EP4727589A1 - Protamine-coated nucleic acid/therapeutic agent complexes, and uses thereof - Google Patents

Protamine-coated nucleic acid/therapeutic agent complexes, and uses thereof

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Publication number
EP4727589A1
EP4727589A1 EP24857117.6A EP24857117A EP4727589A1 EP 4727589 A1 EP4727589 A1 EP 4727589A1 EP 24857117 A EP24857117 A EP 24857117A EP 4727589 A1 EP4727589 A1 EP 4727589A1
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EP
European Patent Office
Prior art keywords
dna
dox
composition
fragments
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24857117.6A
Other languages
German (de)
French (fr)
Inventor
Young Jik Kwon
Yeon Su Choi
Juwan KIM
Minhyeong PARK
Youngwoo Kim
Hyunchu CHO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmaresearch Co Ltd
University of California
University of California Berkeley
University of California San Diego UCSD
Original Assignee
Pharmaresearch Co Ltd
University of California
University of California Berkeley
University of California San Diego UCSD
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Application filed by Pharmaresearch Co Ltd, University of California, University of California Berkeley, University of California San Diego UCSD filed Critical Pharmaresearch Co Ltd
Publication of EP4727589A1 publication Critical patent/EP4727589A1/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin

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Abstract

The disclosure provides for compositions that comprise nanocomplexes formed by complexing one or more therapeutic agents with nucleic acid fragments of varying lengths and sizes that are coated or complexed with protamine sulfate, and uses thereof, including for the treatment of cancer in a subject in need thereof.

Description

Attorney docket No.00058-079WO1 PROTAMINE-COATED NUCLEIC ACID/THERAPEUTIC AGENT COMPLEXES, AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. §119 from Provisional Application Serial No.63/533,589 filed August 18, 2023, the disclosure of which is incorporated herein by reference. TECHNICAL FIELD [0002] The disclosure provides for compositions that comprise nanocomplexes formed by complexing one or more therapeutic agents with nucleic acid fragments of varying lengths and sizes that are coated or complexed with protamine sulfate, and uses thereof, including for the treatment of cancer in a subject in need thereof. BACKGROUND [0003] The development of effective drug delivery systems is crucial in achieving optimal drug uptake and release rates, especially in the context of cancer therapy. For a drug delivery system to be successful, it must strike a balance between stability and efficacy. If a drug is released too slowly, it may not reach therapeutic levels in the target cells, while a rapid release can lead to systemic toxicity and reduced efficacy. Therefore, ensuring that drugs are released at a controlled and sustained rate is essential for maximizing therapeutic outcomes and minimizing adverse effects. [0004] In clinical practice, the repeated administration of chemotherapeutic agents is often necessary to maintain therapeutic drug levels and manage cancer progression. However, this approach is frequently accompanied by significant side effects, which can limit the dosage and frequency of administration. Doxorubicin (DOX) is a widely used chemotherapeutic drug known for its efficacy against various cancers. Despite its effectiveness, DOX is associated with severe side effects such as non-specific distribution in the body and leading to cardiotoxicity, which poses a challenge in its repeated use. SUMMARY [0005] Provided herein is a platform for the efficient and safe delivery of polyphenol therapeutics that are self-assembled with nucleic acids. In the exemplary studies presented herein, doxorubicin (DOX) self-assembled with a mixture of nucleic acid fragments ranging from 50 to 2,000 nucleotides to form nanoparticles that further self-assembled with protamine sulfate (PS) to form PS/DOX-DNA nanocomplexes. PS/DOX-DNA nanocomplexes were prepared via self-assembly techniques, achieving particle sizes of approximately 60 nm with Attorney docket No.00058-079WO1 negative zeta potentials conducive to systemic circulation. In vitro studies demonstrated controlled release kinetics of DOX from PS/DOX-DNA nanocomplexes under physiological conditions, enhancing cellular uptake and intracellular delivery compared to free DOX and DoxilTM. Evaluation across multiple cancer cell lines revealed superior cytotoxicity of PS/DOX-DNA nanocomplexes, attributed to enhanced drug accumulation in the nucleus. In vivo pharmacokinetic studies in mice showed prolonged circulation and enhanced tumor accumulation of PS/DOX-DNA nanocomplexes, with reduced distribution in cardiotoxicity- sensitive organs. Furthermore, PS/DOX-DNA nanocomplexes exhibited potent antitumor efficacy in murine models with minimal systemic toxicity, suggesting promise for clinical translation. Importantly, PS/DOX-DNA nanocomplexes administration mitigated cardiac troponin-I elevation associated with DOX, highlighting its potential to reduce cardiotoxicity. These findings underscore PS/DOX-DNA nanocomplexes as a promising strategy to improve the therapeutic index of DOX-based chemotherapy, offering enhanced efficacy and reduced toxicity profiles suitable for clinical applications. [0006] Accordingly, the studies presented herein found that the PS/DOX-DNA nanocomplexes exhibited improved stability and enhanced nucleus-targeted intracellular localization in comparison to other DOX-nucleic acid nanoparticles. Further, the PS/DOX- DNA nanocomplexes were far more monodispersed than other DOX-nucleic acid nanoparticles. As is further shown in the in vitro and in vivo studies presented herein, the PS/DOX-DNA nanocomplexes exhibited significantly improved therapeutic delivery efficacy and safety in comparison to DOX, DoxilTM and DOX-nucleic acid nanoparticles. [0007] In a particular embodiment, the disclosure provides a composition comprising nanocomplexes that have been coated or complexed with protamine sulfate to form protamine sulfate coated nanocomplexes, wherein the nanocomplexes comprise one or more therapeutic compounds that have been complexed with nucleic acid fragments of varying lengths and sizes, and wherein the one or more therapeutic compounds are small molecule drugs that can associate or bind with DNA or RNA. In a further embodiment, the nucleic acid fragments are complexed with the one or more therapeutic compounds at a wt/wt ratio of 2:1 to 10:1. In yet a further embodiment, the nucleic acid fragments are complexed with the one or more therapeutic compounds at a wt/wt ratio of 4:1 to 7:1. In another embodiment, the protamine sulfate coated nanocomplexes are from 20 nm to 500 nm in size. In yet another embodiment, the protamine sulfate coated nanocomplexes are from 100 nm to 200 nm in size. In a further embodiