)OR^†, —C(O)C(O)R^†, —C(O)CH₂C(O)R^†, —S(O)₂R^†, — S(O)₂NR^† ₂, —C(S)NR^† ₂, —C(NH)NR^† ₂, or —N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3- 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [001296] Suitable substituents on the aliphatic group of R^† are independently halogen, —R^●, - (haloR^●), —OH, —OR^●, —O(haloR^●), —CN, —C(O)OH, —C(O)OR^●, —NH₂, —NHR^●, —NR^● ₂, or —NO2, wherein each R^● is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH₂Ph, —O(CH₂)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [001297] Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, or elimination. [001298] In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. [001299] In various embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, each of which optionally is substituted with one or more suitable substituents. In some embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can be further substituted with one or more suitable substituents. [001300] Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, thioketone, ester, heterocyclyl, –CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, carboxy esters, carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. In some embodiments, the substituent is selected from cyano, halogen, hydroxyl, and nitro. Substantially [001301] As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. Target or target nucleic acid [001302] A “target” or “target nucleic acid” as used herein is a polynucleotide (e.g., DNA such as genomic DNA) that includes a site ("target site" or "target sequence") targeted by a nucleic acid programmable DNA binding protein of the present disclosure. The target sequence is the sequence to which the guide sequence of a subject nucleic acid programmable DNA binding protein will hybridize. For a double stranded target nucleic acid, the strand of the target nucleic acid that is complementary to and hybridizes with the guide RNA is referred to as the “complementary strand” or “target strand”; while the strand of the target nucleic acid that is complementary to the “target strand” (and is therefore not complementary to the guide RNA) is referred to as the “non-target strand” or “non-complementary strand.” Terminus [001303] As used herein the terms “termini” or “terminus” when referring to polypeptides or polynucleotides refers to an extremity of a polypeptide or polynucleotide respectively. Such extremity is not limited only to the first or final site of the polypeptide or polynucleotide but may include additional amino acids or nucleotides in the terminal regions. Polypeptide-based molecules may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group (NH2)) and a C-terminus (terminated by an amino acid with a free carboxyl group (COOH)). Proteins are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers). These proteins have multiple N- and C-termini. Alternatively, the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide based moiety such as an organic conjugate. Treating [001304] The terms “treat,” “treating,” and “treatment,” as used herein, refer to therapeutic or preventative measures such as those described herein. Unmodified [001305] As used herein, “unmodified” refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification. Upstream and downstream [001306] As used herein, the terms “upstream” and “downstream” are terms of relativity that define the linear position of at least two elements located in a nucleic acid molecule (whether single or double-stranded) that is orientated in a 5ʹ-to-3ʹ direction. A first element is said to be upstream of a second element in a nucleic acid molecule where the first element is positioned somewhere that is 5ʹ to the second element. Conversely, a first element is downstream of a second element in a nucleic acid molecule where the first element is positioned somewhere that is 3ʹ to the second element. Vaccine [001307] As used herein, the phrase “vaccine” refers to a biological preparation that improves immunity in the context of a particular disease, disorder or condition. Vector [001308] As used herein, a "vector" is any molecule or moiety which transports, transduces or otherwise acts as a carrier of a heterologous molecule. Vectors of the present disclosure may be produced recombinantly and may be based on and/or may comprise viral parent or reference sequence. Such parent or reference viral sequences may serve as an original, second, third or subsequent sequence for engineering vectors. In non-limiting examples, such parent or reference viral sequences may comprise any one or more of the following sequences: a polynucleotide sequence encoding a polypeptide or multi-polypeptide, which sequence may be wild-type or modified from wild-type and which sequence may encode full-length or partial sequence of a protein, protein domain, or one or more subunits of a protein; a polynucleotide comprising a modulatory or regulatory nucleic acid which sequence may be wild-type or modified from wild-type; and a transgene that may or may not be modified from wild-type sequence . These viral sequences may serve as either the "donor" sequence of one or more codons (at the nucleic acid level) or amino acids (at the polypeptide level) or "acceptor" sequences of one or more codons (at the nucleic acid level) or amino acids (at the polypeptide level). The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred materials and methods are now described. Other features, objects and advantages of the disclosure will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present description will control. 3′ untranslated region [001309] A “3′ untranslated region” (UTR) refers to a region of an mRNA that is directly downstream (i.e., 3′) from the stop codon (i.e., the codon of an mRNA transcript that signals a termination of translation) that does not encode a polypeptide. 5′ untranslated region [001310] A “5′ untranslated region” (UTR) refers to a region of an mRNA that is directly upstream (i.e., 5′) from the start codon (i.e., the first codon of an mRNA transcript translated by a ribosome) that does not encode a polypeptide. [001311] The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred materials and methods are now described. Other features, objects and advantages of the disclosure will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present description will control. [001312] As used herein, the following abbreviations and initialisms have the indicated meanings:

ENUMERATED EMBODIMENTS [001313] In some embodiments, the present disclosure includes the enumerated embodiments listed below: 1. A compound of Formula (CT): (CT), or a pharmaceutically acceptable salt thereof, wherein: wherein the bond marked with an "*" is attached to X¹; X¹ is optionally substituted C1-C6 aliphatic; and R¹ is selected from the group consisting of -OH, -OAc, -NR2, ii) A is CH; marked with an "*" is attached to X¹; X¹ is a bond or optionally substituted C1-C6 aliphatic; and R¹ is selected from the group consisting of -OH, -OAc, -NR2, each R is independently -H or C1-C6 aliphatic; X² and X³ are each independently optionally substituted C¹-C¹² aliphatic; Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to X² for Y¹ or X³ for Y²; R² is a bond or optionally substituted C1-C6 aliphatic; R³ is a bond or optionally substituted C1-C6 aliphatic; R⁴ is -CH(OR⁶)(OR⁷), -CH(SR⁶)(SR⁷), -CH(R⁶)(R⁷), or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C³-C⁸ cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, - C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R⁵ is -R⁸, -CH(OR⁸)(OR⁹), -CH(SR⁸)(SR⁹), -CH(R⁸)(R⁹), or optionally substituted -C1- C6aliphatic-R⁸; R⁶ and R⁷ are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, - OC(O)-, -NHC(O)- or -C(O)O-; R⁸ is optionally substituted C1-C14 aliphatic, wherein at least one methylene linkage is replaced with an optionally substituted divalent radical of a structure selected from R⁹ is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-. 2. The compound of embodiment 1, wherein A is CH. 3. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-A): (CT-A), or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-A1): (CT-A1), or a pharmaceutically acceptable salt thereof, wherein , wherein the bond marked with an "*" is attached to X¹; and Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y². 5. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-A2): or a pharmaceutically acceptable salt thereof, wherein Z is , wherein the bond marked with an "*" is attached to X¹; and Y¹ and Y² are each ,wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y². 6. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-B) or (CT-B’) or a pharmaceutically acceptable salt thereof. 7. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-C): or a pharmaceutically acceptable salt thereof. 8. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-D) or (CT-D’): or a pharmaceutically acceptable salt thereof. 9. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-E), (CT-E’), or (CT-E’’): or a pharmaceutically acceptable salt thereof. 10. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-F), (CT-F’), (CT-F’’), (CT-F’’’), (CT-F’’’’), or (CT-F’’’’’): or a pharmaceutically acceptable salt thereof. 11. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-G), (CT-G’) or (CT-G’’): or a pharmaceutically acceptable salt thereof. 12. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-H), (CT-H’), (CT-H’’), (CT-H’’’), (CT-H’’’’), or (CT-H’’’’’): or a pharmaceutically acceptable salt thereof. 13. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-I): or a pharmaceutically acceptable salt thereof. 14. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-J) or (CT-J’): or a pharmaceutically acceptable salt thereof. 15. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-K), (CT-K’), or (CT-K’’): or a pharmaceutically acceptable salt thereof. 16. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-L), (CT-L’), (CT-L’’), (CT-L’’’), (CT-L’’’’), or (CT-L’’’’’): or a pharmaceutically acceptable salt thereof. 17. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-M): or a pharmaceutically acceptable salt thereof. 18. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-N) or (CT-N’): or a pharmaceutically acceptable salt thereof. 19. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-O), (CT-O’), or (CT-O’’):

or a pharmaceutically acceptable salt thereof. 20. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-P), (CT-P’), (CT-P’’), (CT-P’’’), (CT-P’’’’), or (CT-P’’’’’): or a pharmaceutically acceptable salt thereof. 21. The compound of embodiment 1, wherein A is N. 22. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-Q): or a pharmaceutically acceptable salt thereof. 23. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-Q1): or a pharmaceutically acceptable salt thereof, wherein Y¹ and Y² are independently selected from the group consisting of ; wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y². 24. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-R) or (CT-R’):

or a pharmaceutically acceptable salt thereof. 25. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-S), (CT-S’) or (CT-S’’): or a pharmaceutically acceptable salt thereof. 26. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-T), (CT-T’), (CT-T’’), (CT-T’’’), (CT-T’’’’), or (CT-T’’’’’):

or a pharmaceutically acceptable salt thereof. 27. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-U), (CT-U’), (CT-U’’), (CT-U’’’), (CT-U’’’’), or (CT-U’’’’’):

or a pharmaceutically acceptable salt thereof. 28. The compound of embodiment 1, wherein the compound is a compound of Formula (CT-V), (CT-V’), (CT-V’’), (CT-V’’’), (CT-V’’’’), or (CT-V’’’’’): or a pharmaceutically acceptable salt thereof. 29. The compound of any one of embodiments 1-3, 6, and 9, 10, wherein Z is , , 30. The compound of any one of embodiments 1-3, 6, 9, 10, and 29, wherein Z is 31. The compound of any one of embodiments 1-20 and 29-30, wherein X¹ is a bond. 32. The compound of any one of embodiments 1-30, wherein X¹ is optionally substituted C1-C6 alkylene. 33. The compound of any one of embodiments 1-30 and 32, wherein X¹ is unsubstituted C1-C6 alkylene. 34. The compound of any one of embodiments 1-26 and 29-33, wherein R¹ is -OH. 35. The compound of any one of embodiments 1-26 and 29-33, wherein R¹ is -NR2. 36. The compound of any one of embodiments 1-35, wherein X² is an optionally substituted C1-C12 alkylene. 37. The compound of any one of embodiments 1-35, wherein X² is an optionally substituted C1-C10 alkylene. 38. The compound of any one of embodiments 1-37, wherein X³ is an optionally substituted C1-C12 alkylene. 39. The compound of any one of embodiments 1-37, wherein X³ is an optionally substituted C1-C10 alkylene. 40. The compound of any one of embodiments 1-39, wherein X² and X³ are the same. 41. The compound of embodiment 40, wherein X² and X³ are both optionally substituted C6-C8 alkylene. 42. The compound of embodiment 40, wherein X² and X³ are both –(CH₂)7-. 43. The compound of any one of embodiments 1-39, wherein X² and X³ are different. 44. The compound of any one of embodiments 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-43, wherein Y¹ and Y² are each independently , , , 45. The compound of any one of embodiments 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-44, wherein Y¹ and Y² are each independently . 46. The compound of any one of embodiments 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-45, wherein Y¹ and Y² are both . 47. The compound of any one of embodiments 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-45, wherein Y¹ and Y² are both . 48. The compound of any one of embodiments 1-47, wherein R² is a bond. 49. The compound of any one of embodiments 1-47, wherein R² is an optionally substituted C1-C6 alkylene. 50. The compound of any one of embodiments 1-49, wherein R³ is a bond. 51. The compound of any one of embodiments 1-49, wherein R³ is an optionally substituted C1-C6 alkylene. 52. The compound of any one of embodiments 1-51, wherein R² and R³ are the same. 53. The compound of any one of embodiments 1-51, wherein R² and R³ are different. 54. The compound of any one of embodiments 1-8, 13, 14, 17, 18, 21-24, and 29-53, wherein R⁴ is optionally substituted C1-C14 aliphatic. 55. The compound of any one of embodiments 1-8, 13, 14, 17, 18, 21-24, and 29-54, wherein R⁴ is selected from 56. The compound of any one of embodiments 1-8, 13, 14, 17, 18, 21-24, and 29-55, wherein R⁵ is -R⁸ or optionally substituted -C1-C6 aliphatic-R⁸. 57. The compound of any one of embodiments 1-8, 13, 14, 17, 18, 21-24, and 29-56, wherein R⁵ is optionally substituted C1-C14 aliphatic. 58. The compound of any one of embodiments 1-8, 13, 14, 17, 18, 21-24, and 29-56, wherein R⁵ is -R⁸. 59. The compound of any one of embodiments 1-56 and 58, wherein R⁸ is optionally substituted C1-C13 alkylene terminated with a structure selected from the group 60. The compound of any one of embodiments 1-56, 58, and 59, wherein R⁸ is an optionally substituted C1-C13 alkylene terminated with a structure selected from the group 61. The compound of any one of embodiments 1-56 and 58-60, wherein R⁸ is an optionally substituted -CH₂-, -(CH₂)2-, -(CH₂)3-, -(CH₂)4-, -(CH₂)5-, or -(CH₂)6-, terminated with a structure selected from the group consisting of , 62. The compound of any one of embodiments 1-56 and 58, wherein R⁸ is a structure selected from the group consisting of , , , ,

63. The compound of any one of embodiments 1-56 and 58-60, wherein R⁸ is a structure selected from , , , , , , 64. The compound of embodiment 1 selected from any one or more of the compounds of Table (I), or a pharmaceutically acceptable salt thereof. 65. A pharmaceutical composition comprising: a) at least one lipid nanoparticle comprising at least one compound of any one of embodiments 1-64; and b) at least one nucleobase editing system. 66. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a CRISPR-Cas gene editing system. 67. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a prime editing system or components thereof. 68. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a retron editing system. 69. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a TnpB editing system. 70. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises an integrase editing system. 71. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises an integrase editing system. 72. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises an epigenetic editing system. 73. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a gene writing system. 74. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a gene inactivating system. 75. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises zinc finger nuclease. 76. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a TALE Nuclease, a TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, meganuclease, or a combination thereof. 77. The pharmaceutical composition of embodiment 65, wherein the nucleobase editing system comprises a meganuclease. 78. The pharmaceutical composition of any one of embodiments 65-77, wherein the at least one lipid nanoparticle further comprises: i) at least one structural lipid; ii) at least one phospholipid; and iii) at least one PEGylated lipid. 79. The pharmaceutical composition of embodiment 78, wherein the at least one structural lipid is selected from cholesterol, fecosterol, fucosterol, beta sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, litocholic acid, tomatine, ursolic acid, alpha-tocopherol, Vitamin D3, Vitamin D2, Calcipotriol, botulin, lupeol, oleanolic acid, beta-sitosterol-acetate and any combinations thereof. 80. The pharmaceutical composition of embodiment 78, wherein the at least one phospholipid is selected from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero- 3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn- glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuc cinoyl- sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3- phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, 1,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2- diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn- glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), 1,2-Dielaidoyl-sn- phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3- phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn- glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L- serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. 81. The pharmaceutical composition of embodiment 78, wherein the at least one PEGylated lipid is selected from (R)-2,3-bis(octadecyloxy)propyl-1- (methoxypoly(ethyleneglycol)2000)propylcarbamate, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG- DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG 2000, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEGA, PEG750-C-DMA, PEG400, PEG2k-DMG, PEG2k-C11, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG Click C12, PEG Click C10, N(Carbonyl-methoxypolyethylenglycol-2000)-l,2-distearoyl-sn- glycero3-phosphoethanolamine, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000- DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000- DMPE, mPEG2000-DMG, mDPPE-PEG2000, l,2-distearoyl-sn-glycero-3- phosphoethanolamine-PEG2000, HPEG-2K-LIPD, Folate PEG-DSPE, DSPE- PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K- NAG, DSPE-PEG2k, DSPE-PEG2000maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-Peg, DMPE-mPEG2000, DMG-PEGMA, DMG-PEG2000, DMG-PEG, distearoyl-glycerol-polyethyleneglycol, Cl8PEG750, CI8PEG5000, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C16 mPEG (polyethylene glycol) 2000 Ceramide, C14-PEG-DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, 1,2-distearoyl- sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3-bis(octadecyloxy)propyl-1- (methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C- DMA, and DSPE-PEG-X. 82. The pharmaceutical composition of any one of embodiments 65-81, wherein the LNP further comprises at least one additional lipid component selected from 1,2-di-O- octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1,2-dilinolenoyl-sn- glycero-3-phosphocholine (18:3 PC), Acylcarnosine (AC), 1-hexadecyl-sn-glycero-3- phosphocholine (C16 Lyso PC), N-oleoyl-sphingomyelin (SPM) (C18:l), N- lignoceryl SPM (C24:0), N-nervonoylshphingomyelin (C24:l), Cardiolipin (CL), l,2- bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), 1,2-Dipalmitoylglycerol-3- hemisuccinate (DGSucc), short-chain bis-n-heptadecanoyl phosphatidylcholine (DHPC), dihexadecoyl-phosphoethanolamine (DHPE), 1,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), l,2-dilauroyl-sn-glycero-3-PE (DLPE), dimyristoyl glycerol hemisuccinate (DMGS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzylalcohol (DOBA), 1,2-dioleoylglyceryl-3-hemisuccinate (DOGHEMS), N-[2-(2-{2-[2-(2,3-Bis-octadec-9-enyloxy-propoxy)-ethoxy]-ethoxy}- ethoxy)-ethyl]-3-(3,4,5-1rihydroxy-6-hydroxymethyl-1etrahydro-pyran-2-ylsulfanyl)- propionamide (DOGP4αMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl- ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), histaminedistearoylglycerol (HDSG), 1,2-Dipalmitoylglycerol-hemisuccinate-Nα- Histidinyl-Hemisuccinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12- pentacosadiynamide (h-Pegi-PCDA), 2-[l-hexyloxyethyl]-2- devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1,2-Dipalmitoylglycerol-O-α-histidinyl-Nα-hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), l,2-Dioleoyl-sn- Glycero-3-Phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane- carboxamide] (MCC-PE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), a thiol- reactive maleimide headgroup lipid e.g.1,2-dioleoyl-sn-glycero-3- phosphoethanolamine-N-[4-(p-maleimidophenyl)but-yramid (MPB-PE), Nervonic Acid (NA), sodium cholate (NaChol), l,2-dioleoyl-sn-glycero-3- [phosphoethanolamine-N-dodecanoyl (NC12-DOPE), 1-oleoyl-2-cholesteryl hemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethylene glycol(PEG) (e.g., polyethylene glycol-distearoylphosphatidylethanolamine lipid (PEG-PE)), phosphatidylglycerol (PG), partially hydrogenated soy phosphatidylchloline (PHSPC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lissamine rhodamineB-phosphatidylethanolamine lipid (Rh-PE), purifiedsoy- derivedmixtureofphospholipids (SIOO), phosphatidylcholine (SM), 18-1-trans-PE,1- stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), soybean phosphatidylcholine (SPC), sphingomyelins (SPM), alpha,alpha-trehalose-6,6'-dibehenate (TDB), l,2- dielaidoyl-sn-glycero-3-phophoethanolamine (transDOPE), ((23S,5R)-3- (bis(hexadecyloxy)methoxy)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)tetrahydrofuran-2-yl)methylmethylphosphate, 1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero- 3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl- sn-glycero-3-phosphoethanolamine, 16-O-monomethyl PE, 16-O-dimethyl PE, and dioleylphosphatidylethanolamine. 83. A method of delivering a nucleobase editing system to a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 65-82. 84. The pharmaceutical composition of any one of embodiments 65-82 for use as a medicament. 85. Use of a pharmaceutical composition of any one of embodiments 65-82 for the manufacture of a medicament for delivery of a nucleobase editing system. 86. A lipid nanoparticle (LNP) comprising a compound of any one of embodiments 1-64, or a pharmaceutically acceptable salt thereof. 87. The LNP of embodiment 86, further comprising: (a) a PEG-lipid (b) a structural lipid; and (c) a non-ionizable lipid and/or a zwitterionic lipid. 88. The LNP of embodiment 87, wherein the lipid nanoparticle further comprises an additional ionizable lipid, besides a compound of Formula (AC). 89. The LNP of embodiment 87 or 88, wherein the PEG-lipid is selected from the group consisting of PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE. 90. The LNP of any one of embodiments 86-89, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha- tocopherol. 91. The LNP of any one of embodiments 87-89, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1- oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero- 3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3- phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)- 2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3- phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn- glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L- serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. 92. The LNP of any one of embodiments 86-91, further comprising a targeting moiety. 93. The LNP of embodiment 92, wherein the targeting moiety is an antibody or a fragment thereof. 94. The LNP of any one of embodiments 86-93, further comprising an active agent. 95. The LNP of embodiment 94, wherein the active agent is a nucleic acid. 96. The LNP of embodiment 95, wherein the nucleic acid is a ribonucleic acid. 97. The LNP of embodiment 96, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and a long non-coding RNA (lncRNA). 98. The LNP of embodiment 95, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA. 99. The LNP of embodiment 98, wherein the mRNA includes an open reading frame encoding a cancer antigen. 100. The LNP of embodiment 98, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator. 101. The LNP of any one of embodiments 98-100, wherein the mRNA includes at least one motif selected from the group consisting of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and a 5' cap structure. 102. The LNP of embodiment 95, wherein the nucleic acid is suitable for a genome editing technique. 103. The LNP of embodiment 102, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator-like effector nuclease (TALEN). 104. The LNP of embodiment 95, wherein the nucleic acid is at least one nucleic acid suitable for a genome editing technique selected from the group consisting of a CRISPR RNA (crRNA), a trans-activating crRNA (tracrRNA), a single guide RNA (sgRNA), and a DNA repair template. 105. The LNP of embodiment 98, wherein the mRNA is at least 30 nucleotides in length. 106. The LNP of embodiment 98, wherein the mRNA is at least 300 nucleotides in length. 107. A pharmaceutical composition comprising a LNP of any one of embodiments 86-106, and a pharmaceutically acceptable carrier. 108. The pharmaceutical composition of embodiment 107, formulated for intravenous or intramuscular administration. 109. The pharmaceutical composition of embodiment 108, which is formulated for intravenous administration. 110. A method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP of any one of embodiments 86-106 or a pharmaceutical composition of any one of embodiments 107-109. 111. A method for treating a disease characterized by a deficiency of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP of any one of embodiments 86-106, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein. 112. A method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP of any one of embodiments 86-106 and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide. EQUIVALENTS AND SCOPE [001314] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims. [001315] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [001316] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [001317] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. [001318] All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control. EXAMPLES [001319] The following examples represent exemplary aspects of the present disclosure. EXAMPLE 1: Synthesis of Exemplary Ionizable Lipids [001320] The following synthetic scheme contemplated by the present disclosure can be used to achieve the synthesis of exemplary ionizable lipids contemplated here that may be useful in forming the LNP-based RNA vaccine and therapeutics of the present disclosure. In some embodiments, the below synthetic scheme can be used for the synthesis of exemplary LNPs disclosed herein.

General Scheme for the synthesis of Intermediates 1 through 10

Synthesis of methyl 9-chloro-9-oxononanoate (Int-2) [001321] To a solution of 9-methoxy-9-oxononanoic acid (50 g, 247 mmol) in dichloromethane (0.5 L) was added oxalic dichloride (31.8 mL, 1.5 eq., 371 mmol) drop wise at 0 °C. To the above solution N,N-dimethylformamide (1.91 mL, 0.1 eq., 24.7 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for overnight. After 12 h, the color of the reaction mixture changed from colorless to yellow. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was concentrated under vacuum, and again co-evaporated with toluene to obtain the crude methyl 9-chloro-9-oxononanoate (53.4 g, 92.9%) as yellow oil. The crude compound was used in next step without purification. Synthesis of 9-oxoheptadecanedioic acid (3) [001322] To a solution of methyl 8-(chloroformyl)octanoate 2 (53.4 g, 242 mmol) in dry toluene (345 mL) was added triethylamine (50.5 mL, 1.5 eq., 363 mmol) at 0 °C dropwise over 10 min. After the completion of addition, ice bath was replaced with hot water bath to allow the temperature of reaction to rise up to 40 °C, after reaching the temperature to 40 °C, the hot water bath was removed and reaction was stirred at room temperature for 1.5 h. The progress of the reaction was monitored by TLC. The suspension formed was filtered off through the pad of celite. The filtrate was concentrated under reduced pressure to obtain the crude dimethyl 8-(chloroformyl)-9- oxoheptadecanedioate (50 g, 51.0%) as yellow oil. [001323] The oily residue of 8-(chloroformyl)-9-oxoheptadecanedioic acid (50 g, 133 mmol) was dissolved in ethanol (250 mL). To the above solution, potassium hydroxide (74.4 g, 10 eq., 1.33 mol) solution in water (250 mL) was added at room temperature and the resulting reaction mixture was refluxed at 110 °C for 16 h. After the complete conversion of the starting material, the reaction mixture was acidified with 6 N HCl to pH = 2. The precipitate obtained was collected by filtration through sintered funnel, washed with water and diethyl ether, dried in vacuo to obtain 9- oxoheptadecanedioic acid 3 (31 g, 41.0%) as white solid. ELSD analysis: Purity 98.16%, Calculated C17H30O5 = 314.21, Observed = 315.20 (m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 11.99 (s, 2H), 2.38 (t, J = 7.2 Hz, 4H), 2.18 (t, J = 7.6 Hz, 4H), 1.49 – 1.41 (m,8H), 1.40 – 1.12 (m, 12H). Synthetic Scheme for 3-pentyloctan-1-ol (Int-4) Route A: [001324] To a stirred solution of ethyl (diethoxyphosphoryl)acetate 11 (115 mL, 581 mmol) in tetrahydrofuran (0.2 L) was added sodium hydride (18.6 g, 388 mmol) lot wise over 30 minutes at 0 °C and the mixture was stirred at room temperature until gas evolution ceased (approximately 30 min). At 0 °C, 6-undecanone 12 (39.8 mL, 194 mmol) was added dropwise. The reaction was gradually warmed to room temperature and stirred at 80 °C for 8h. The progress of the reaction was monitored by TLC. The reaction was cooled to room temperature prior to being quenched with saturated aqueous sodium bicarbonate solution (50 ml). The aqueous phase was extracted with diethyl ether (2 x 200 ml), and the organic extracts were washed by using brine solution (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure get crude. The crude material was purified by silica gel chromatography 0-3% ethyl acetate in heptane to afford ethyl 3-pentyl-2- octenoate 13 (38.0 g, 81%) as clear oil.¹H NMR (400 MHz; CDCl3): δ 5.63 (s, 1H), 4.18-4.12 (q, J = 7.2 Hz, 2H), 2.61-2.57 (t, J = 7.60 Hz, 2H), 2.16-2.12 (t, J = 7.6 Hz, 2H), 1.50-1.43 (m, 4H), 1.37- 1.25 (m, 11H), 0.91-0.88 (t, J = 6.80 Hz, 6H). Synthesis of ethyl 3-pentyloctanoate (14) [001325] To a stirred solution of ethyl 3-pentyl-2-octenoate 13 (150 g, 624 mmol) in ethyl acetate (1.8 L) at room temperature was added 10% Pd/C (70 g) under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature under hydrogen pressure (100 PSI). The progress of the reaction was monitored by TLC and ELSD. The reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to offer ethyl 3-pentyloctanoate 14 (130 g, 86%) as a yellow color liquid.¹H NMR (400 MHz; CDCl₃): δ 4.16-4.11 (q, J = 6.8 Hz, 2H), 2.24-2.22 (d, J = 6.80 Hz, 2H), 1.87-1.85 (m, 1H), 1.34-1.22 (m, 19H), 0.91-0.88 (t, J = 6.80 Hz, 6H). Synthesis of 3-pentyloctan-1-ol (Int-4) [001326] To a stirred solution of ethyl 3-pentyloctanoate 14 (65 g, 285 mmol) in tetrahydrofuran (455 mL) was added aluminum lithium tetrahydride (10.8 g, 285 mmol, 2M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2h. The progress of the reaction was monitored by TLC, starting material was consumed. The reaction was cooled to 0 °C and quenched dropwise by 75 mL of sodium hydroxide solution. Ethyl acetate (1 L) and water (75 mL) were added slowly to the reaction mixture at 0-5 °C. The reaction mixture was stirred for 30 min at the same temperature and sodium sulfate (250 g) was added. Upon completion, the mixture was filtered. The solid was washed with ethyl acetate (3x 500 mL) and the filtrate was concentrated under reduced pressure to give 3-pentyloctan-1-ol 4 (40 g, 70%) as a colorless oil.¹H NMR (400 MHz; CDCl3): δ 3.70-3.66 (t, J = 6.8 Hz, 2H), 1.57-1.52 (q, J = 6.80 Hz, 2H), 1.45-1.43 (m, 1H), 1.34-1.27 (m, 16H), 0.92-0.88 (t, J = 6.80 Hz, 6H). Route B: [001327] A three necked flask (1000 mL) and stirrer bar were dried with a heat gun and cooled under vacuum. Once cooled, nitrogen was introduced into the flask. Copper bromide (3.03 g, 0.1 eq., 21.1 mmol) and lithium chloride (1.79 g, 0.2 eq., 42.2 mmol) were added, then the flask was placed under vacuum, heated with a heat gun. The flask was allowed to cool to room temperature and nitrogen was introduced into the flask. Dry tetrahydrofuran (264 mL) was added and the mixture was stirred for 10 min during which time the solid was dissolved. The flask was placed in an ice bath and stirred for 5 min. Methyl (E)-2-octenoate 15 (33 g, 211 mmol) and chlorotris(methyl)silane (27.5 g, 1.2 eq., 253 mmol) were added to the reaction mixture at 0 °C and the solution was stirred for 30 min at 0 °C.1M THF solution of magnesium 1-pentanide bromide 16 (253 mL, 1.2 eq., 253 mmol) was added dropwise to the reaction mixture and stirred at 0 °C for another 1 h. The progress of the reaction was monitored by TLC. The solution was poured into saturated NH4Cl solution (250 mL) and extracted with Et2O (2 × 250 mL). The combined organic extracts were washed with brine (250 mL), dried over sodium sulfate, and filtered and the solvent was evaporated under vacuum to get crude which was purified by column chromatography using heptane as eluent to afford the methyl 3- pentyloctanoate 14a (25 g, 51.8%) as a yellow liquid.¹H NMR (400 MHz; CDCl₃): δ 3.66 (s, 3H), 2.24 (d, J = 6.8 Hz, 2H), 1.80 – 1.91 (m, 1H), 1.33 – 1.27 (m, 18H), 0.89 (t, J = 6.8 Hz, 6H). Synthesis of 3-pentyloctan-1-ol (Int-4) [001328] To a stirred solution of methyl 3-pentyloctanoate 14a (25 g, 109 mmol) in tetrahydrofuran (175 mL) was added aluminum (3+) lithium tetrahydride (54.7 mL, 109 mmol) (2M in THF) slowly at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2h. The progress of the reaction was monitored by TLC until starting material was consumed. The reaction was cooled to 0 °C and quenched dropwise by addition of 10 mL of sodium hydroxide solution. Ethyl acetate (500 mL) and water (50 mL) were added to the reaction mixture slowly at 0-5 °C. The reaction mixture was stirred for 30 min at the same temperature and sodium sulfate (10 g) was added into the reaction mixture and filtered. The solid was washed with ethyl acetate (3x 200 mL) and the filtrate was concentrated under reduced pressure to give 3-pentyl-1-octanol Int-4 (21.2 g, 96.6%) as colorless oil.¹H NMR (400 MHz; CDCl3): δ 1.58 – 1.49 (m, 2H), 1.45 – 1.38 (m, 3H), 1.34 – 1.28 (m, 4H), 1.27 – 1.20 (m, 11H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of 9-oxo-16-(3-pentyloctyloxycarbonyl)hexadecanoic acid (5) [001329] To a stirred solution of 9-oxoheptadecanedioic acid 3 (31 g, 98.6 mmol), and 3- pentyl-1-octanol Int-4 (17.8 g, 0.9 eq., 88.7 mmol) in tetrahydrofuran (930 mL) was added EDC.HCl (22.7 g, 1.2 eq., 118 mmol) and N,N-dimethyl-4-pyridylamine (12 g, 98.6 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to get the crude mixture which was purified with column chromatography using 0-5% Methanol in DCM as eluent to afford 9-oxo-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid 5 (20 g, 40.8%) as a brown color liquid. ELSD analysis: Purity 89.28%, Calculated C30H56O5 = 496.41, Observed = 497.30 (m/z, M+H⁺). Synthesis of tert-butyl 3-pentyloctyl 9-oxoheptadecanedioate (6) [001330] To a stirred solution of 9-oxo-16-(3-pentyloctyloxycarbonyl)hexadecanoic acid 5 (20 g, 40.24 mmol) in dichloromethane (250 mL) was added 2,2,2-trifluoroacetyl trifluoroacetate (20.32 g, 2.4 eq., 97 mmol) dropwise at 0 °C. After 15 min, tert-butyl alcohol (10.56 g, 3.5 eq., 142 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 36h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with DCM, and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated to dryness. The resultant crude compound was purified by column chromatography using 0-5% ethyl acetate in heptane as eluent to give tert-butyl 3-pentyloctyl 9- oxoheptadecanedioate 6 (14 g, 69.7%) as brown color liquid.¹H NMR (400 MHz; CDCl₃): δ 4.07 (t, J = 6.8 Hz, 2H), 2.37 (t, J = 7.6 Hz, 4H), 2.27 (t, J = 7.2 Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.62 – 1.57 (m, 3H), 1.55 – 1.51 (m, 6H), 1.43 (s, 9H), 1.32 – 1.25 (m, 30H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of tert-butyl 3-pentyloctyl 9-hydroxyheptadecanedioate (7) [001331] To a stirring solution of tert-butyl 3-pentyloctyl 9-oxoheptadecanedioate 6 (0.8 g, 1.45 mmol) in tetrahydrofuran (10 mL) was added Sodium borohydride (54.7 mg, 1.45 mmol) at room temperature under nitrogen atmosphere. Then the reaction mixture was stirred for 1h at room temperature. The progress of the reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate and concentrated to get the crude compound which was purified by flash column chromatography using 0 - 4% ethyl acetate in hheptane as eluent to get tert-butyl 3-pentyloctyl 9- hydroxyheptadecanedioate 7 (720 mg, 89.6%) as colorless liquid.¹H-NMR (400 MHz, CDCl₃): δ 4.07 (t, J = 8 Hz, 2H), 2.37 (t, J = 7.6 Hz, 4H), 2.27 (t, J = 7.2 Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.62 – 1.51 (m, 8H), 1.43 (s, 9H), 1.35 – 1.20 (m, 28H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of tert-butyl 3-pentyloctyl 9-[4-(dimethylamino)butyroxy]heptadecanedioate (9) [001332] To a stirring solution of 4-(dimethylamino)butyric acid-hydrogen chloride 8 (435 mg, 2.6 mmol) in dichloromethane (31.6 mL) was added N-ethylbis(isopropyl)amine (2.33 mL, 5 eq., 13 mmol) and N,N-dimethyl-4-pyridylamine (555 mg, 1.8 eq., 4.54 mmol) at room temperature. The reaction mixture was stirred until the reaction mixture became clear then EDC.HCl (2.49 g, 5 eq., 13 mmol) was added and stirred for another 10 min followed by the addition of tert-butyl 3-pentyloctyl 9-hydroxyheptadecanedioate 7 (720 mg, 0.5 eq., 1.3 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 24h at room temperature. The progress of the reaction was monitored by TLC and ELSD. After complete consumption of the starting material, water (15 mL) and DCM (20 mL) were added to the reaction mixture and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to get a crude mixture. The resultant crude material was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% ethyl acetate in heptane as eluent to afford tert-butyl 3-pentyloctyl 9-[4- (dimethylamino)butyroxy]heptadecanedioate 9 (0.4 g, 23.0%) as a yellow liquid. ELSD analysis: Purity 82.35%, Calculated C40H77NO6 = 667.58, Observed = 668.35 (m/z, M+H⁺). A second batch was prepared starting with 14 g of Int-7 and 13.6 g (80.6%) of compound 9 was isolated as a yellow liquid. ELSD analysis: Purity 99.87%, Calculated C40H77NO6 = 667.58; Observed = 668.40 (m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.90 – 4.83 (m, 1H), 4.07 (t, J = 6.8 Hz, 2H), 2.33 – 2.2.25 (m, 6H), 2.21 (s, 6H), 2.20 – 2.2.16 (m, 2H), 1.79 – 1.76 (m, 2H), 1.66 – 1.48 (m, 8H), 1.43 (s, 9H), 1.32 – 1.19 (m, 35H), 0.87 (t, J = 6.8 Hz, 6H). Synthesis of 9-[4-(dimethylamino)butyroxy]-16-(3-pentyloctyloxycarbonyl)hexadecanoic acid (10)

[001333] To a stirred solution of tert-butyl 3-pentyloctyl 9-[4-(dimethylamino) butyroxy]heptadecanedioate 9 (0.4 g, 0.599 mmol) in dichloromethane (10 mL), was added trifluoroacetic acid (688 µL, 15 eq., 8.98 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to get the crude product which was dissolved in Ethyl acetate (30 mL) and washed with saturated sodium bicarbonate (2 x 20 mL) solution. The aqueous layer was extracted with ethyl acetate (2 x 30 mL), then all the organic layers were combined, dried over sodium sulfate, concentrated under reduced pressure to give 9-[4-(dimethylamino)butyroxy]-16-(3-pentyloctyloxycarbonyl)hexadecanoic acid - trifluoroacetic acid 10 (0.30 g, 81.8%) as a yellow liquid. ELSD analysis: Purity 98.06%, Calculated C36H69NO6 = 611.51, Observed = 612.25 (m/z, M+H⁺). A second batch was prepared starting with 13.5 g of compound-9 and 11 g (88.9%) of compound 10 was isolated as a yellow color liquid.¹H NMR (400 MHz, CDCl₃): δ 4.92 – 4.85 (m, 1H), 4.07 (t, J = 6.8 Hz, 2H), 2.92 – 2.51 (m, 2H), 2.51 (s, 6H), 2.45 – 2.32 (m, 2H), 2.45 – 2.23 (m, 4H), 2.04 (m, 2H), 1.65 – 1.53 (m, 6H), 1.51 – 1.45 (m, 2H), 1.41 – 1.38 (m, 2H), 1.35 – 1.18 (m, 34H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-46 Synthesis of tricyclo[3.3.1.02,7]nonan-6-ylmethanol (18) [001334] A 30 mL reaction vial equipped with a magnetic bar was charged with tricyclo[3.3.1.02,7]nonane-6-carboxylic acid 17 (150 mg, 1 eq., 902 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (102 mg, 3 eq., 2.71 mmol) and the reaction temperature was raised to 40 °C then BF₃·OEt₂ (226 µL, 2 eq., 1.8 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The progress of the reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactants, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (5 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (2- methylbicyclo[2.2.1]heptan-2-yl)methanol 18 (120 mg) as light yellow semi solid. The crude product was used in the next step without purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid by TLC using 20% ethyl acetate in heptane as the mobile phase. In bromocresol stain, the acid starting materials appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-(tricyclo[3.3.1.02,7]nonan-6-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-46) [001335] To a stirred solution of 9-((4-(dimethylamino)butanoyl)oxy)-17-oxo-17-((3- pentyloctyl)oxy)heptadecanoic acid - trifluoroacetic acid 10 (250 mg, 1 eq., 344 µmol) in dichloromethane (10.6 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) at room temperature and the resulting mixture was stirred until the reaction mixture became clear (10 min). Then EDC.HCl (330 mg, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.75 eq., 603 µmol) were added to the reaction mixture and stirred for another 10 min. Then (2- methylbicyclo[2.2.1]heptan-2-yl)methanol 18 (52.34 mg, 1.0 eq., 344 mmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (5 mL) and DCM (10 mL) were added to the reaction and extracted with DCM (2 x 5 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get the crude mixture. The resultant crude was purified by flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 1-(3-pentyloctyl) 17- (tricyclo[3.3.1.02,7]nonan-6-ylmethyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-46 (100 mg, 38.92%) as colorless liquid. ELSD analysis: Purity 99.00%, Calculated C₄₆H₈₃NO₆ = 745.62; Observed = 746.75 (m/z, M+H⁺). ¹H NMR (400 MHz, CDCl₃): δ 4.88-4.82 (m, 1H), 4.21- 4.04 (m, 4H), 2.37-2.25 (m, 9H), 2.22 (s, 6H), 2.14-2.09 (m, 1H), 1.80-1.73 (m, 4H), 1.68-1.43 (m, 16H), 1.41-1.38 (m, 1H), 1.37-1.19 (m, 35H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-55 Synthesis of (2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)methanol (20) [001336] A 30 mL reaction vial equipped with magnetic bar was charged 2,3,3- trimethylbicyclo[2.2.1]heptane-2-carboxylic acid 19 (150 mg, 1 eq., 823 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (93.4 mg, 3 eq., 2.47 mmol) and the reaction temperature was raised to 40 °C, and BF3.OEt2 (207 µL, 2 eq., 1.65 mmol) was added dropwise. The reaction was then stirred at 70 °C for 24 h. The reaction was monitored by TLC (bromocresol stain). After complete consumption of the reactant, the reaction was quenched with water (5.0 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (5 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)methanol 20 (120 mg) as light yellow semi-solid crude. The crude product was used in the next step without purification. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as the mobile phase. In bromocresol stain, the acid appears as a yellow stain and the new product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-((2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)methyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-55) [001337] To a stirred solution of 9-((4-(dimethylamino)butanoyl)oxy)-17-oxo-17-((3- pentyloctyl)oxy)heptadecanoic acid - trifluoroacetic acid 10 (250 mg, 408 µmol) in dichloromethane (12.5 mL), was added N-ethylbis(isopropyl)amine (366 µL, 5 eq., 2.04 mmol) at room temperature and stirred until reaction mixture became clear (10 min). Then EDC.HCl (391 mg, 5 eq., 2.04 mmol) and N,N-dimethyl-4-pyridylamine (87.2 mg, 1.75 eq., 714 µmol) were added to the reaction mixture and stirred for another 10 min. (2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)methanol 20 (68.7 mg, 1.0 eq., 408 mmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (15 mL) and DCM (10 mL) were added and extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 1-(3- pentyloctyl) 17-((2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)methyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-55 (82 mg, 26.37%) as colorless liquid. ELSD analysis: Purity 99.91%; Calculated C₄₇H₈₇NO₆ = 761.65; Observed = 762.65 (m/z, M+H⁺). ¹H NMR (400 MHz, CDCl3): δ 4.88 - 4.82 (m, 1H), 4.09 – 4.03 (m, 3H), 3.95 – 3.92 (m, 1H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 1.91–1.88 (m, 1H), 1.84 (bs, 1H), 1.82 – 1.74 (m, 2H), 1.68 (bs, 1H), 1.65 – 1.53 (m, 6H), 1.52-1.43 (m, 5H), 1.42 – 1.37 (m, 1H), 1.34 – 1.23 (m, 35H), 1.10 – 1.07 (m, 1H), 0.97-0.95 (m, 6H), 0.92 (s, 3H), 0.91- 0.86 (m, 6H). Synthesis of CT-47 Synthesis of rac-((1R,6R,7S)-bicyclo[4.2.0]octan-7-yl)methanol (22) [001338] To a 30 mL reaction vial equipped with a magnetic bar was charged (1R,6R,7S)- bicyclo[4.2.0]octane-7-carboxylic acid 21 (150 mg, 973 µmol) in tetrahydrofuran (10 mL) at room temperature. To this suspension was added sodium borohydride (110 mg, 3 eq., 2.92 mmol) slowly and the reaction temperature was raised to 40 °C, then BF₃.OEt₂ (244 µL, 2 eq., 1.95 mmol) was added drop wise under stirring. The reaction mixture was heated at 70 °C for 16h. The reaction progress was monitored by TLC. After consumption of the starting material, the reaction was allowed to cool to room temperature. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction mixture and the organic layer was separated. The organic layer was washed with brine (25 mL) and dried with sodium sulfate, filtered and concentrated under reduced pressure to yield {(1R,6R,7S)- bicyclo[4.2.0]oct-7-yl}methanol 22 (120 mg, 87.9%) as light yellow color semi solid. The crude compound was used for the next reaction without purification.The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as the mobile phase. In bromocresol stain, the acid starting material appeared as a yellow stain and the new spot for the product disappeared. Synthesis of rac-1-(((1R,6R,7S)-bicyclo[4.2.0]octan-7-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-47) [001339] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 344 µmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N- dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature and the mixture was stirred until the reaction mixture became clear. EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added to the reaction mixture and stirred for another 10 minutes. Then a solution of {(1S,6S,7R)-bicyclo[4.2.0]oct- 7-yl}methanol 22 (48.3 mg, 344 µmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (10 mL) and DCM (100 mL) were added, and the mixture was extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get a crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50 % ethyl acetate in heptane to afford rac-1-(((1R,6R,7S)- bicyclo[4.2.0]octan-7-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-47 (117 mg, 46.2%) as yellow color liquid. ELSD analysis: Purity 99.20%; Calculated C₄₅H₈₃NO₆ = 733.62; Observed = 734.45(m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.88 – 4.82 (m, 1H), 4.09- 3.98 (m, 4H), 2.51 – 2.41 (m, 1H), 2.37 – 2.23 (m, 9H), 2.21 (s, 6H), 1.86 – 1.73 (m, 4H), 1.61 – 1.53 (m, 10H), 1.51 – 1.46 (m, 4H), 1.44 – 1.38 (m, 3H), 1.32 – 1.19 (m, 35H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-48 Synthesis of (1,6,6-trimethylbicyclo[2.1.1]hexan-5-yl)methanol (24) [001340] A 30 mL reaction vial equipped with magnetic bar was charged with 1,6,6- trimethylbicyclo[2.1.1]hexane-5-carboxylic acid 23 (150 mg, 892 µmol) in tetrahydrofuran (10 mL) at room temperature. To this suspension was added sodium borohydride (101 mg, 3 eq., 2.67 mmol) and the reaction temperature was raised to 40 °C, then BF3.OEt2 (223 µL, 2 eq., 1.78 mmol) was added dropwise. The reaction was then stirred at 70 °C for 24 h. The reaction was monitored by TLC (bromocresol stain). After complete consumption of the reactant, the reaction was quenched with water (10.0 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (1,6,6-trimethylbicyclo[2.1.1]hex-5-yl)methanol 24 (120 mg) as light yellow color semi solid. The crude compound was used for the next reaction without purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. Using bromocresol stain, the starting acid appeared as a yellow stain and the product alcohol spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-((1,6,6-trimethylbicyclo[2.1.1]hexan-5-yl)methyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-48) [001341] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 344 µmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N- dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature and stirred until reaction mixture became clear. EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added and stirred for another 10 minutes. Then a solution of (1,6,6-trimethylbicyclo[2.1.1]hex-5-yl)methanol 24 in DCM (2 mL) was added in to reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (10 mL) were added and extracted with DCM (2 x 15 mL), the combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50 % ethyl acetate in heptane to afford 1-(3-pentyloctyl) 17-((1,6,6- trimethylbicyclo[2.1.1]hexan-5-yl)methyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-48 (105 mg, 40.7%) as yellow color liquid. ELSD analysis: Purity 99.12%; Calculated C₄₆H₈₅NO₆ = 747.64; Observed = 748.45(m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.88 – 4.82 (m, 1H), 4.44 – 4.33 (m, 2H), 4.09 – 4.05 (m, 2H), 2.37 – 2.23 (m, 8H), 2.21 (s, 6H), 1.81 – 1.74 (m, 2H), 1.67 – 1.45 (m, 12H), 1.44 – 1.39 (m, 2H), 1.33 – 1.22 (m, 35H), 1.08 (s, 3H), 0.92 – 0.86 (m, 9H), 0.70 (s, 3H). Synthesis of CT-44 Synthesis of {(1R,2R,3S,4S,6R,7S,9R,11R,12S)-pentacyclo[7.3.1.1⁴,¹².0²,⁷.0⁶,¹¹]tetradec-3- yl}methanol (26) [001342] A 30 mL reaction vial equipped with magnetic bar was charged with (1R,2S,3R,4R,6R,7S,9S,11S,12S)-pentacyclo[7.3.1.1⁴,¹².0²,⁷.0⁶,¹¹]tetradecane-3-carboxylic acid 25 (150 mg, 646 µmol) in tetrahydrofuran (10 mL) at room temperature. To this suspension was added sodium borohydride (73.3 mg, 3 eq., 1.94 mmol) and the reaction temperature was raised to 40 °C, then BF3.OEt2 (161 µL, 2 eq., 1.29 mmol) was added dropwise. The reaction was then stirred at 70 °C for 24 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and water (20 mL), and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine (25 mL) and dried over sodium sulfate, concentrated under reduced pressure to get {(1R,2R,3S,4S,6R,7S,9R,11R,12S)-pentacyclo[7.3.1.1⁴,¹².0²,⁷.0⁶,¹¹]tetradec-3- yl}methanol 26 (130 mg) as light yellow color semi solid. The crude compound was used for the next reaction without purification. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the starting material acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(((2S,4R,4aS,6S,10S,11S)-decahydro-2,8,4,6-(epibutane[1,2,3,4]tetrayl) naphthalen-1-yl)methyl) 17-(3-pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy) heptadecanedioate (CT-44) [001343] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 344 µmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N- dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature. The reaction mixture was stirred until it became clear, then EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added and stirred for 10 min. at RT. {(1R,2S,3R,4R,6R,7S,9S,11S,12S)-pentacyclo [7.3.1.1⁴,¹².0²,⁷.0⁶,¹¹]tetradec-3-yl}methanol 26 (75.2 mg, 344 µmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (monitored by TLC), water (20 mL) and DCM (20 mL) were added, extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get the crude product. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% ethyl acetate in heptane to afford 1-(((2S,4R,4aS,6S,10S,11S)-decahydro-2,8,4,6-(epibutane[1,2,3,4]tetrayl) naphthalen-1- yl)methyl) 17-(3-pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy) heptadecanedioate CT-44 (77 mg, 27.5%) as light yellow liquid. ELSD analysis: Purity 99.69%; Calculated C₅₁H₈₉NO₆ = 811.67; Observed = 812.75(m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.96 (m, 1H), 4.16 (d, J = 7.6 Hz, 2H), 4.06 (t, J = 2.8 Hz, 2H), 2.34 – 2.25 (m, 8H), 2.22 (s, 6H), 1.90 – 1.97 (m, 1H), 1.84 – 1.78 (m, 7H), 1.76 – 1.70 (m, 10H), 1.63 – 1.44 (m, 9H), 1.43 – 1.1.39 (m, 1H), 1.33 – 1.20 (m, 36H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-45 Synthesis of 3-pentyloctyl (tricyclo[3.3.0.0³,⁷]oct-1-yl)methyl 9-[4-(dimethylamino) butyroxy]heptadecanedioate (28) [001344] A 30 mL reaction vial equipped with magnetic bar was charged with tricyclo[3.3.0.0³,⁷]octane-1-carboxylic acid 27 (150 mg, 1 eq., 986 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (112 mg, 1 eq, 2.96 mmol). Then, the reaction temperature was raised to 40 °C, and BF3·OEt2 (247 µL, 2 eq., 1.97 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The progress of the reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine (10 mL) and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product ((tricyclo[3.3.0.0³,⁷]oct-1-yl)methanol 28 (110 mg) as off white semi-solid. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-(tricyclo[3.3.0.03,7]octan-1-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-45) [001345] To a stirring solution of 9-hydroxy-16-(3-pentyloctyloxycarbonyl)hexadecanoic acid- trifluoroacetic acid 10 (250 mg, 1 eq., 408 µmol) in dichloromethane (12.5 mL) was added N- ethylbis(isopropyl)amine (366 µL, 5 eq., 2.04 mmol) and N,N-dimethyl-4-pyridylamine (87.2 mg, 1.8 eq., 714 µmol) at room temperature. The reaction mixture was stirred until the mixture became clear and EDC.HCl (391 mg, 5 eq., 2.04 mmol) was added. The mixture was stirred for another 10 min and then (tricyclo[3.3.0.0³,⁷]oct-1-yl)methanol 28 (56.4 mg, 1 eq., 408 µmol) was added at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (10 mL), and DCM (20 mL) were added to the reaction mixture and the mixture was extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to get the crude compound. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% ethyl acetate in heptane to afford 1-(3- pentyloctyl) 17-(tricyclo[3.3.0.03,7]octan-1-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-45 (70 mg, 23.4%) as yellow color liquid. ELSD analysis: Purity 99.33%; Calculated C51H89NO6 = 731.61; Observed = 732.70 (m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.91 – 4.82 (m, 1H), 4.32 (s, 2H), 4.07 (t, J = 6.8 Hz, 2H), 2.33 – 2.25 (m, 10H), 2.22 (s, 6H), 2.15 (t, J = 2.4 Hz, 1H), 1.83 – 1.78 (m, 2H), 1.80 – 1.65 (m, 1H), 1.63 – 1.54 (m, 7H), 1.50 – 1.37 (m, 9H), 1.33 – 1.20 (m, 34H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-52 Synthesis of rac-((1R,5R)-bicyclo[3.2.0]heptan-2-yl)methanol (30) [001346] A 30 mL reaction vial equipped with magnetic bar was charged with (1S,5S)- bicyclo[3.2.0]heptane-2-carboxylic acid 29 (150 mg, 1.07 mmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (121 mg, 3 eq., 3.21 mmol). Then, the reaction temperature was raised to 40 °C, and BF₃·OEt₂ (269 µL, 2 eq., 2.14 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC. After complete consumption of the reactant, the reaction was quenched with brine (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product {(1S,5S)-bicyclo[3.2.0]hept-2- yl}methanol (80 mg) as colorless oil. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of rac-1-(((1R,5R)-bicyclo[3.2.0]heptan-2-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-52) [001347] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 344 µmol/0.344 mmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature. The reaction was stirred until the mixture became clear and EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added. The reaction was stirred for another 10 minutes and {(1S,5S)-bicyclo[3.2.0]hept-2-yl}methanol (43.5 mg, 344 µmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (20 mL) were added and extracted with DCM (2 x 15 mL), the combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50 % Ethyl Acetate in Heptane to afford rac-1-(((1R,5R)-bicyclo[3.2.0]heptan-2-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-52 (70 mg, 28.2%) as light yellow liquid. ELSD analysis: Purity 99.89%; Calculated C44H81NO6 = 719.61; Observed = 720.60(m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.88 – 4.82 (m, 1H), 4.05 (t, J = 7.2 Hz, 2H), 3.744 (d, J = 7.6 Hz, 1H), 2.82 – 2.75 (m, 1H), 2.55 – 2.48 (m, 1H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 2.19 – 2.06 (m, 3H), 1.82 – 1.74 (m, 2H), 1.71 – 1.68 (m, 2H), 1.67 – 1.59 (m, 6H), 1.57 – 1.49 (m, 6H), 1.45 – 1.39 (m, 1H), 1.35 – 1.18 (m, 35H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-51 Synthesis of (octahydro-1H-3,5,1-(epiethane[1,1,2]triyl)cyclobuta[cd]pentalen-2-yl)methanol (32) [001348] A 30 mL reaction vial equipped with a magnetic bar was charged with pentacyclo[5.4.0.0²,⁶.0³,¹⁰.0⁵,⁹]undecane-8-carboxylic acid 31 (150 mg, 788 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (89.5 mg, 3 eq., 2.37 mmol). Then, the reaction temperature was raised to 40 °C, and BF₃.OEt₂ (198 µL, 2 eq., 1.58 mmol) was added dropwise. The reaction mixture was then heated at 70 °C for 24 h. The reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (pentacyclo[5.4.0.0²,⁶.0³,¹⁰.0⁵,⁹]undec-8-yl)methanol 32 (70 mg) as off white semi-solid. The crude product was used for the next reaction without further purification. Synthesis of 1-((octahydro-1H-3,5,1-(epiethane[1,1,2]triyl)cyclobuta[cd]pentalen-2-yl)methyl) 17-(3-pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (CT-51) [001349] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (0.3 g, 413 µmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (371 µL, 5 eq., 2.07 mmol) and N,N-dimethyl-4-pyridylamine (88.4 mg, 1.8 eq., 723 µmol) at room temperature. The reaction mixture was stirred until the mixture became clear and EDC.HCl (396 mg, 5 eq., 2.07 mmol) was added and stirred for another 10 minutes. Then (pentacyclo[5.4.0.0²,⁶.0³,¹⁰.0⁵,⁹]undec-8-yl)methanol 32 (72.8 mg, 413 µmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (10 mL) were added and the reaction mixture was extracted with DCM (2 x 15 mL), and the combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 1-((octahydro-1H-3,5,1- (epiethane[1,1,2]triyl)cyclobuta[cd]pentalen-2-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-51 (235 mg, 73.8%) as yellow color liquid. ELSD analysis: Purity 99.07%, Calculated C₄₈H₈₃NO₆ = 769.62; Observed = 770.65(m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.89 – 4.82 (m, 1H), 4.07 (t, J = 7.2 Hz, 2H), 3.74 – 3.65 (m, 2H), 2.66 – 2.59 (m, 1H), 2.56 – 2.49 (m, 2H), 2.44 – 2.41 (m, 1H), 2.33 – 2.25 (m, 9H), 2.21 (s, 7H), 2.17 – 2.12 (m, 1H), 1.99 (t, J = 7.6 Hz, 1H), 1.81 – 1.74 (m, 2H), 1.63 – 1.55 (m, 9H), 1.54 – 1.46 (m, 5H), 1.43 – 1.37 (m, 1H), 1.34 – 1.20 (m, 32H), 1.04 – 1.00 (m, 1H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-43 Synthesis of (2-methylbicyclo[2.2.1]heptan-2-yl)methanol (34) [001350] A 30 mL reaction vial equipped with magnetic bar was charged with 2- methylbicyclo[2.2.1]heptane-2-carboxylic acid 33 (200 g, 1.30 mmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (147 mg, 3 eq., 3.89 mmol) and the temperature of the reaction was raised to 40 °C, then BF3.OEt2 (325 µL, 2 eq., 2.59 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC (bromocresol stain). After complete consumption of the starting material, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (2- methylbicyclo[2.2.1]heptan-2-yl)methanol 34 (150 mg) as light yellow semi solid, which was used into next step without futher purification. Synthesis 1-((2-methylbicyclo[2.2.1]heptan-2-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-43) [001351] To a stirred solution of 9-((4-(dimethylamino)butanoyl)oxy)-17-oxo-17-((3- pentyloctyl)oxy)heptadecanoic acid - trifluoroacetic acid 10 (250 mg, 408 µmol) in dichloromethane (12.5 mL) was added N-ethylbis(isopropyl)amine (366 µL, 5 eq., 2.04 mmol) at room temperature. The reaction mixture was stirred until the mixture became clear and added EDC.HCl (391 mg, 5 eq., 2.04 mmol) and N,N-dimethyl-4-pyridylamine (87.2 mg, 1.75 eq., 714 µmol) to the reaction mixture, stirred for another 10 min. To reaction solution was added (2-methylbicyclo[2.2.1]heptan-2- yl)methanol 34 (85.8 mg, 1.5 eq., 6.12 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (10 mL) and DCM (10 mL) were added and the reaction mixture was extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 3-pentyloctyl (tricyclo[4.3.1.1³,⁸]undec-1-yl)methyl 9-[4-(dimethylamino)butyroxy] heptadecanedioate CT-43 (115 mg, 43.1%) as a colorless liquid. ELSD analysis: Purity 99.48%, Calculated C45H83NO6 = 733.62; Observed = 734.75(m/z, M+H⁺). ¹H NMR (400 MHz, CDCl3): δ 4.88-4.82 (m, 1H), 4.07 (t, J = 7.2 Hz, 2H), 3.88 (s, 2H), 2.33-2.25 (m, 8H), 2.21 (s, 6H), 1.94-1.93 (bs, 1H), 1.80-1.76 (m, 2H), 1.63-1.59 (m, 6H), 1.57-1.47(m, 6H), 1.34- 1.17 (m, 38H), 1.09-0.93 (m, 5H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-56 Synthesis of {(1R,2S,3r,4R,5S)-tricyclo[3.2.1.0²,⁴]oct-3-yl}methanol (36) [001352] To a stirred solution of (1R,2S,3r,4R,5S)-tricyclo[3.2.1.0²,⁴]octane-3-carboxylic acid 17 (0.2 g, 1eq., 1.31 mmol) in tetrahydrofuran (10 mL) was added sodium borohydride (149 mg, 3 eq., 3.94 mmol) slowly at room temperature, and then the temperature was raised up to 40 °C. BF₃.OEt₂ (373 mg, 2 eq., 2.63 mmol) was added drop wise under stirring at 40 °C . The reaction temperature was then raised up to 70 °C and the reaction mixture was stirred at the same temperature for 16h. The reaction progress was monitored by TLC. After consumption of the starting material, the reaction was cooled to room temperature. Then, water (20 mL) and ethyl acetate (20 mL) were added and the organic layer was separated. The organic layer was washed with brine (25 mL), dried with sodium sulfate, filtered, and concentrated under reduced pressure to get {(1R,2S,3r,4R,5S)- tricyclo[3.2.1.0²,⁴]oct-3-yl}methanol 36 (145 mg) as yellow color semi solid. The crude compound was used in next step without further purification. The reaction was performed in three batches and combined for the next reaction. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-(((1R,2S,3r,4R,5S)-tricyclo[3.2.1.02,4]octan-3-yl)methyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-56) [001353] To a stirring solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid 10 (3.51 g, 1 eq., 5.74 mmol) in dichloromethane (35 mL) was added N,N-dimethyl-4-pyridylamine (701 mg, 5.74 mmol) and EDC.HCl (5.5 g, 5 eq., 28.7 mmol). The reaction mixture was stirred for 10 min and added {(1R,2S,3r,4R,5S)- tricyclo[3.2.1.0²,⁴]oct-3-yl}methanol 36 (555 mg, 0.7 eq., 4.02 mmol). The reaction mixture was stirred at room temperature for 16h. After completion of reaction, the reaction mixture was diluted with DCM (50 mL), washed with saturated sodium bicarbonate solution (50 mL X 2) and water (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% EA in Heptane to afford {(1R,2S,3r,4R,5S)-tricyclo[3.2.1.0²,⁴]oct-3-yl}methyl 3-pentyloctyl 9-[4- (dimethylamino)butyroxy]heptadecanedioate CT-56 (2.4 g, 57.1%) as a yellow color liquid. ELSD analysis: Purity 99.74%; Calculated C45H81NO6 = 731.61; Observed = 732.50 (m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.88 – 4.83 (m, 1H), 4.07 (t, J = 7.0 Hz, 2H), 3.79 (d, J = 7.36 Hz, 2H), 2.41 - 2.25 (m, 9H), 2.22 (s, 6H), 1.82 - 1.75 (m, 2H), 1.65 - 1.55 (m, 7H), 1.53 - 1.48 (m, 4H), 1.44 – 1.38 (m, 3H), 1.34 – 1.20 (m, 34H), 1.08-1.03 (m, 1H), 0.94-0.92 (m, 1H), 0.88 (t, J = 6.8 Hz, 6H), 0.66 - 0.64 (m, 1H), 0.61 (s, 1H). Synthesis of CT-53 Synthesis of {(1S,5S)-bicyclo[3.2.0]hept-2-yl}methanol (38) [001354] To a stirred solution of (1S,5S)-bicyclo[3.2.0]heptane-2-carboxylic acid 37 (150 mg, 1.07 mmol) in tetrahydrofuran (10 mL) was added sodium borohydride (121 mg, 3 eq., 3.21 mmol) slowly at room temperature. The temperature of the reaction mixture was raised up to 40 °C and BF₃.OEt₂ (269 µL, 2 eq., 2.14 mmol) was added drop wise under stirring. The reaction temperature was raised up to 70 °C and the reaction mixture was stirred at the same temperature for 16h. The reaction progress was monitored by TLC. After starting material was consumed, the reaction was allowed to cool to room temperature. Then water (10 mL) and ethyl acetate (10 mL) were added and the organic layer was separated. The organic layer was washed with brine (20 mL) and dried with sodium sulfate, filtered and concentrated under reduced pressure to get {(1S,5S)-bicyclo[3.2.0]hept-2- yl}methanol 38 (120 mg) as light yellow color semi solid. The crude compound was used in next step without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(((1R,5S)-bicyclo[3.2.0]heptan-3-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-53) [001355] To a stirring solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (0.3 g, 413 µmol) in dichloromethane (12.7 mL, 198 mmol) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) were added at room temperature and stirred until reaction mixture became clear. Then, EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added and stirred for another 10 minutes. {(1R,5S)-bicyclo[3.2.0]hept-3-yl}methanol 38 (52.2 mg, 413 µmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (10 mL) were added and the mixture was extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% ethyl acetate in heptane to afford 1-(((1R,5S)-bicyclo[3.2.0]heptan-3-yl)methyl) 17-(3- pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-53 (0.2 g, 67.2%) as yellow liquid. ELSD analysis: Purity 99.71%; Calculated C₄₄H₈₁NO₆ = 719.61; Observed = 720.60 (m/z, M+H⁺). ¹H NMR (400 MHz, CDCl₃): δ 4.88 – 4.82 (m, 1H), 4.18 – 4.05 (m, 4H), 2.81 – 2.72 (m, 2H), 2.70 – 2.64 (m, 1H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 2.19 – 2.13 (m, 2H), 1.81 – 1.76 (m, 2H), 1.63 – 1.55 (m, 7H), 1.53 – 1.45 (m, 6H), 1.43 – 1.39 (m, 1H), 1.32 – 1.21 (m, 35), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-49 Synthesis of rac-((1R,7R,8S)-bicyclo[5.2.0]nonan-8-yl)methanol (40) [001356] A 30 mL reaction vial equipped with magnetic bar was charged with (1S,7S,8R)- bicyclo[5.2.0]nonane-8-carboxylic acid 39 (0.3 g, 1.78 mmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (202 mg, 3 eq., 5.35 mmol) and the reaction temperature was raised to 40 °C. Then BF₃.OEt₂ (447 µL, 2 eq., 3.57 mmol) was added dropwise. The reaction was heated and stirred at 70 °C for 24 h. The reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product {(1S,7S,8R)-bicyclo[5.2.0]non-8- yl}methanol 40 (240 mg) as off white semi-solid. The crude product was used for the next reaction without further purification. The reaction was performed in two batches. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of rac-1-(((1R,7R,8S)-bicyclo[5.2.0]nonan-8-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-49) [001357] To a stirring solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (2 g, 2.75 mmol) in DCM (84 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature. The reaction mixture was stirred until the reaction mixture became clear and EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added and stirred for another 10 minutes. A solution of {(1R,7R,8S)-bicyclo[5.2.0]non-8-yl}methanol 40 (297 mg, 0.7 eq., 1.93 mmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (20 mL) were added and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford rac-1- (((1R,7R,8S)-bicyclo[5.2.0]nonan-8-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-49 (980 mg, 47.5%) as light yellow liquid. ELSD analysis: Purity 99.54%; Calculated C₄₆H₈₅NO₆ = 747.64; Observed = 748.55 (m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.87 - 4.82 (m, 1H), 4.09 - 3.97 (m, 4H), 2.58 – 2.42 (m, 4H), 2.38 – 2.32 (m, 7H), 2.29 – 2.24 (m, 4H), 2.21 – 2.15 (m, 1H), 1.95 – 1.71 (m, 8H), 1.65 – 1.55 (m, 9H), 1.53 – 1.46 (m, 3H), 1.43 – 1.37 (m, 1H), 1.34 – 1.19 (m, 34H), 1.17 – 1.15 (m, 1H), 1.01 – 0.98 (m, 2H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-50 Synthesis of {(1R,2S,5R,6S)-tricyclo[4.2.0.0²,⁵]oct-3-yl}methanol (42) [001358] A 30 mL reaction vial equipped with magnetic bar was charged with (1R,2S,5R,6S)- tricyclo[4.2.0.0²,⁵]octane-3-carboxylic acid 41 (150 mg, 1eq., 986 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (112 mg, 3 eq., 2.96 mmol). The reaction temperature was raised to 40 °C, and BF₃.OEt₂ (247 µL, 2 eq., 1.97 mmol) was added dropwise. The reaction mixture was then heated at 70 °C for 24h. The progress of the reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine (15 mL) and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product {(1R,2S,5R,6S)-tricyclo[4.2.0.0²,⁵]oct-3-yl}methanol 42 (90 mg) as off white semi-solid. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of rac-1-(3-pentyloctyl) 17-(((1R,2S,5R,6S)-tricyclo[4.2.0.02,5]octan-3-yl)methyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-50) [001359] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 1 eq., 344 µmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature. The reaction mixture was stirred until the mixture became clear. EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added to the reaction mixture and was stirred for another 10 minutes. A solution of {(1R,2S,5R,6S)- tricyclo[4.2.0.0²,⁵]oct-3-yl}methanol 42 (47.6 mg, 1.75 eq., 344 µmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was then stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (10 mL) were added and extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50 % ethyl acetate in heptane to afford rac-1-(3- pentyloctyl) 17-(((1R,2S,5R,6S)-tricyclo[4.2.0.02,5]octan-3-yl)methyl) 9-((4- (dimethylamino)butanoyl)oxy) heptadecanedioate CT-50 (87 mg, 34.5%) as yellow liquid. ELSD analysis: Purity 99.25%; Calculated C₄₅H₈₁NO₆ = 731.61; Observed = 732.55(m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.88 – 4.81 (m, 1H), 4.19 – 4.03 (m, 4H), 2.96 – 2.78 (m, 1H), 2.75 – 2.66 (m, 2H), 2.62 – 2.44 (m, 4H), 2.33 – 2.23 (m, 7H), 2.21 (s, 6H), 2.10 – 2.03 (m, 1H), 1.96 – 1.89 (m, 2H), 1.82 – 1.74 (m, 2H), 1.67 – 1.53 (m, 6H), 1.52 – 1.43 (m, 4H), 1.42 – 1.37 (m, 1H), 1.33 – 1.20 (m, 34H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-54 Synthesis of {(1R,2R,6S,8R)-pentacyclo[6.3.0.0²,⁶.0³,¹⁰.0⁵,⁹]undec-4-yl}methanol (44) [001360] A 30 mL reaction vial equipped with magnetic bar was charged with (1R,2R,6S,8R)- pentacyclo[6.3.0.0²,⁶.0³,¹⁰.0⁵,⁹]undecane-4-carboxylic acid 43 (150 mg, 2.3 eq., 788 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium boranuide (39.1 mg, 3 eq., 1.03 mmol). The reaction temperature was raised to 40 °C, and added BF3.OEt2 (86 µL, 2 eq., 689 µmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product {(1R,2R,6S,8R)- pentacyclo[6.3.0.0²,⁶.0³,¹⁰.0⁵,⁹]undec-4-yl}methanol 44 (96 mg) as colorless liquid. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-((decahydro-1,3,5-(epimethanetriyl)cyclopenta[cd]pentalen-2-yl)methyl) 17-(3- pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (CT-54) [001361] To a stirring solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid 10 (0.3 g, 1.4 eq., 490 µmol) in dichloromethane (10 mL) was added N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) at room temperature. The reaction mixture was stirred until the mixture became clear, then EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added. The reaction mixture was stirred for another 10 minutes and {(1R,2R,6S,8R)-pentacyclo[6.3.0.0²,⁶.0³,¹⁰.0⁵,⁹]undec-4-yl}methanol 44 (60.7 mg, 1 eq., 344 µmol) in DCM (2 mL) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (20 mL) were added and extracted with DCM (2 x 15 mL), the combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50 % Ethyl Acetate in Heptane to afford 1-((decahydro-1,3,5-(epimethanetriyl)cyclopenta [cd]pentalen-2-yl)methyl) 17-(3- pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy) heptadecanedioate CT-54 (0.2 g, 75.4%) as yellow liquid. ELSD analysis: Purity 99.53%; Calculated C₄₈H₈₃NO₆ = 769.62; Observed = 770.65(m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.88 – 4.82 (m, 1H), 4.09 – 3.97 (m, 4H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 2.10 – 1.88 (m, 7H), 1.81 – 1.74 (m, 2H), 1.65 – 1.59 (m, 2H), 1.57 – 1.53 (m, 4H), 1.52 – 1.45 (m, 4H), 1.43 – 1.39 (m, 2H), 1.34 – 1.24 (m, 37H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-57 Synthesis of (tricyclo[5.2.1.0²,⁶]dec-2-yl)methanol (46) [001362] A 30 mL reaction vial equipped with magnetic bar was charged with tricyclo[5.2.1.0²,⁶]decane-2-carboxylic acid 45 (150 mg, 832 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (94.5 mg, 3 eq., 2.5 mmol). Then, the reaction temperature was raised to 40 °C, and BF3.OEt2 (208 µL, 2 eq., 1.66 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine (10 mL) and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (tricyclo[5.2.1.0²,⁶]dec-2- yl)methanol (105 mg) as colorless oil. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-((octahydro-3aH-4,7-methanoinden-3a-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-57) [001363] To a stirring solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (211 mg, 344 µmol) in dichloromethane (10 mL, 156 mmol), N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) were added at room temperature and stirred until the reaction mixture became clear. Then, EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added and stirred for another 10 minutes. (tricyclo[5.2.1.0²,⁶]dec-2-yl)methanol 46 (57.3 mg, 344 µmol) in DCM (2 mL) was added to the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (15 mL) and DCM (10 mL) were added and the reaction mixture was extracted with DCM (2 x 15 mL), the combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 1-((octahydro-3aH-4,7-methanoinden-3a-yl)methyl) 17-(3-pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-57 (185 mg, 70.6%) as yellow liquid. ELSD analysis: Purity 99.76%; Calculated C47H85NO6 = 759.64; Observed = 760.65(m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.88 – 4.82 (m, 1H), 4.07 (t, J =7.2 Hz, 2H), 3.97 – 3.77 (m, 2H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 2.14 – 2.04 (m, 2H), 1.98 – 1.88 (m, 1H), 1.82 – 1.78 (m, 2H), 1.76 – 1.68 (m, 4H), 1.59 – 1.57 (m, 7H), 1.53 – 1.48 (m, 4H), 1.46 – 1.35 (m, 4H), 1.34 – 1.21 (m, 35H), 1.10 – 0.98 (m, 1H), 0.88 (d, J = 6.8 Hz, 6H). Synthesis of CT-60 Synthesis of tricyclo[3.2.1.02,4]octan-6-ylmethanol (48) [001364] A reaction vial equipped with magnetic bar was charged with tricyclo[3.2.1.0²,⁴]octane-6-carboxylic acid 47 (150 mg, 986 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (112 mg, 3 eq., 2.96 mmol). Then, the reaction temperature was raised to 40 °C, and BF3.OEt2 (247 µL, 2 eq., 1.97 mmol) was added dropwise. The reaction mixture was then stirred at 70 °C for 24 h. The progress of the reaction was monitored by TLC and bromocresol stain. After complete consumption of the starting material, the reaction was quenched with brine and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product (tricyclo[3.2.1.0²,⁴]oct-6-yl)methanol (90 mg) as colorless oil. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at Rf = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-(tricyclo[3.2.1.02,4]octan-6-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-60) [001365] To a stirring solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 344 µmol) in dichloromethane (10.6 mL), N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) and N,N- dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) were added at room temperature and stirred until the reaction mixture became clear. EDC.HCl (330 mg, 5 eq., 1.72 mmol) was added to reaction mixture and stirred for another 10 min. (Tricyclo[4.3.1.1³,⁸]undec-1-yl)methanol 48 (62.1 mg, 344 µmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was then stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, water (10 mL) and DCM (10 mL) were added and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude compound was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% ethyl acetate in heptane. Initial ELSD data showed only 61% desired product, therefore the compound was further purified by Prep HPLC, and lyophilized to get to 1-(3-pentyloctyl) 17-(tricyclo[4.3.1.13,8]undecan-1-ylmethyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-60 (91 mg, 30.4%) as light yellow liquid. ELSD analysis: Purity 99.81%; Calculated C₄₅H₈₁NO₆ = 731.61; Observed = 732.55(m/z, M+H⁺).¹ NMR (400 MHz, CDCl₃): δ 4.88 – 4.82 (m, 1H), 4.12 (d, J = 8 Hz, 1H), 4.07 (t, J = 6.8 Hz, 2H), 3.89 – 3.80 (m, 1H), 2.39 – 2.16 (m, 16H), 1.87 – 1.82 (m, 2H), 1.67 – 1.48 (m, 12H), 1.43 – 1.38 (m, 1H), 1.34 – 1.19 (m, 32H), 1.04 – 1.01 (m, 1H), 0.89 – 0.84 (m, 7H), 0.80 – 0.69 (m, 3H), 0.42 - 0.39 (m, 1H), 0.03 – -0.06 (m, 1H). Synthesis of CT-58 Synthesis of (4-methyltricyclo[4.3.1.13,8]undecan-4-yl)methanol (50) [001366] A 30 mL reaction vial equipped with magnetic bar was charged with 4- methyltricyclo[4.3.1.13,8]undecane-4-carboxylic acid 49 (150 mg, 720 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (112 mg, 3 eq., 2.96 mmol). Then, the reaction temperature was raised to 40 °C, and BF3·OEt2 (247 µL, 2 eq., 1.97 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC (bromo cresol stain). After complete consumption of the reactant, the reaction was quenched with brine (10 mL) and extracted with ethyl acetate (2x 20 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (4- methyltricyclo[4.3.1.13,8]undecan-4-yl)methanol 50 (95 mg) as colorless crude. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-((4-methyltricyclo[4.3.1.13,8]undecan-4-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-58) [001367] To a stirred solution of 9-((4-(dimethylamino)butanoyl)oxy)-17-oxo-17-((3- pentyloctyl)oxy)heptadecanoic acid-trifluoroacetic acid 10 (300 mg, 490 µmol) in dichloromethane (15 mL), N-ethylbis(isopropyl)amine (440 µL, 5 eq., 2.45 mmol) was added at room temperature and stirred for another 10 minutes until reaction mixture became clear. Then EDC.HCl (470 mg, 5 eq., 2.45 mmol) and N,N-dimethyl-4-pyridylamine (105 mg, 1.75 eq., 858 µmol) were added to the reaction mixture and stirred for another 10 min. (2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)methanol 50 (95.3 mg, 1.0 eq., 490 mmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (10 mL) and DCM (10 mL) were added and the reaction mixture was extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 1-((4-methyltricyclo[4.3.1.13,8]undecan-4- yl)methyl) 17-(3-pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-58 (140 mg, 36.2%) as yellow liquid. ELSD analysis: Purity 99.14%; Calculated C₄₉H₈₉NO₆ = 787.67; Observed = 788.65(m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.88 - 4.82 (m, 1H), 4.09 – 4.03 (m, 3H), 3.80 – 3.77 (m, 1H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 2.04–2.02 (m, 1H), 1.95-1.91 (m, 1H), 1.90 –1.82 (m, 4H), 1.81 – 1.73 (m, 4H), 1.63-1.58 (m, 8H), 1.57 – 1.55 (m, 2H), 1.54-1.46 (m, 8H), 1.42 – 1.37 (m, 1H), 1.33 – 1.22 (m, 32H), 1.07 (s, 3H), 0.89 (t, J=6.4 Hz, 6H). Synthesis of CT-59 Synthesis of rac-((1R,4R)-bicyclo[2.2.0]hexan-2-yl)methanol (52) [001368] A reaction vial equipped with magnetic bar was charged with rac-(1R,4R)- bicyclo[2.2.0]hexane-2-carboxylic acid 51 (150 mg, 1.19 mmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (135 mg, 3 eq., 3.57 mmol). Then, the reaction temperature was raised to 40 °C, and BF_3.OEt₂ (299 µL, 2 eq., 2.38 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC (bromocresol stain). After complete consumption of the reactant, the reaction was quenched with brine and extracted with ethyl acetate (2x 20 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product rac-((1R,4R)-bicyclo[2.2.0]hexan-2-yl)methanol 52 (110 mg) as off white semi-solid. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of rac-1-(((1R,4R)-bicyclo[2.2.0]hexan-2-yl)methyl) 17-(3-pentyloctyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-59) [001369] To a stirred solution of 9-((4-(dimethylamino)butanoyl)oxy)-17-oxo-17-((3- pentyloctyl)oxy)heptadecanoic acid 10 (250 mg, 409 µmol) in dichloromethane (10 mL, 82 mmol/L) was added EDC.HCl (392 mg, 5 eq., 2.04 mmol) and N,N-dimethyl-4-pyridylamine (87.3 mg, 1.75 eq., 715 µmol) and stirred for another 10 min. Then rac-((1R,4R)-bicyclo[2.2.0]hexan-2-yl)methanol 52 (91.7 mg, 1.0 eq., 817 mmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (15 mL) and DCM (10 mL) were added and extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford rac-1-(((1R,4R)-bicyclo[2.2.0]hexan-2-yl)methyl) 17-(3-pentyloctyl) 9- ((4-(dimethylamino)butanoyl)oxy)heptadecanedioate CT-59 (145 mg, 205 mmol, 50.27%) as yellow liquid. ELSD analysis: Purity 99.25%; Calculated C43H79NO6 = 705.59; Observed = 706.55(m/z, M+H⁺).¹H NMR (400 MHz, CDCl3): δ 4.88 - 4.82 (m, 1H), 4.30 – 4.18 (m, 1H), 4.09 – 4.01 (m, 3H), 2.91-2.86 (m, 1H), 2.74-2.58 (m, 1H), 2.51–2.44 (m, 2H), 2.33-2.24(m, 9H), 2.21 (s, 6H), 2.19–2.17 (m, 1H), 2.10-1.95 (m, 1H), 1.85-1.76 (m, 3H), 1.65 –1.61 (m, 1H), 1.59 – 1.54 (m, 4H), 1.53-1.48 (m, 4H), 1.42 – 1.38 (m, 1H), 1.37-1.19 (m, 34H), 0.88 (t, J=6.8 Hz, 6H). Synthesis of CT-62 Synthesis of (tricyclo[4.3.1.1³,⁸]undec-1-yl)methanol (54) [001370] A 30 mL reaction vial equipped with magnetic bar was charged with tricyclo[4.3.1.1³,⁸]undecane-1-carboxylic acid 53 (150 mg, 772 µmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (87.6 mg, 3 eq., 2.32 mmol). Then, the reaction temperature was raised to 40 °C, and BF₃.OEt₂ (193 µL, 2 eq., 1.54 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC and bromocresol stain. After complete consumption of the reactant, the reaction was quenched with brine and extracted with ethyl acetate (20 mL X 2). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product (tricyclo[4.3.1.1³,⁸]undec-1- yl)methanol 54 (110 mg) as colorless liquid. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-(tricyclo[4.3.1.13,8]undecan-1-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-62) [001371] To a stirred solution of 9-[4-(dimethylamino)butyroxy]-16-(3- pentyloctyloxycarbonyl)hexadecanoic acid-trifluoroacetic acid 10 (250 mg, 344 µmol) in dichloromethane (10 mL), N-ethylbis(isopropyl)amine (309 µL, 5 eq., 1.72 mmol) was added at room temperature and stirred until reaction mixture became clear (10 min). Then EDC.HCl (330 mg, 5 eq., 1.72 mmol) and N,N-dimethyl-4-pyridylamine (73.6 mg, 1.8 eq., 603 µmol) were added to the reaction mixture and stirred for another 10 min. (tricyclo[4.3.1.1³,⁸]undec-1-yl)methanol 54 (58 mg, 1 eq., 322 µmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (15 mL) and DCM (30 mL) were added and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 3- pentyloctyl (tricyclo[4.3.1.1³,⁸]undec-1-yl)methyl 9-[4-(dimethylamino)butyroxy]heptadecanedioate CT-62 (115 mg, 43.1%) as colorless oil. ELSD analysis: Purity 99.81%; Calculated C48H87NO6 = 773.65; Observed = 774.65(m/z, M+H⁺).¹H NMR (400 MHz, CDCl₃): δ 4.88 – 4.82 (m, 1H), 4.07 (t, J = 8 Hz, 2H), 3.67 – 3.66 (m, 2H), 2.33 – 2.25 (m, 8H), 2.21 (s, 6H), 2.16 -2.11 (m, 2H), 2.02 – 1.99 (m, 1H), 1.83 – 1.76 (m, 4H), 1.74 (s, 3H), 1.61 – 1.53 (m, 9H), 1.52 – 1.38 (m, 7H), 1.32 - 1.21 (m, 36H), 0.88 (t, J = 6.8 Hz, 6H). Synthesis of CT-62 Synthesis of tricyclo[4.1.0.02,4]heptan-5-ylmethanol (56) [001372] A reaction vial equipped with a magnetic bar was charged with tricyclo[4.1.0.02,4]heptane-5-carboxylic acid 55 (150 mg, 1.09 mmol) and tetrahydrofuran (10 mL). To this suspension was added sodium borohydride (123 mg, 3 eq., 3.26 mmol). Then, the reaction temperature was raised to 40 °C, and BF₃.OEt₂ (272 µL, 2 eq., 2.17 mmol) was added dropwise. The reaction was heated at 70 °C for 24 h. The reaction was monitored by TLC (bromocresol stain). After complete consumption of the reactant, the reaction was quenched with brine and extracted with ethyl acetate (2x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product tricyclo[4.1.0.02,4]heptan-5-ylmethanol 56 (100 mg) as off white semi-solid. The crude product was used for the next reaction without further purification. The product was confirmed by TLC and bromocresol stain. The product was observed at R_f = 0.4 just above the starting material acid in TLC using 20% ethyl acetate in heptane as mobile phase. In bromocresol stain, the acid appeared as a yellow stain and the product spot disappeared. Synthesis of 1-(3-pentyloctyl) 17-(tricyclo[4.1.0.02,4]heptan-5-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (CT-62) [001373] To a stirred solution of 9-((4-(dimethylamino)butanoyl)oxy)-17-oxo-17-((3- pentyloctyl)oxy)heptadecanoic acid 10 (250 mg, 409 µmol) in dichloromethane (5 mL, 82 mmol/L) was added EDC.HCl (392 mg, 5 eq., 2.04 mmol) and N,N-dimethyl-4-pyridylamine (87.3 mg, 1.75 eq., 715 µmol) and stirred for another 10 min. Then tricyclo[4.1.0.02,4]heptan-5-ylmethanol 56 (91.7 mg, 1.0 eq., 817 mmol) was added into the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After the starting material was consumed, water (5 mL) and DCM (10 mL) were added and extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to get crude mixture. The resultant crude was purified with flash column chromatography (the flash column was equilibrated with 10% triethylamine in heptane before use) using 0-50% Ethyl Acetate in Heptane to afford 1-(3-pentyloctyl) 17-(tricyclo[4.1.0.02,4]heptan-5-ylmethyl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate CT-62 (160 mg, 53.5%) as yellow liquid. ELSD analysis: Purity 99.04%; Calculated C₄₄H₇₉NO₆ = 717.59; Observed = 718.60 (m/z, M+H⁺). ¹H NMR (400 MHz, CDCl3): δ 4.87 - 4.81 (m, 1H), 4.09 – 3.98 (m, 4H), 2.56 – 2.51 (m, 1H), 2.46-2.29 (m, 13H), 1.89 – 1.87 (m, 2H), 1.63-1.53 (m, 6H), 1.50-1.48 (m, 4H), 1.44-1.38 (m, 3H), 1.35-1.19 (m, 33H), 1.02-0.99 (m, 1H), 0.88 (t, J=6.8, 6H), 0.67-0.65 (m, 1H), 0.61-0.58 (m, 1H), 0.38-0.34 (m, 1H), 0.29-0.27 (m, 1H), 0.15-0.12 (m,1H). Synthetic Scheme for Compound C82

Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-bromooctanoate (L168-2): [001374] To a solution of L168-1 (1.74 g, 7.78 mmol) in anhydrous dichloromethane (100 mL) was added EDC-HCl (2.49 g, 12.97 mmol) and DMAP (792 mg, 6.48 mmol), and the reaction was stirred at room temperature under nitrogen for 15 min. To this was added the bicycle alcohol (1.00 g, 6.48 mmol) in anhydrous dichloromethane (5 mL). The resulting mixture was stirred under nitrogen at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO₂: ethyl acetate/hexane 0-5%) to get L168-2 (2.21 g, 95%) as a clear oil; ¹H NMR (300 MHz, CDCl₃): δ ppm: δ 4.05 (t, J = 7.5 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), 2.26 (t, J = 7.5 Hz, 2H), 1.84 (p, J = 6.9 Hz, 2H), 1.65 – 1.21 (m, 23H). Synthesis of 3-pentyloctyl 8-bromooctanoate (L168-4) [001375] To a solution of the starting acid L168-1 (1.79 g, 8.05 mmol) in DCM (50 mL) was added DMAP (756 mg, 6.19 mmol) and EDC-HCl (3.54 g, 18.47 mmol) and the reaction was stirred at room temperature for 15 minutes. To this was added the alcohol L168-3 (1.24 g, 6.19 mmol) in anhydrous dicholoromethane (5 mL). The resulting mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash column chromatography (SiO₂: 0 to 5% ethyl acetate in hexane gradient) to yield 3-pentyloctyl 8-bromooctanoate L168-4 as colorless oil (1.96 g, 78%); ¹H-NMR (300 MHz, CDCl₃) δ 4.07 (t, J =7.3 Hz, 2H), 3.39 (t, J =6.9 Hz, 2H), 2.28 (t, J = 7.7 Hz, 2H), 1.90-1.15 (m, 29H), 0.88 (t, J = 6.9 Hz, 6H). Synthesis of 3-pentyloctyl 8-((2-hydroxyethyl)amino)octanoate (L168-5) [001376] To a mixture of 3-pentyloctyl 8-bromooctanoate L168-4 (2.55 g, 6.29 mmol) in ethanol (40 mL) was added 2-aminoethanol (3.83 g, 62.9 mmol) and the reaction mixture was heated to 65-70 °C and stirred overnight. The reaction mixture was concentrated, and DCM (150 mL) was added to the residue. The solution was washed with water and brine, then the organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to give crude product, which was purified by flash chromatography (SiO₂: 0 to 10% MeOH in DCM (1% NH₄OH) gradient) to yield L168-5 as colorless oil (1.55 g, 64%); ¹H-NMR (300 MHz, CDCl₃) δ 4.07 (t, J = 7.14 Hz, 2H), 3.65 (t, J = 5.22 Hz, 2H), 2.79 (t, J = 5.22 Hz, 2H), 2.62 (t, J = 7.14 Hz, 2H), 2.48 (m, 2H), 2.27 (t, J = 7.44 Hz, 2H), 1.48-1.6 (m, 5H), 1.17-1.31 (m, 24H) 0.87 (t, J = 6.33 Hz, 6H); CIMS m/z [M+H]⁺ 386.3. Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-((2-hydroxyethyl)(8-oxo-8-((3- pentyloctyl)oxy)octyl)amino)octanoate (Compound C82) [001377] A mixture of L168-2 (391 mg, 1.09 mmol), L168-5 (350 mg, 0.91 mmol), K2CO3 (376 mg, 2.72 mmol) and KI (75 mg, 0.45 mmol) in acetonitrile and cyclopentylmethyl ether (1:1, 5 mL) was stirred at 80 ⁰C for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified using column chromatography (SiO₂: 0-10% methanol and 0-1% ammonium hydroxide in dicholoromethane gradient) to afford Compound C82 as a yellow translucent oil (315 mg, 52%); ¹H-NMR (300 MHz, CDCl₃) δ 4.05 (q, J = 7.5 Hz, 4H), 3.54 (t, J = 5.3 Hz, 2H), 2.60 (t, J = 5.4 Hz, 2H), 2.47 (t, J = 7.6 Hz, 4H), 2.26 (q, J = 7.4 Hz, 4H), 1.69 – 1.12 (m, 54H), 0.87 (t, J = 6.9 Hz, 6H); CIMS m/z [M+H]⁺ 664.6; Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505-0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t_R = 7.03 min, purity: >99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, tR = 10.77 min, purity: 98.82%.

Synthetic Scheme for Compound C88 Synthesis of bicyclo[3.2.1]octan-6-yl 8-bromooctanoate (L170-3) [001378] To an oven dried 100 mL round bottom flask containing a solution of L170-1 (932 mg, 4.18 mmol) in dichloromethane (10 mL) under nitrogen was added EDC-HCl (1.33 g, 6.98 mmol) and DMAP (212 mg, 1.74 mmol). After completion of addition, the mixture was stirred at room temperature for 15 min. L170-2 (440 mg, 3.49 mmol) was added in, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and water, and the resulting phases were separated. The aqueous phase was extracted again with EtOAc. Combined organic extracts were washed with H₂O (50 mL x 2) and dried over anhydrous MgSO₄. Filtration and concentration provided crude product, which was purified by flash column chromatography (SiO₂: 0 to 10% ethyl acetate in hexanes gradient) to yield L170-3 (830 mg, 72%) as colorless oil; ¹H-NMR (400 MHz, CDCl3) δ 4.95 (m, 1H), 3.38 (t, J = 6.87, 2H), 2.3 (m, 1H), 2.23 (t, J = 7.56, 2H), 2.03 (m, 2H), 1.83 (m, 2H), 1.73 (m, 1H), 1.6 (m, 4H), 1.29-1.37 (m, 12H). Synthesis of 3-pentyloctyl 8-bromooctanoate (L170-5) [001379] To an oven dried 250 mL round bottom flask containing a solution of L170-1 (9.36 g, 42 mmol) in dichloromethane (80 mL) under nitrogen were added EDC-HCl (15.28 g, 80 mmol) and DMAP (2.44 g, 20 mmol). After completion of addition, the mixture was stirred at room temperature for 15 min. Int-4 (8.0 g, 40 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and water, and the resulting phases were separated. The aqueous phase was extracted again with EtOAc. Combined organic extracts were washed with H₂O (100 mL x 2) and dried over anhydrous MgSO₄. Filtration and concentration provided crude product, which was purified by flash column chromatography (SiO2: 0 to 5% ethyl acetate in hexanes gradient) to yield L170-5 (11.06 g, 68%) as colorless oil; ¹H- NMR (400 MHz, CDCl3) δ 4.06 (t, J = 6.87 Hz, 2H), 3.38 (t, J = 6.64 Hz, 2H), 2.27 (t, J = 7.33 Hz, 2H), 1.81-1.85 (m, 2H), 1.52-1.62 (m, 4H), 1.23-1.43 (m, 23H) 0.86 (t, J = 6.87 Hz, 6H). Synthesis of 3-pentyloctyl 8-((2-hydroxyethyl)amino)octanoate (L170-6) [001380] To a solution of L170-5 (12 g, 29.6 mmol) in ethanol (240 mL) was added 2- aminoethanol (18 g, 296 mmol) and reaction mixture was heated to 70 °C and stirred overnight. The reaction mixture was concentrated, DCM (400 mL) was added to residue, washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure to give crude product, which was purified by flash chromatography (SiO₂: 0 to 10% MeOH in DCM (1% NH₄OH) gradient) to yield L70-6 (8.0 g, 70%) as colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ 4.07 (t, J = 7.1 Hz, 2H), 3.61 (t, J = 5.27 Hz, 2H), 2.75 (t, J = 5.27 Hz, 2H), 2.59 (t, J = 7.1 Hz, 2H), 2.26 (t, J = 7.33 Hz, 2H), 1.52-1.6 (m, 4H), 1.23-1.46 (m, 26H), 0.86 (t, J = 6.87 Hz, 6H); CIMS m/z [M+H]⁺ 386.3. Synthesis of bicyclo[3.2.1]octan-6-yl 8-((2-hydroxyethyl)(8-oxo-8-((3-pentyloctyl)oxy)octyl) amino)octanoate (Compound C88) [001381] To a solution containing L170-6 (300 mg, 0.726 mmol) and L170-3 (331 mg, 1.0 mmol) in a mixture of acetonitrile/CPME (1:1, 10 mL) under nitrogen were added K₂CO₃ (300 mg, 2.17 mmol) and KI (120 mg, 0.726 mmol). The reaction mixture was heated at 80 °C for 18 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through Celite and the celite cake was washed with acetonitrile (50 mL). The filtrate was concentrated to give crude product, which was purified by flash chromatography (SiO2: 0 to 5% MeOH in DCM (1% NH₄OH) gradient) to yield Compound C88 (350 mg, 76%) as colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ 4.95 (m, 1H), 4.06 (t, J = 7.1 Hz, 2H), 3.5 (t, J = 5.27 Hz, 2H), 3.0 (s, 1H), 2.54 (t, J = 5.27 Hz, 2H), 2.4 (t, J = 7.33 Hz, 4H), 2.22-2.26 (m, 4H), 1.99-2.07 (m, 2H), 1.71 (m, 1H), 1.54-1.58 (m, 10H), 1.23-1.38 (m, 38H), 0.87 (t, J = 6.64 Hz, 6H); CIMS m/z [M+H]⁺ 636.5; Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505-0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t_R = 6.42 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, tR = 9.69 min, purity: > 99%. Synthetic Scheme for Compound C83 Synthesis of (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 8-bromooctanoate (L169-2) [001382] A solution of the starting compound L169-1 (2.17 g, 9.72 mmol), EDC-HCl (4.97 g, 25.9 mmol), and DMAP (795 mg, 6.48 mmol) in DCM (20 mL) was stirred for 5 minutes at room temperature to form a clear solution. Reaction mixture was stirred at room temperature for 15 min, 1R-(+)-Borneol (1.0 g, 6.48 mmol) in DCM (5 mL) was added to the reaction mixture. Reaction mixture was stirred at room temperature overnight. Reaction mixture was diluted with DCM, washed with water and brine. DCM layer was dried over Na2SO4 and concentrated under reduced pressure to give crude product. Crude product was purified by flash chromatography (SiO2: 0-30% hexane/ethyl acetate gradient) to yield L169-2 as colorless oil (1.8 g, 77%).¹H-NMR (400 MHz, CDCl3) δ: 4.87- 4.84 (m, 1H), 3.38 (t, 2H), 2.32-2.27 (m, 3H), 1.91-1.59 (m, 7H), 1.43-1.99 (m, 8H), 0.94-0.80 (m, 10H); CIMS m/z [M+H]⁺: 359.3. Synthesis of 3-pentyloctyl 8-bromooctanoate (L169-4) [001383] To a solution of the starting alcohol L169-3 (0.8 g, 4.0 mmol) in DCM (10 mL) was added 8-bromooctanoic acid L169-1 (1.0 g, 4.4 mmol) followed by DMAP (0.24 g, 2.0 mmol) and EDC-HCl (1.5 g, 8.0 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was diluted with DCM (10 mL) and washed with saturated NaHCO3 aqueous solution (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na₂SO₄. Filtration and concentration provided crude material which was purified by flash column chromatography (SiO₂: 0 to 10% ethyl acetate in hexane gradient) to yield 3- pentyloctyl 8-bromooctanoate L169-4 as colorless oil (1.0 g, 61%); ¹H-NMR (300 MHz, CDCl3) δ 4.07 (t, J =7.3 Hz, 2H), 3.39 (t, J =6.9 Hz, 2H), 2.28 (t, J = 7.7 Hz, 2H), 1.90-1.15 (m, 29H), 0.88 (t, J = 6.9 Hz, 6H). Synthesis of 3-pentyloctyl 8-((2-hydroxyethyl)amino)octanoate (L169-5) [001384] To a mixture of 3-pentyloctyl 8-bromooctanoate L169-4 (2.55 g, 6.29 mmol) in ethanol (40 mL) was added 2-aminoethanol (3.83 g, 62.9 mmol) and the reaction mixture was heated to 65-70 °C and stirred overnight. The reaction mixture was concentrated, and DCM (150 mL) was added to the residue. The solution was washed with water and brine, the organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to give crude product, which was purified by flash chromatography (SiO₂: 0 to 10% MeOH in DCM (1% NH₄OH) gradient) to yield L169-5 as colorless oil (1.55 g, 64%); ¹H-NMR (300 MHz, CDCl3) δ 4.07 (t, J = 7.14 Hz, 2H), 3.65 (t, J = 5.22 Hz, 2H), 2.79 (t, J = 5.22 Hz, 2H), 2.62 (t, J = 7.14 Hz, 2H), 2.48 (m, 2H), 2.27 (t, J = 7.44 Hz, 2H), 1.48-1.6 (m, 5H), 1.17-1.31 (m, 24H) 0.87 (t, J = 6.33 Hz, 6H); CIMS m/z [M+H]⁺ 386.3. Synthesis of 3-pentyloctyl 8-((2-hydroxyethyl)(8-oxo-8-(((1R,2S,4R)-1,7,7- trimethylbicyclo[2.2.1]heptan-2-yl)oxy)octyl)amino)octanoate (Compound 83) [001385] A mixture of L169-2 (391 mg, 1.08 mmol), L169-5 (300 mg, 0.77 mmol), K₂CO₃ (430 mg, 3.11 mmol) and KI (129 mg, 0.77 mmol) in cyclopentyl methyl ether (5 mL) and acetonitrile (5 mL) was heated at 110 °C under nitrogen with stirring for 18 h. After cooled to room temperature, the reaction mixture was filtered through Celite and washed with ethyl acetate. The combined filtrates were concentrated under vacuum to give the crude product which was purified by flash chromatography (40 g SiO2: 0 to 40% ethyl acetate in hexane with 3% triethylamine gradient) to yield Compound 83 as colorless oil (390 mg, 76%); ¹H-NMR (400 MHz, CDCl₃) δ 4.87-4.84 (m, 1H), 4.05 (t, 2H), 3.49 (t, 2H), 2.53 (t, 2H), 2.40 (t, 4H), 2.36-2.24 (m, 5H), 1.91-1.79 (s, 1H), 1.66-1.52 (m, 8H), 1.41-1.36 (m, 5H), 1.30-1.18 (m, 31H), 0.94-0.84 (m, 13H), 0.80 (s, 3H); CIMS m/z [M+H]⁺ 664.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t_R = 6.73 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mmol, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1 mL/min, column temperature: 20±2 °C, detector: CAD, tR = 10.4 min, purity: > 99%. Synthetic Scheme for Compound C86 Synthesis of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-bromobutanoate (L171-2) [001386] To a solution of L171-1 (1.30 g, 7.78 mmol) in DCM (30 mL), EDC-HCl (3.73 g, 19.46 mmol) and DMAP (783 mg, 6.49 mmol) were added. The mixture was left to stir for 15 minutes before a solution of (1S)-(-)-borneol (1.00 g, 6.49 mmol) in DCM (5 mL) was added. After 48 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO₂: 0-5% ethyl acetate in hexanes gradient) to afford L171-2 as a yellow translucent oil (370 mg, 19%); ¹H-NMR (300 MHz, CDCl3) δ 4.94–4.84 (m, 1H), 3.46 (t, J = 6.4 Hz, 2H), 2.51 (t, J = 7.2 Hz, 2H), 2.41–2.29 (m, 1H), 2.24–2.04 (m, 2H), 1.91 (m, 1H), 1.81–1.61 (m, 2H), 1.37–1.15 (m, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H). Synthesis of 6-bromohexyl 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanoate (L171-4) [001387] To an oven dried 50 mL round bottom flask containing a solution of acid L171-3 (0.79 g, 2.0 mmol) in dichloromethane (10 mL) under nitrogen was added EDC-HCl (0.77 g, 4.0 mmol) and DMAP (48 mg, 0.4 mmol). After completion of addition, the mixture was stirred at room temperature for 15 min. The alcohol (0.32 g, 1.8 mmol) was then added, and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with dichloromethane and water and the resulting phases were separated. The aqueous phase was extracted again with EtOAc (50 mL). Combined organic extracts were washed with H2O (60 mL x 2) and dried over anhydrous MgSO₄. Filtration and concentration provided crude product which was purified by flash column chromatography (SiO₂: 0 to 10% ethyl acetate in hexanes gradient) to yield L171-4 as colorless oil (880 mg, 87%); ¹H-NMR (300 MHz, CDCl₃) δ : 5.08 (t, J = 7.14 Hz, 2H), 4.48 (t, J = 5.49 Hz, 1H), 4.06 (t, J = 6.57 Hz, 2H), 3.57 (m, 2H), 3.43 (m, 2H), 3.4 (t, J = 6.87 Hz, 2H), 2.37 (t, J = 7.41 Hz, 2H) 1.93 (m, 8H), 1.55-1.67 (m, 16H), 1.36 (m, 10H), 1.15 (m, 2H), 0.87 (d, J = 6.33 Hz, 6H). Synthesis of 6-((2-hydroxyethyl)amino)hexyl 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanoate (L171-5) [001388] To a solution of L171-4 (1.60 g, 2.86 mmol) ethanol (10 mL) was added ethanolamine (1.75 g, 28.59 mmol). The mixture was allowed to stir at 60 ⁰C for 18 h. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure then purified using flash chromatography (SiO₂: 0-10% methanol and 0-1% ammonium hydroxide in dichloromethane gradient) to afford L171-5 as yellow translucent oil (670 mg, 43%); ¹H-NMR (300 MHz, CDCl₃) δ 5.08 (t, J = 7.3 Hz, 2H), 4.48 (t, J = 5.6 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.66 (t, J = 5.2 Hz, 2H), 3.58 (dt, J = 14.8, 7.6 Hz, 2H), 3.49 – 3.36 (m, 2H), 2.80 (t, J = 5.1 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.36 (t, J = 7.6 Hz, 2H), 2.06–1.76 (m, 6H), 1.69 –1.46 (m, 18H), 1.41–1.08 (m, 12H), 0.88 (d, J = 6.3 Hz, 6H); CIMS m/z [M+H]⁺ 540.2. Synthesis of 6-((2-hydroxyethyl)(4-oxo-4-(((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2- yl)oxy)butyl)amino)hexyl 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanoate (Compound C86) [001389] A mixture of L171-2 (236 mg, 0.78 mmol), L171-5 (350 mg, 0.65 mmol), K2CO3 (269 mg, 1.95 mmol), and KI (54 mg, 0.32 mmol) in acetonitrile and cyclopentylmethyl ether (1:1, 5 mL) was stirred at 80 ⁰C for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified using column chromatography (SiO₂: 0-10% methanol and 0-1% ammonium hydroxide in dicholoromethane gradient) to afford Compound C86 as a yellow translucent oil (300 mg, 61%); ¹H-NMR (300 MHz, CDCl₃) δ 5.08 (t, J = 7.1 Hz, 2H), 4.96 – 4.78 (m, 1H), 4.48 (t, J = 5.6 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.67–3.56 (m, 2H), 3.53 (t, J = 5.4 Hz, 2H), 3.51–3.37 (m, 2H), 2.59 (t, J = 5.3 Hz, 2H), 2.55–2.41 (m, 4H), 2.41–2.28 (m, 4H), 2.04 – 1.88 (m, 6H), 1.84–1.49 (m, 25H), 1.49–1.07 (m, 14H), 0.92–0.85 (m, 12H), 0.82 (s, 3H); CIMS m/z [M+H]⁺ 762.6; Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505- 0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t_R = 6.89 min, purity: 99.42%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1 mL/min, column temperature: 20±2 °C, detector: CAD, tR = 10.61 min, purity: 94.12%. Synthetic Scheme for Compound C94 Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-bromooctanoate (L172-2): [001390] To a solution of L172-1 (1.74 g, 7.78 mmol) in anhydrous dichloromethane (100 mL) was added EDC-HCl (2.49 g, 12.97 mmol) and DMAP (792 mg, 6.48 mmol), and the reaction was stirred at room temperature under nitrogen for 15 min. To this was added 2-(bicyclo[2.2.2]octan-1- yl)ethan-1-ol (1.00 g, 6.48 mmol) in anhydrous dichloromethane (5 mL). The resulting mixture was stirred under nitrogen at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2: ethyl acetate/hexane 0- 5%) to get L172-2 (2.21 g, 95%) as a clear oil; ¹H NMR (300 MHz, CDCl3): δ ppm: δ 4.05 (t, J = 7.5 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), 2.26 (t, J = 7.5 Hz, 2H), 1.84 (p, J = 6.9 Hz, 2H), 1.65 – 1.21 (m, 23H). Synthesis of 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butan-1-ol (L172-4) [001391] A solution of L172-3 (1.80 g, 4.54 mmol) in anhydrous THF (60 mL) was cooled to 0 °C. Lithium aluminum hydride (2.7 mL of 2.0 M solution in THF, 5.45 mmol) was added in small portions and the reaction mixture was stirred under nitrogen atmosphere at 0 °C for 30 min, then at room temperature for 45 min. After completion of the reaction, sodium sulfate decahydrate (5.0 g, 15.5 mmol) was added in small portions and the mixture was stirred for 15 min. The reaction mixture was filtered through Celite, and the solvents were removed under vacuum to give a residue which was purified by flash chromatography (SiO2: hexanes/ethyl acetate 0-10%) to get L172-4 (1.70 g, 98%) as an oil; ¹H-NMR (400 MHz, CDCl₃) δ 5.13–5.03 (m, 2H), 4.48 (t, J = 5.2 Hz, 1H), 3.69–3.54 (m, 4H), 3.51–3.38 (m, 2H), 2.06–1.89 (m, 4H), 1.76–1.49 (m, 20H), 1.45–1.26 (m, 4H), 1.22–1.08 (m, 2H), 0.88 (d, J = 6.5 Hz, 6H). Synthesis of 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butyl 8-bromooctanoate (L172-5) [001392] To an oven dried round bottom flask containing a solution of 8-bromooctanoic acid (1.19 g, 5.33 mmol) in dichloromethane (45 mL) under nitrogen was added EDC-HCl (1.70 g, 8.89 mmol) and DMAP (543 mg, 4.44 mmol). After completion of addition, the mixture was stirred at room temperature for 15 min. L172-4 (1.70 g, 4.44 mmol) was then added, and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (SiO2: 0 to 5% ethyl acetate in hexanes gradient) to yield L172-5 as yellowish oil (2.40 g, 92%); ¹H-NMR (300 MHz, CDCl₃ δ 5.12 – 5.03 (m, 2H), 4.49–4.41 (m, 1H), 4.06 (t, J = 4.1 Hz, 2H), 3.67–3.51 (m, 2H), 3.51– 3.35 (m, 4H), 2.28 (t, J = 7.5 Hz, 2H), 2.06–1.89 (m, 4H), 1.84 (p, J = 6.9 Hz, 2H), 1.78–1.48 (m, 22H), 1.48–1.22 (m, 10H), 1.21–1.08 (m, 2H), 0.88 (d, J = 6.3 Hz, 6H). Synthesis of 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butyl 8-((2-hydroxyethyl)amino)octanoate (L172-6) [001393] To a solution of L172-5 (2.30 g, 3.91 mmol) in ethanol (10 mL) was added ethanolamine (2.39 g, 39.13 mmol). The resulting mixture was stirred at 60 ⁰C for 24 h. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (50 mL x 3) and brine (50 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified using flash chromatography (SiO₂: 0-10% methanol and 0-1% ammonium hydroxide in dichloromethane gradient) to afford L172-6 as yellow translucent oil (1.42 g, 64%); ¹H-NMR (300 MHz, CDCl₃) δ 5.13–5.03 (m, 2H), 4.47 (t, J = 5.1 Hz, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.68–3.52 (m, 4H), 3.50–3.36 (m, 2H), 2.77 (t, J = 5.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.27 (t, J = 7.5 Hz, 2H), 2.06–1.89 (m, 4H), 1.89–1.74 (m, 2H), 1.74–1.23 (m, 32H), 1.23–1.07 (m, 2H), 0.88 (d, J = 6.4 Hz, 6H); CIMS m/z [M+H]⁺ 568.5. Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-((8-(4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butoxy)- 8-oxooctyl)(2-hydroxyethyl)amino)octanoate (C94) [001394] A mixture of L172-2 (1.10 g, 3.06 mmol), L172-6 (2.09 g, 3.67 mmol), K₂CO₃ (1.27 g, 9.18 mmol), and KI (254 mg, 1.53 mmol) in acetonitrile and cyclopentylmethyl ether (1:1, 10 mL) was stirred at 80 ⁰C for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified using column chromatography (SiO2: 0-10% methanol and 0-1% ammonium hydroxide in dicholoromethane gradient) to afford Compound C94 as a yellow translucent oil (2.20 g, 85%); ¹H-NMR (300 MHz, CDCl₃) δ 5.08 (t, J = 7.2 Hz, 2H), 4.47 (d, J = 5.1 Hz, 1H), 4.05 (q, J = 6.7 Hz, 4H), 3.57 (ddd, J = 23.7, 9.4, 6.0 Hz, 4H), 3.43 (dq, J = 15.6, 7.0 Hz, 2H), 2.59 (t, J = 5.2 Hz, 2H), 2.45 (t, J = 7.6 Hz, 4H), 2.26 (q, J = 8.0 Hz, 4H), 1.96 (tq, J = 14.7, 7.5 Hz, 4H), 1.76–1.07 (m, 61H), 0.88 (d, J = 6.3 Hz, 6H); CIMS m/z [M+H]⁺ 846.7; Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505-0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t_R = 7.90 min, purity: 99.42%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, tR = 12.32 min, purity: 97.39%. EXAMPLE 2A: LNP Formulations A [001395] Ionizable lipids, DSPC, cholesterol, and PEG2K-DMG are dissolved in pure ethanol at about a 48.5:10:39:2.5 mol% ratio with a total lipid concentration of about 10.8 mM. A 0.10 mg/mL mRNA solution is prepared using acidic buffer (pH 4.0-5.0) containing mRNAs encoding human erythropoietin (hEPO) and firefly luciferase (fLuc) (1:2 ratio). The nucleotide and lipid solutions are mixed at a 3:1 volume ratio using a NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations are further dialyzed against PBS (pH 7.4) overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 µm pore size). The particle size and polydispersity index (PDI) of formulations are measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) is determined by Ribogreen assay. EXAMPLE 2B: LNP Formulations B [001396] Ionizable lipids, DSPC, cholesterol, and PEG2K-DSPE are dissolved in pure ethanol at about a 48.5:10:40:1.5 mol% ratio with a total lipid concentration of about 10.8 mM. A 0.10 mg/mL mRNA solution is prepared using acidic buffer (pH 4.0-5.0) containing mRNAs encoding firefly luciferase (fLuc). The nucleotide and lipid solutions are mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations are further dialyzed against PBS (pH 7.4) overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 µm pore size). The particle size and polydispersity index (PDI) of formulations are measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) is determined by Ribogreen assay. EXAMPLE 2C: LNP Formulations C [001397] Ionizable lipids, DSPC, cholesterol, and PEG2K-DMG are dissolved in pure ethanol at about a 48.5:10:40:1.5 mol% ratio (formulations comprising ionizable lipids of the present disclosure) or about a 50:10:38.5:1.5 mol% ratio (for SM102 lipid control formulations) with a total lipid concentration of about 10.8 mM. A 0.10 mg/mL RNA solution is prepared using acidic buffer (pH 4.0-5.0) containing circular RNAs (oRNA) or linear mRNA encoding COVID spike protein. The nucleotide and lipid solutions are mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations are further dialyzed against cryobuffer overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 µm pore size). The formulations are then stored at -80°C until use. The particle size and polydispersity index (PDI) of formulations are measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) is determined by Ribogreen assay. EXAMPLE 2D: LNP Formulations D – Gene Editing [001398] Ionizable lipids, DSPC, cholesterol, and PEG-lipids were dissolved in pure ethanol in the specified mol% ratio (Table 2D) with a total lipid concentration of 10.8 mM. A 0.102 mg polynucleotide / mL solution was prepared using acidic buffer (pH 4.0-5.0) containing Cas9 mRNA/sgRNA (1:1 ratio or 2:1 ratio as designated below, SEQ ID NO: 35 and SEQ ID NO: 37 respectively, prepared as described in PCT Publication WO2020118041A1, which is incorporated by reference herein in its entirety). The nucleotide and lipid solutions were mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations were further dialyzed against PBS (pH 7.4) overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 µm pore size). The particle size and polydispersity index (PDI) of formulations was measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) was determined by Ribogreen assay. Table 2D: LNP Formulations * = 1:1 Cas9 mRNA/sgRNA; ** = 2:1 Cas9 mRNA/sgRNA; N:P ratio = 6 for all formulations

EXAMPLE 2E: LNP formulation E – Barcoding [001399] Ionizable lipids, phospholipid, cholesterol, PEG-lipid were dissolved in pure ethanol at the specified mol% ratio (Table 2E) with a total lipid concentration of 10.8 mM. A 0.10-0.20 mg/mL reporter mRNA + barcoded DNA solution was prepared using acidic buffer (pH 4.0-5.0) at a ratio of 1:1, 10:1, or 100:1 ratios by weight. The nucleotide and lipid solutions were mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations were further dialyzed against PBS (pH 7.4) overnight at 4 °C, and buffer exchanged into a sucrose-containing Tris-HCl cryoprotectant buffer for subsequent storage at -80°C. The individual particle sizes of formulations was measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency was determined by Ribogreen assay. LNPs were pooled at the appropriate dose concentration and injected as described in the barcoding Examples below. Formulation Ratios Table 2E: Barcoded LNP Formulations

ESM = Egg Sphingomyelin; C66 = Compound C66 of WO2023122752A1 EXAMPLE 2F: LNP Formulations F – VHH Formulations [001400] Ionizable lipids, phospholipid, cholesterol, and a PEG lipid were dissolved in pure ethanol at the specified mol% ratios with a total lipid concentration of 10.8 mM. A 0.10 mg/mL mRNA solution was prepared using acidic buffer (pH 4.0-5.0) containing mRNA encoding VHH (SEQ ID NO: 36). The nucleotide and lipid solutions were mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self- assembly of LNPs. Formulations were further dialyzed against PBS (pH 7.4) overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 µm pore size). The particle size and polydispersity index (PDI) of formulations was measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) was determined by Ribogreen assay. Table 2F: In Vivo VHH Formulation N:P of 6 for each formulation mRNA encoding VHH (SEQ ID NO: 36) EXAMPLE 2G: LNP formulation G – Biodistribution [001401] Ionizable lipids, phospholipid, cholesterol, PEG-lipid were dissolved in pure ethanol at the specified mol% ratio (Table 2G) with a total lipid concentration of ~10.8 mM. 0.10 mg/mL mRNA solution was prepared using acidic buffer (pH 4.0-5.0) containing mRNAs encoding VHH and Cas9 in a 2:1 ratio. The nucleotide and lipid solutions were mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 135 mL/min total flow rate resulting in rapid mixing and self- assembly of LNPs. Formulations were further dialyzed against PBS (pH 7.4) overnight at 4 °C, and buffer exchanged into a sucrose-containing Tris-HCl cryoprotectant buffer for subsequent storage at - 80°C. The individual particle sizes of formulations was measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency was determined by Ribogreen assay. Table 2G: LNP Formulations C66 = Compound C66 of WO2023122752A1; N:P of 6 for each formulation EXAMPLE 3: hEPO and fLUC in vivo reporter assays [001402] Balb/cAnNCrl mice (female, 6-8 weeks) are administrated with LNPs (formulated with 0.1 mg/kg EPO and 0.2 mg/kg Luc, see Example 2A) by intravenous injection. Plasma samples are harvested at 5, 23 and 47 hours post dose for hEPO analysis. Bioluminescence imaging (BLI) of the mice is taken at 6, 24 and 48 hours post-dosing using an IVIS Lumina III LT system (PerkinElmer) after injection of D-luciferin solution (150 mg/kg, intraperitoneal injection (IP)). hEPO concentrations are measured using an ELISA kit (DEP00, R&D Systems). The maximal concentration or BLI signal (Cmax) and area under concentration vs time curve (AUC) of the individual mouse plasma hEPO or whole body BLI data is calculated using a non-compartment analysis (NCA) program (WinNonlin^®, Version 8.3.4 [Pharsight Corp (Mountain View, CA, USA)]). EXAMPLE 4: In Vivo Organ Tropism assays [001403] Balb/cAnNCrl mice (female, 6-8 weeks) are dosed LNP formulations (formulated with 0.2 mg/kg Luc mRNA, see Example 2B) by IV injection. At 6 hour post LNP dose, the mice are injected with D-luciferin solution (150 mg/kg, intraperitoneal (IP)).10 minutes post D-luciferin dosing, mice will be sacrificed and organs (liver, spleen, lung, heart, kidney) are harvested. Bioluminescence imaging of the organs from each dosing groups is taken simultaneously using an IVIS Lumina III LT system (PerkinElmer). [001404] The sum of the bioluminescence of all organs from each individual mouse is summed as the total flux (photons/second). The percentage of bioluminescence of each individual organ is calculated to determine the organ tropism of the LNP formulations. EXAMPLE 5A: In Vivo T cell responses to spike protein encoding RNA - Murine Dosing Protocol [001405] LNP formulations are prepared as described in Example 2C. Each formulation is injected in 5 BALB/c mice intramuscularly on day 0 and 21 with 0.02 mg/ml oRNA or linear mRNA encoding COVID spike protein in a total volume of 0.5 mL. Prior to dosing BALB/c mice are placed in a chamber prefilled with isoflurane at a flow rate of 0.4-0.8 liter/min until sedated so that no movement occurs during injection. The injection site is monitored for irritation after both doses. On day 35 all mice are humanely euthanized by CO2 inhalation and spleens are collected and stored on wet ice until processing. All in vivo experiments in this study are performed under the approved animal care guidelines. Analysis [001406] Spleens are harvested and manually dissociated into single cell suspensions by filtration using a 70µm filter (Miltenyi 130-098-462) and washed with 1x PBS (Fisher 10010049) containing 2mM EDTA (ThermoFisher 15575-020) and 0.5% BSA (Miltenyi 130-091-376). Red blood cells are lysed using ACK Lysisg Buffer (ThermoFisher A1049201) and washed twice with 1x PBS + 2mM EDTA + 0.5% BSA. Following final wash, cells are resuspended in 1x PBS and counted (ViCell XR, Beckman Coulter 731196). Cells are resuspended in CTL Test Plus Medium (C.T.L. CTLTP-005) containing 1x GlutaMAX (ThermoFisher TP-050122) and 1x Pen/Strep (ThermoFisher 15-140-122) at appropriate concentrations and plated for downstream functional assays. [001407] ELISpot analysis are performed using the mouse IFN-γ ELISpotPLUS Kit (Mabtech 3321-4HST-10), according to the manufacturer’s protocol. Briefly, plates are washed with 1x PBS and blocked with RPMI (ThermoFisher 72400-047) containing 10% FBS (ThermoFisher A38400-01) for 1 h at 37°C. Following blocking, cells re plated at 200,000 cells/well for DMSO and peptide-stimulated wells or 25,000 cells/well for PMA/Ionomycin treatment. Cells are incubated with either 1% DMSO (ThermoFisher D12345), 7.5µg/mL of S1 or S2 peptide pools spanning the Spike protein of SARS-CoV-2 (JPT PM-WCPV-S-1), or 1x PMA/Ionomycin (ThermoFisher 00-4970-93) in triplicate. The plates re incubated overnight 37°C, 5% CO2. Following incubation, plates are washed, and 1 µg/mL detection antibody is added for 2h at room temperature. Washes are repeated and 1x Streptavidin-HRP is added and incubated for 1hr at room temperature. Finally, plates are washed and TMB substrate is added, incubated in the dark for spot development, then washed out using tap water. Plates are allowed to dry and counted by an ELISpot analyzer (ZellNet Consulting). [001408] For intracellular staining (ICS) 5,000,000 cells per well are plated in a 96-well round bottom plate (Costar 3799) and stimulated using the same ELISpot conditions as described above and incubated at 37°C with 5% CO2 for a total of 5.5h. Golgi Plug (BD 555029) are added to all wells for the last 4.5h of stimulation. Following incubation, cells are stained for flow cytometry using surface or intracellular antibodies. Briefly, cells are washed with 1x PBS and stained with Live/Dead Fixable Aqua (Invitrogen L34966) for 20min at room temperature. Cells are then washed twice with Cell Staining Buffer (BioLegend 420201) and incubated with Fc Block (Biolegend 156604) for 5min at 4°C, followed by surface antibody staining for 30min at 4°C. Thereafter, cells are washed twice with Cell Staining Buffer, fixed at 4°C for 30min IC Fixation Buffer (ThermoFisher 88-8824-00) and permeabilized in 1x permeabilization buffer (ThermoFisher 88-8824-00) and intracellular staining is performed overnight at 4°C. Thereafter, cells are washed twice with 1x permeabilization buffer, resuspended in 1x PBS, and acquired on cytometer (ThermoFisher Attune NXT with a laser configuration of Blue(3)/Red(3)/Violet(4)/Yellow(4)) equipped with a high-throughput autosampler (ThermoFisher CytKick). Compensation is performed using UltraComp eBeads (ThermoFisher 01-3333-41) and ArC Amine Reactive Compensation Bead Kit (ThermoFisher A10346). EXAMPLE 5B: In Vivo T cell responses to spike protein encoding RNA – Non-human Primate Dosing Protocol [001409] LNP formulations are prepared as described in Example 2C. Each formulation is injected in 3 non-naïve Cynomolgus monkeys once on Day 1 and once on Day 22 via intramuscular injections at a dose level of 100 µg. All NHPs are temporarily restrained for dose administration and not sedated. Prior to dosing, the dosing site is shaved and marked as necessary for clinical observations. Each dose is administered using a syringe/needle within the demarcated area. Samples re collected throughout the study for clinical pathology parameters, pharmacokinetic analysis and immunogenicity analysis. Analysis [001410] Cryopreserved PBMCs are thawed in a 37°C water bath and cells are transferred to conical tube containing complete RPMI (RPMI [ThermoFisher 72400-047] containing 10% FBS [ThermoFisher A38400-01] and 1x Pen/Strep [ThermoFisher 15-140-122]. Cells are centrifuged, resuspended in complete RPMI containing 50U/mL Benzonase (EMD 70664-10KUN), and incubated for 15min at 37°C. Cells are centrifuged, resuspended in complete RPMI, and rested for 3hr. Cells are centrifuged and resuspended in CTL Test Plus Medium (C.T.L. CTLTP-005) containing 1x GlutaMAX (ThermoFisher TP-050122) and 1x Pen/Strep and counted (ViCell XR, Beckman Coulter 731196). Concentrations are adjusted and cells plated for downstream functional assays. [001411] ELISpot analysis is performed using the Monkey IFN-γ ELISpotPLUS Kit (Mabtech 3421M-4HST-10) according to the manufacturer’s protocol. Briefly, plates are washed with 1x PBS and blocked with RPMI (ThermoFisher 72400-047) containing 10% FBS (ThermoFisher A38400-01) for 1h at 37°C. Following blocking, cells are plated in triplicate and stimulated under the following conditions: no peptide (1% DMSO (ThermoFisher D12345)),0.5µg/mL of S1+S2 peptide pools spanning the Spike protein of SARS-CoV-2 (JPT PM-WCPV-S-1), and 1x PMA/Ionomycin (ThermoFisher 00-4970-93). 200,000 cells/well are plated for DMSO and peptide pool stimulations and 10,000/well from pooled samples from each group for PMA/Ionomycin stimulation. [001412] The plates are incubated overnight 37°C, 5% CO2. Following incubation plates are washed, and 1 µg/mL detection antibody added for 2h at room temperature. Washes are repeated and 1x Streptavidin-HRP added and incubated for 1h at room temperature. Finally, plates are washed and TMB substrate are added, incubated in the dark for spot development, then washed out using tap water. Plates re allowed to dry and counted using an ELISpot analyzer (ZellNet Consulting). [001413] For intracellular staining (ICS), approximately 2,000,000 cells per well from each animal are plated in a 96-well round bottom plate (Costar 3799) and stimulated using the same ELISpot conditions described above. After one hour of stimulation, Golgi Plug (BD 555029) is added to all wells and plates are incubated overnight at 37°C with 5% CO2. Thereafter, cells are washed and stained for flow cytometry. Briefly, cells are washed with 1x PBS and stained with Live/Dead Fixable Aqua (Invitrogen L34966) for 20min at room temperature. Cells are then washed twice with Cell Staining Buffer (BioLegend 420201) and incubated with Fc Block (Biolegend 156604) for 5min at 4°C, followed by surface antibody staining for 30min at 4°C. Following surface staining, cells are washed twice with Cell Staining Buffer and fixed at 4°C for 30min in IC Fixation Buffer and permeabilized in (ThermoFisher 88-8824-00) 1x permeabilization buffer (ThermoFisher 88-8824-00). Intracellular staining is performed for 1hr at 4°C. Thereafter, cells are washed twice with 1x permeabilization buffer, resuspended in 1x PBS, and acquired on a cytometer (ThermoFisher Attune NXT with a laser configuration of Blue(3)/Red(3)/Violet(4)/Yellow(4)) equipped with a high-throughput autosampler (ThermoFisher CytKick). Compensation is performed using UltraComp eBeads (ThermoFisher 01-3333-41) and ArC Amine Reactive Compensation Bead Kit (ThermoFisher A10346). EXAMPLE 6: In vivo Editing Delivery in Mice – TTR KD In Vivo Protocol [001414] CD-I female mice, ranging from 6-10 weeks of age were used in each study. LNP formulations were prepared as described in Example 2D. LNPs were dosed via the lateral tail vein in a volume of approximately 5 mL per kilogram body weight. The animals were periodically observed for adverse effects for at least 24 hours post dose. Mice were dosed at 0.1 mpk or 0.075 mpk. Each formulation was dosed in 3 animals. Animals were euthanized at 7 days by exsanguination via cardiac puncture under isoflurane anesthesia. Liver tissue was collected from each animal for DNA extraction and analysis. Blood was collected into serum separator tubes or into tubes containing buffered sodium citrate for plasma as described herein. Cohorts of mice were measured for editing by Next-Generation Sequencing (NGS). Transthyretin (TTR) ELISA analysis [001415] Blood was collected and the serum was isolated as indicated. The total mouse TTR serum levels were determined using a Mouse Prealbumin (Transthyretin) ELISA Kit (Aviva Systems Biology, Cat. OKIAOOl 11). Briefly, sera were serial diluted with kit sample diluent, e.g. to a final dilution of 10,000-fold and/or 2,500-fold. The diluted sample was then added to the ELISA plates and the assay was then carried out according to manufacturer directions. Serum TTR data from treatment groups are expressed as a percentage of day 0 TTR levels. Lower percentage values correlate with greater editing efficiency. Table 6: Gene Editing Data - Mouse PBS negative control mean TTR % of pre dose = 103.84% NGS Sequencing [001416] In brief, to quantitatively determine the efficiency of editing at the target location in the genome, genomic DNA is isolated and deep sequencing is utilized to identify the presence of insertions and deletions (“indels”) introduced by gene editing. [001417] PCR primers are designed around the target site (e.g., B2M), and the genomic area of interest is amplified. Additional PCR is performed according to the manufacturer's protocols (Illumina) to add the necessary chemistry for sequencing. The amplicons are sequenced on an Illumina NextSeq 2000 instrument. The reads are aligned to the relevant reference genome (e.g., GRCm38) after eliminating those having low quality scores. The resulting files containing the reads are mapped to the reference genome (BAM files), where reads that overlapped the target region of interest are selected and the number of wild type reads versus the number of reads which contain an insertion, substitution, or deletion is calculated. [001418] The editing percentage (e.g., the “editing efficiency” or “percent editing”) is defined as the total number of sequence reads with insertions or deletions over the total number of sequence reads, including wild type. EXAMPLE 7: In vivo Editing Delivery in Non-Human Primates – TTR KD In Vivo Protocol [001419] LNP formulations are prepared as described in Example 2D. Each formulation is administered to 3 non-naïve Cynomolgus monkeys on Day 1 via 60-min intravenous infusion into an appropriate peripheral vein using an infusion pump at a dose level of 2.0 mg/kg (dose volume of 5 mL/kg; concentration 0.4 mg/mL). Samples are collected throughout the study for clinical pathology parameters, pharmacokinetic/pharmacodynamic (PK/PD) analysis and immunostimulation. Blood samples are collected daily up to study day 29 and on day 29, the test subjects are terminated. Test subject livers and spleens are collected for NGS analysis. NGS Sequencing [001420] NGS sequencing is carried out as described in Example 6. Transthyretin (TTR) Analysis [001421] The TTR concentration in cynomolgus monkey plasma samples is measured using an LC/MS/MS method. A Sciex Triple Quad 7500 mass spectrometer (Framingham, MA) coupled with a Waters Acquity UPLC (Milford, MA) is used for samples analysis. A BEH C18 columns (Waters, Milford, MA) is used for chromatographic separation. A recombinant monkey TTR protein is used as reference material (ab239566, abcam, Waltham, MA). Plasma samples are digested by trypsin. A selected tryptic peptide is used to quantitate TTR. Stable isotopic labelled internal standards are used as internal standard. EXAMPLE 8: Barcoding – Non-Human Primates In Vivo Protocol [001422] Cynomolgus monkeys were injected IV with study formulation comprising a cocktail of barcoded LNPs formulated as described in Example 2E, along with a standard benchmark panel of LNPs which included MC3 formulation F-STD. At 24 hr post injection, the study animals were humanely euthanized and organs including liver, spleen, heart, quad, diaphragm, bone marrow and lungs were collected and snap frozen using liquid nitrogen. Blood plasma was collected for cytokine analysis and both full body and individual organ fluorescence measurements were also taken. All in vivo experiments in this study were performed under the approved animal care guidelines. Tissue homogenization [001423] Entire organs were harvested from each study animal and snap frozen. Snap frozen tissues were cooled in liquid nitrogen and then homogenized using the GENOMAX^® Homogenizer (SPEX EW-41019-48) for 1 minute 45 seconds at 1500 RPM. Powderized tissues were stored in -80 °C freezer until used for barcode extraction. DNA barcode extraction and library prep [001424] DNA barcodes were extracted first by scooping a consistent weight of tissue into 1mL QUICKEXTRACT^TM DNA extraction solution (Lucigen QE09050) and extraction followed the manufacturer’s suggested protocol. Two separate PCRs were then performed from each extraction sample – one to amplify the delivered barcodes and one to amplify an endogenous housekeeping gene. Both PCRs were performed as follows: 1μL QUICKEXTRACT^TM product was added into a 20μL PCR reaction containing 1μL 10μM forward primer, 1μL 10μM reverse primer, 10μL PHUSION^TM Hotstart 2X Master Mix (ThermoFisher Scientific), 1μL DNA barcode spike-in, and 6μL H₂O. A thermocycler protocol was used with the following parameters: an initial denaturation of 98 °C for 3 minutes, followed by cycling conditions of 98 °C for 5 seconds, 65 °C for 10 seconds, and 72 °C for 15 seconds for 10 cycles, and a final extension at 72 °C for 5 minutes. PCR product was cleaned using a 1.8X bead cleanup with AMPURE^® XP (Beckman Coulter A63881) following manufacturer protocols using the KINGFISHER^TM Apex. For each biological sample, 10μL of barcode cleanup product was pooled with its respective 10μL of endogenous control cleanup product. 2μL pooled product was then used for a second PCR to add indexes and NGS adapters with the following in each sample mix: 5μL Unique Dual Index mix (IDT for Illumina), 12.5μL PHUSION^TM Hotstart 2X Master Mix (ThermoFisher Scientific), and 5.5μL H2O. PCR product was cleaned again using a 1.8X bead cleanup with AMPURE^® XP (Beckman Coulter A63881) following manufacturer protocols using the KINGFISHER^TM Apex. DNA quantification [001425] PCR products were run on the Tapestation (Agilent G2991AA) using the D1000 kit (Agilent 5067-5582) to confirm existence of the desired amplicon. All barcode libraries were then quantified using the QUBIT^TM 1X dsDNA Kit (ThermoFisher Q33231) following manufacturer's protocol. Sequencing [001426] Libraries were diluted to 400pM in resuspension buffer (RSB) Tween provided with the Illumina sequencing cartridge. A PhiX control was also diluted to 550pM and added at 30% of the entire final loading library.20μL of the library mixed with the PhiX control were loaded onto the sequencing cartridge and the sequencer was loaded and started according to manufacturer's instructions. Libraries were sequenced on the NextSeq2000 (Illumina). Data analysis [001427] Data was analyzed similar to methods previously described in the literature (e.g. Dahlman, et al. Proc Natl Acad Sci U S A.2017 Feb 21; 114(8): 2060–2065; Guimaraes, et al. J Control Release.2019 Dec 28; 316: 404–417.). Briefly, custom python scripts were written to produce a count of each barcode in each sample. These scripts process sequencing reads by running quality control metrics, merging pairs into single reads, inspecting the reads for the presence of expected constant regions of the PCR amplicon, identifying the barcode and UMI, and binning them according to the barcode/UMI combination they harbor. These bins of reads were then quantitated to produce an estimate of the relative abundance of each barcoded species in the samples and then compared to the apparent abundance of the endogenous control gene (beta-actin). Briefly, the relative abundance of barcode reads was divided by the relative abundance of the endogenous reads divided by two (accounting for the approximation that cells in the samples of interest contain an average of two copies of the genome). This estimated barcode count per genome was then corrected for input material as the injected formulation mixes were also sequenced. Abundances are then compared between samples representing distinct tissues to estimate the distribution of the barcoded species across the tested tissues. Key: Data reported as “log2-fold change in barcode amount vs F-RS standard” ** < -0.5; -0.5 ≤ * < 0; 0≤ # < 0.25; 0.25 ≤ ## < 0.5; 0.5 ≤ ### < 0.75; 0.75 ≤ #### < 1.0; 1.0 ≤ ##### Table 8: NHP Barcode Results

EXAMPLE 9: LNP Delivery to T and NK cells – Non-Human Primates [001428] LNP formulations were prepared as described in Example 2F. Each formulation was administered to 3 Cynomolgus monkeys on Day 1 via 60-min intravenous infusion into an appropriate peripheral vein using an infusion pump at a dose level of 2.0 mg/kg mRNA (dose volume of 5 mL/kg; concentration 0.4 mg/mL). Blood samples were collected at 6 and 24 hours after dosing for peripheral blood mononuclear cells, and at 24 hours the test subjects were terminated. Peripheral blood mononuclear cell were purified from blood and cryopreserved in Cryostor CS10 at a density of approximately 5e6 PBMC per mL. On day of analysis, cryopreserved PBMC were thawed into pre- warmed complete RPMI containing RPMI 1640 (GIBCO, 72400-047) with 10% heat inactivated FBS (GIBCO, A38400-01) and 1% Pen/Strep (GIBCO, 15-140-122). Cells were spun down and resuspended in RPMI 1640 supplemented with 50U/mL benzonase (EMD, 70664-10KUN) and incubated for 10 minutes at 37⁰C. Cells were then spun down and resuspended in complete RPMI and counted (Cellaca MX, PerkinElmer MX-AOPI). Cells were diluted, plated (5,000,000 per well) in a 96-well round bottom plate (Costar 3799), and stained for flow cytometry. Test subject femurs were flushed for collection of bone marrow and spleens and lungs were collected for analysis by flow cytometry. Up to 1 gram of harvested spleen per animal was dissociated into single cell suspension of splenocytes using the gentleMACS Octo Dissociator with Heaters (Miltenyi 130-096-427) with the Multi Tissue Dissociation Kit I (Miltenyi 130-110-201) per manufacturer’s instructions. Dissociated splenocytes were then passed through a 70µm filter (Miltenyi 130-098-462) and washed with 1x PBS (ThermoFisher 10010049) containing 2mM EDTA (ThermoFisher 15575-020), 0.5% BSA (Miltenyi 130-091-376) and 1x + 1x Antimycotic/Antibiotic (ThermoFisher 15240-062). Red blood cells were lysed using ACK Lysing Buffer (Thermo Fisher A1049201) and washed twice with 1x PBS + 2mM EDTA + 0.5% BSA, passing the cell suspension through an additional 70µm filter prior to the last wash. Following final wash, cells were resuspended in 1x PBS + 2mM EDTA + 0.5% BSA + 1x Antimycotic/Antibiotic and counted (Cellaca MX, PerkinElmer MX-AOPI). Cells were diluted, plated (5,000,000 per well) in a 96-well round bottom plate (Costar 3799), and stained for flow cytometry. Up to 3 grams of harvested lung per animal was dissociated into single cell suspension of cells using the gentleMACS Octo Dissociator with Heaters (Miltenyi 130-096-427) with the Multi Tissue Dissociation Kit I (Miltenyi 130-110-201) per manufacturer’s instructions. Dissociated lung cells were then passed through a 70µm filter (Miltenyi 130-098-462) and washed with 1x PBS + 2mM EDTA + 0.5% BSA + 1x Antimycotic/Antibiotic. Red blood cells were lysed using ACK Lysing Buffer (Thermo Fisher A1049201) and washed twice with 1x PBS + 2mM EDTA + 0.5% BSA + 1x Antimycotic/Antibiotic, passing the cell suspension through an additional 70µm filter prior to the last wash. Following final wash, cells were resuspended in 1x PBS + 2mM EDTA + 0.5% BSA + 1x Antimycotic/Antibiotic and counted (Cellaca MX, PerkinElmer MX-AOPI). Cells were diluted, plated (2,000,000 per well) in a 96-well round bottom plate (Costar 3799), and stained for flow cytometry. Flushed bone marrow was centrifuged and cells were collected, passed through a 70µm filter, and washed with 1x PBS + 2mM EDTA + 0.5% BSA+ 1x Antimycotic/Antibiotic. Red blood cells were lysed using ACK Lysing Buffer and washed twice with 1x PBS + 2mM EDTA + 0.5% BSA+ 1x Antimycotic/Antibiotic, passing the cell suspension through an additional 70µm filter prior to the last wash. Following final wash, cells were resuspended in 1x PBS + 2mM EDTA + 0.5% BSA+ 1x Antimycotic/Antibiotic and counted. Cells were diluted, plated (15 million per well) in a 96-well bottom plate, and stained for flow cytometry. Cells were stained in 1x PBS with Live/Dead Fixable Aqua (Invitrogen L34966) at 1:1000 for 20min at room temperature. Cells were then washed twice with Cell Staining Buffer (BioLegend 420201) and incubated with Fc block for 5min at 4°C and surface antibody stains either in full or FMO (fluorescence minus one) master mixes (panels and dilutions shown below in Tables 9A-9D) added on top of the Fc Block for an additional 30min at 4°C. Cells were then washed three times with Cell Staining Buffer and fixed with Cytofix (BD 554655) at 4°C for 20min. Cells were washed twice with 1x PBS and filtered through a 30-40 µm filter (Pall 8027) and acquired on cytometer(Sony ID7000 Cell Analyzer: Cat # LE-ID7000C with UV/V/B/YG/R lasers). Single stain controls were made using UltraComp eBeads (ThermoFisher 01- 3333-41) and ArC Amine Reactive Compensation Bead Kit (ThermoFisher A10346). Analysis was performed using Flowjo (BD V10.8.1). Cells were identified with markers in Tables 9E-9H and VHH reporter+ gates placed so that the negative control would be ≤0.5%⁺. [001429] The percentage of cells of the noted varieties expressing VHH mRNA is reported below in Table 9I (as the mean of 3 animals). Robust VHH expression was detected in many organs and cell types, including B and NK cells. Table 9A: Splenocyte surface antibody stains used in Example 9 Table 9B: PBMC surface antibody stains used in Example 9

Table 9C: NHP Bone Marrow antibodies used in Example 9 Table 9D: Lung Antibodies used in Example 9

Table 9E: Definition of Cell Subsets in NHP Spleen by Flow Cytometry used in Example 9 Table 9F: Definition of Cell Subsets in NHP PBMC by Flow Cytometry used in Example 9

Table 9G: Definition of Cell Subsets in NHP BM by Flow Cytometry used in Example 9 *Lineage is defined as including CD3, CD4, CD8, CD14, CD16, CD20, CD11b, and CD11c. Table 9H: Definition of Cell Subsets in NHP Lung by Flow Cytometry used in Example 9 Table 9I: Percentage of cells of various types expressing VHH mRNA

NK = Natural killer cells; DN NK = double negative NK cells; DC = dendritic cells; HSPCs = hematopoietic stem and progenitor cells; HSCs = hematopoietic stem cells; MPP = multipotent progenitor cells; GMP = Granulocyte-monocyte progenitor cells EXAMPLE 10: VHH Biodistribution in HSCs and Spleen– BALB/c mice [001430] LNP formulations were prepared as described in Example 2G. Each formulation was administered to BALB/c mice on Day 1, injected via tail vein.16-24 h post injection, animals were euthanized by CO2 inhalation, and spleens, femurs, and tibiae/fibulae were harvested. Harvested spleens were dissociated into single cell suspension of splenocytes using the gentleMACS Octo Dissociator with Heaters with the Mouse Spleen Dissociation Kit per manufacturer’s instructions. Dissociated splenocytes were then passed through a 70µm filter and washed with 1x PBS containing 2mM EDTA and 0.5% BSA. Red blood cells were lysed using ACK Lysing Buffer and washed twice with 1x PBS + 2mM EDTA + 0.5% BSA, passing the cell suspension through an additional 70µm filter prior to the last wash. Following final wash, cells were resuspended in 1x PBS + 2mM EDTA + 0.5% BSA and counted. Cells were diluted, plated, and stained for flow cytometry. Bone marrow (BM) cells were harvested, passed through a 70µm filter, and washed with 1x PBS + 2mM EDTA + 0.5% BSA. Red blood cells were lysed using ACK Lysing Buffer and washed twice with 1x PBS + 2mM EDTA + 0.5% BSA, passing the cell suspension through an additional 70µm filter prior to the last wash. Following final wash, cells were resuspended in 1x PBS + 2mM EDTA + 0.5% BSA and counted. Cells were diluted, plated, and stained for flow cytometry. Briefly, cells were stained with Live/Dead Fixable Aqua, incubated with Fc block (splenocytes) or labeled CD16/32 antibody (bone marrow) for 5min at 4°C and surface antibody stains (panel shown below in Table 10B). Cells were then washed and filtered and acquired on cytometer (ThermoFisher Attune NXT or Sony ID7000 Cytometer) equipped with a high-throughput autosampler. Analysis performed using Flowjo (BD V10.8.1). Cells were identified with markers in Table 10A. Flow cytometry was used to define long- term hematopoietic stem cells (LT-HSC) based on the following: Viable, lineage negative, Sca-1+, c- Kit+, CD150+, CD48-. The percentage of LT-HSCs and LSK cells expressing VHH is reported below in Table 10C. Several LNP formulations demonstrated high delivery (>40%) to HSPCs. Specifically, high delivery by many of the LNP formulations to LT-HSCs strongly suggests that delivery of gene editing systems in vivo can be used to treat diseases related to hematopoietic stem cells, such as hemoglobinopathies, in a subject in need thereof. Table 10A: Definition of Cell Subsets in Mouse BM by Flow Cytometry used in Example 10 *Lineage is defined as including CD4, CD8a, CD11b, B220, GR1, Ter119. Table 10B: Bone marrow surface antibody stains used in Example 10 Table 10C: Percentage of cells expressing VHH mRNA Key: * < 5%; 5% ≤ ** < 25%; 25% ≤ *** < 50%; 50% ≤ **** < 75%; 75% ≤ ***** < 100% LSK = Lin-Sca1+c-Kit+ hematopoietic stem cells; LT-HSC = Long Term hematopoietic stem cells

Claims

CLAIMS 1. A compound of Formula (CT): (CT), or a pharmaceutically acceptable salt thereof, wherein: wherein the bond marked with an "*" is attached to X¹; X¹ is optionally substituted C1-C6 aliphatic; and R¹ is selected from the group consisting of -OH, -OAc, -NR2, marked with an "*" is attached to X¹; X¹ is a bond or optionally substituted C1-C6 aliphatic; and R¹ is selected from the group consisting of -OH, -OAc, -NR2,

each R is independently -H or C1-C6 aliphatic; X² and X³ are each independently optionally substituted C1-C12 aliphatic; Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to X² for Y¹ or X³ for Y²; R² is a bond or optionally substituted C¹-C⁶ aliphatic; R³ is a bond or optionally substituted C1-C6 aliphatic; R⁴ is -CH(OR⁶)(OR⁷), -CH(SR⁶)(SR⁷), -CH(R⁶)(R⁷), or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, - C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R⁵ is -R⁸, -CH(OR⁸)(OR⁹), -CH(SR⁸)(SR⁹), -CH(R⁸)(R⁹), or optionally substituted -C1- C6aliphatic-R⁸; R⁶ and R⁷ are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, - OC(O)-, -NHC(O)- or -C(O)O-; R⁸ is optionally substituted C1-C14 aliphatic, wherein at least one methylene linkage is replaced with an optionally substituted divalent radical of a structure selected from R⁹ is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C³-C⁸ cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C14 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-.

2. The compound of claim 1, wherein A is CH.

3. The compound of claim 1, wherein the compound is a compound of Formula (CT-A): or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is a compound of Formula (CT- A1): or a pharmaceutically acceptable salt thereof, wherein , wherein the bond marked with an "*" is attached to X¹; and Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y².

5. The compound of claim 1, wherein the compound is a compound of Formula (CT- A2): (CT-A2), or a pharmaceutically acceptable salt thereof, wherein wherein the bond marked with an "*" is attached to ; a d Y¹ and Y² are each ,wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y².

6. The compound of claim 1, wherein the compound is a compound of Formula (CT-B) or (CT-B’) or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is a compound of Formula (CT-C): or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is a compound of Formula (CT-D) or (CT-D’): or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is a compound of Formula (CT-E), (CT-E’), or (CT-E’’): or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound is a compound of Formula (CT-F), (CT-F’), (CT-F’’), (CT-F’’’), (CT-F’’’’), or (CT-F’’’’’):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is a compound of Formula (CT-G), (CT-G’) or (CT-G’’): or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein the compound is a compound of Formula (CT-H), (CT-H’), (CT-H’’), (CT-H’’’), (CT-H’’’’), or (CT-H’’’’’): or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is a compound of Formula (CT-I): or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein the compound is a compound of Formula (CT-J) or (CT-J’): or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is a compound of Formula (CT-K), (CT-K’), or (CT-K’’): or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is a compound of Formula (CT-L), (CT-L’), (CT-L’’), (CT-L’’’), (CT-L’’’’), or (CT-L’’’’’): or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is a compound of Formula (CT-M): or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is a compound of Formula (CT-N) or (CT-N’): or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is a compound of Formula (CT-O), (CT-O’), or (CT-O’’): or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is a compound of Formula (CT-P), (CT-P’), (CT-P’’), (CT-P’’’), (CT-P’’’’), or (CT-P’’’’’): or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein A is N.

22. The compound of claim 1, wherein the compound is a compound of Formula (CT-Q): or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is a compound of Formula (CT- Q1): or a pharmaceutically acceptable salt thereof, wherein Y¹ and Y² are independently selected from the group consisting of wherein the bond marked with an "*" is attached to R² for Y¹ or R³ for Y².

24. The compound of claim 1, wherein the compound is a compound of Formula (CT-R) or (CT-R’): or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound is a compound of Formula (CT-S), (CT-S’) or (CT-S’’): or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound is a compound of Formula (CT-T), (CT-T’), (CT-T’’), (CT-T’’’), (CT-T’’’’), or (CT-T’’’’’):

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is a compound of Formula (CT-U), (CT-U’), (CT-U’’), (CT-U’’’), (CT-U’’’’), or (CT-U’’’’’):

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein the compound is a compound of Formula (CT-V), (CT-V’), (CT-V’’), (CT-V’’’), (CT-V’’’’), or (CT-V’’’’’): or a pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 1-3, 6, and 9, 10, wherein Z is , ,

30. The compound of any one of claims 1-3, 6, 9, 10, and 29, wherein Z is .

31. The compound of any one of claims 1-20 and 29-30, wherein X¹ is a bond.

32. The compound of any one of claims 1-30, wherein X¹ is optionally substituted C1-C6 alkylene.

33. The compound of any one of claims 1-30 and 32, wherein X¹ is unsubstituted C1-C6 alkylene.

34. The compound of any one of claims 1-26 and 29-33, wherein R¹ is -OH.

35. The compound of any one of claims 1-26 and 29-33, wherein R¹ is -NR2.

36. The compound of any one of claims 1-35, wherein X² is an optionally substituted C1- C12 alkylene.

37. The compound of any one of claims 1-35, wherein X² is an optionally substituted C1- C10 alkylene.

38. The compound of any one of claims 1-37, wherein X³ is an optionally substituted C1- C12 alkylene.

39. The compound of any one of claims 1-37, wherein X³ is an optionally substituted C1- C10 alkylene.

40. The compound of any one of claims 1-39, wherein X² and X³ are the same.

41. The compound of claim 40, wherein X² and X³ are both optionally substituted C6-C8 alkylene.

42. The compound of claim 40, wherein X² and X³ are both –(CH₂)7-.

43. The compound of any one of claims 1-39, wherein X² and X³ are different.

44. The compound of any one of claims 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-43, wherein Y¹ and Y² are each independently , , ,

45. The compound of any one of claims 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-44, wherein Y¹ and Y² are each independently .

46. The compound of any one of claims 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-45, wherein Y¹ and Y² are both .

47. The compound of any one of claims 1-5, 7, 9, 11, 13, 15, 17, 19, 21-23, and 29-45, wherein Y¹ and Y² are both .

48. The compound of any one of claims 1-47, wherein R² is a bond.

49. The compound of any one of claims 1-47, wherein R² is an optionally substituted C¹- C6 alkylene.

50. The compound of any one of claims 1-49, wherein R³ is a bond.

51. The compound of any one of claims 1-49, wherein R³ is an optionally substituted C1- C6 alkylene.

52. The compound of any one of claims 1-51, wherein R² and R³ are the same.

53. The compound of any one of claims 1-51, wherein R² and R³ are different.

54. The compound of any one of claims 1-8, 13, 14, 17, 18, 21-24, and 29-53, wherein R⁴ is optionally substituted C1-C14 aliphatic.

55. The compound of any one of claims 1-8, 13, 14, 17, 18, 21-24, and 29-54, wherein R⁴ is selected from ,

56. The compound of any one of claims 1-8, 13, 14, 17, 18, 21-24, and 29-55, wherein R⁵ is -R⁸ or optionally substituted -C1-C6 aliphatic-R⁸.

57. The compound of any one of claims 1-8, 13, 14, 17, 18, 21-24, and 29-56, wherein R⁵ is optionally substituted C1-C14 aliphatic.

58. The compound of any one of claims 1-8, 13, 14, 17, 18, 21-24, and 29-56, wherein R⁵ is -R⁸.

59. The compound of any one of claims 1-56 and 58, wherein R⁸ is optionally substituted C1-C13 alkylene terminated with a structure selected from the group consisting of

60. The compound of any one of claims 1-56, 58, and 59, wherein R⁸ is an optionally substituted C1-C13 alkylene terminated with a structure selected from the group consisting

61. The compound of any one of claims 1-56 and 58-60, wherein R⁸ is an optionally substituted -CH₂-, -(CH₂)2-, -(CH₂)3-, -(CH₂)4-, -(CH₂)5-, or -(CH₂)6-, terminated with a structure selected from the group consisting of

62. The compound of any one of claims 1-56 and 58, wherein R⁸ is a structure selected from the group consisting of

63. The compound of any one of claims 1-56 and 58-60, wherein R⁸ is a structure selected

64. The compound of claim 1 selected from any one or more of the compounds of Table (I), or a pharmaceutically acceptable salt thereof.

65. A pharmaceutical composition comprising: a) at least one lipid nanoparticle comprising at least one compound of any one of claims 1-64; and b) at least one nucleobase editing system.

66. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a CRISPR-Cas gene editing system.

67. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a prime editing system or components thereof.

68. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a retron editing system.

69. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a TnpB editing system.

70. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises an integrase editing system.

71. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises an integrase editing system.

72. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises an epigenetic editing system.

73. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a gene writing system.

74. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a gene inactivating system.

75. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises zinc finger nuclease.

76. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a TALE Nuclease, a TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, meganuclease, or a combination thereof.

77. The pharmaceutical composition of claim 65, wherein the nucleobase editing system comprises a meganuclease.

78. The pharmaceutical composition of any one of claims 65-77, wherein the at least one lipid nanoparticle further comprises: i) at least one structural lipid; ii) at least one phospholipid; and iii) at least one PEGylated lipid.

79. The pharmaceutical composition of claim 78, wherein the at least one structural lipid is selected from cholesterol, fecosterol, fucosterol, beta sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, litocholic acid, tomatine, ursolic acid, alpha-tocopherol, Vitamin D3, Vitamin D2, Calcipotriol, botulin, lupeol, oleanolic acid, beta-sitosterol-acetate and any combinations thereof.

80. The pharmaceutical composition of claim 78, wherein the at least one phospholipid is selected from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn- glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuc cinoyl- sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3- phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, 1,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2- diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn- glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), 1,2-Dielaidoyl-sn- phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3- phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn- glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L- serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin.

81. The pharmaceutical composition of claim 78, wherein the at least one PEGylated lipid is selected from (R)-2,3-bis(octadecyloxy)propyl-1- (methoxypoly(ethyleneglycol)2000)propylcarbamate, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG- DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG 2000, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEGA, PEG750-C-DMA, PEG400, PEG2k-DMG, PEG2k-C11, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG Click C12, PEG Click C10, N(Carbonyl-methoxypolyethylenglycol-2000)-l,2-distearoyl-sn- glycero3-phosphoethanolamine, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000- DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000- DMPE, mPEG2000-DMG, mDPPE-PEG2000, l,2-distearoyl-sn-glycero-3- phosphoethanolamine-PEG2000, HPEG-2K-LIPD, Folate PEG-DSPE, DSPE- PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K- NAG, DSPE-PEG2k, DSPE-PEG2000maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-Peg, DMPE-mPEG2000, DMG-PEGMA, DMG-PEG2000, DMG-PEG, distearoyl-glycerol-polyethyleneglycol, Cl8PEG750, CI8PEG5000, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C16 mPEG (polyethylene glycol) 2000 Ceramide, C14-PEG-DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, 1,2-distearoyl- sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3-bis(octadecyloxy)propyl-1- (methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C- DMA, and DSPE-PEG-X.

82. The pharmaceutical composition of any one of claims 65-81, wherein the LNP further comprises at least one additional lipid component selected from 1,2-di-O-octadecenyl- sn-glycero-3-phosphocholine (18:0 Diether PC), 1,2-dilinolenoyl-sn-glycero-3- phosphocholine (18:3 PC), Acylcarnosine (AC), 1-hexadecyl-sn-glycero-3- phosphocholine (C16 Lyso PC), N-oleoyl-sphingomyelin (SPM) (C18:l), N- lignoceryl SPM (C24:0), N-nervonoylshphingomyelin (C24:l), Cardiolipin (CL), l,2- bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), 1,2-Dipalmitoylglycerol-3- hemisuccinate (DGSucc), short-chain bis-n-heptadecanoyl phosphatidylcholine (DHPC), dihexadecoyl-phosphoethanolamine (DHPE), 1,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), l,2-dilauroyl-sn-glycero-3-PE (DLPE), dimyristoyl glycerol hemisuccinate (DMGS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzylalcohol (DOBA), 1,2-dioleoylglyceryl-3-hemisuccinate (DOGHEMS), N-[2-(2-{2-[2-(2,3-Bis-octadec-9-enyloxy-propoxy)-ethoxy]-ethoxy}- ethoxy)-ethyl]-3-(3,4,5-1rihydroxy-6-hydroxymethyl-1etrahydro-pyran-2-ylsulfanyl)- propionamide (DOGP4αMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl- ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), histaminedistearoylglycerol (HDSG), 1,2-Dipalmitoylglycerol-hemisuccinate-Nα- Histidinyl-Hemisuccinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12- pentacosadiynamide (h-Pegi-PCDA), 2-[l-hexyloxyethyl]-2- devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1,2-Dipalmitoylglycerol-O-α-histidinyl-Nα-hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), l,2-Dioleoyl-sn- Glycero-3-Phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane- carboxamide] (MCC-PE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), a thiol- reactive maleimide headgroup lipid e.g.1,2-dioleoyl-sn-glycero-3- phosphoethanolamine-N-[4-(p-maleimidophenyl)but-yramid (MPB-PE), Nervonic Acid (NA), sodium cholate (NaChol), l,2-dioleoyl-sn-glycero-3- [phosphoethanolamine-N-dodecanoyl (NC12-DOPE), 1-oleoyl-2-cholesteryl hemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethylene glycol(PEG) (e.g., polyethylene glycol-distearoylphosphatidylethanolamine lipid (PEG-PE)), phosphatidylglycerol (PG), partially hydrogenated soy phosphatidylchloline (PHSPC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lissamine rhodamineB-phosphatidylethanolamine lipid (Rh-PE), purifiedsoy- derivedmixtureofphospholipids (SIOO), phosphatidylcholine (SM), 18-1-trans-PE,1- stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), soybean phosphatidylcholine (SPC), sphingomyelins (SPM), alpha,alpha-trehalose-6,6'-dibehenate (TDB), l,2- dielaidoyl-sn-glycero-3-phophoethanolamine (transDOPE), ((23S,5R)-3- (bis(hexadecyloxy)methoxy)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)tetrahydrofuran-2-yl)methylmethylphosphate, 1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero- 3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl- sn-glycero-3-phosphoethanolamine, 16-O-monomethyl PE, 16-O-dimethyl PE, and dioleylphosphatidylethanolamine.

83. A method of delivering a nucleobase editing system to a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 65-82.

84. The pharmaceutical composition of any one of claims 65-82 for use as a medicament.

85. Use of a pharmaceutical composition of any one of claims 65-82 for the manufacture of a medicament for delivery of a nucleobase editing system.

86. A lipid nanoparticle (LNP) comprising a compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof.

87. The LNP of claim 86, further comprising: (a) a PEG-lipid (b) a structural lipid; and (c) a non-ionizable lipid and/or a zwitterionic lipid.

88. The LNP of claim 87, wherein the lipid nanoparticle further comprises an additional ionizable lipid, besides a compound of Formula (AC).

89. The LNP of claim 87 or 88, wherein the PEG-lipid is selected from the group consisting of PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE.

90. The LNP of any one of claims 86-89, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha-tocopherol.

91. The LNP of any one of claims 87-89, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1- oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero- 3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3- phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)- 2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3- phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn- glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L- serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin.

92. The LNP of any one of claims 86-91, further comprising a targeting moiety.

93. The LNP of claim 92, wherein the targeting moiety is an antibody or a fragment thereof.

94. The LNP of any one of claims 86-93, further comprising an active agent.

95. The LNP of claim 94, wherein the active agent is a nucleic acid.

96. The LNP of claim 95, wherein the nucleic acid is a ribonucleic acid.

97. The LNP of claim 96, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and a long non-coding RNA (lncRNA).

98. The LNP of claim 95, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA.

99. The LNP of claim 98, wherein the mRNA includes an open reading frame encoding a cancer antigen.

100. The LNP of claim 98, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator.

101. The LNP of any one of claims 98-100, wherein the mRNA includes at least one motif selected from the group consisting of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and a 5' cap structure.

102. The LNP of claim 95, wherein the nucleic acid is suitable for a genome editing technique.

103. The LNP of claim 102, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator- like effector nuclease (TALEN).

104. The LNP of claim 95, wherein the nucleic acid is at least one nucleic acid suitable for a genome editing technique selected from the group consisting of a CRISPR RNA (crRNA), a trans-activating crRNA (tracrRNA), a single guide RNA (sgRNA), and a DNA repair template.

105. The LNP of claim 98, wherein the mRNA is at least 30 nucleotides in length.

106. The LNP of claim 98, wherein the mRNA is at least 300 nucleotides in length.

107. A pharmaceutical composition comprising a LNP of any one of claims 86-106, and a pharmaceutically acceptable carrier.

108. The pharmaceutical composition of claim 107, formulated for intravenous or intramuscular administration.

109. The pharmaceutical composition of claim 108, which is formulated for intravenous administration.

110. A method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP of any one of claims 86-106 or a pharmaceutical composition of any one of claims 107-109.

111. A method for treating a disease characterized by a deficiency of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP of any one of claims 86-106, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein.

112. A method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP of any one of claims 86-106 and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide.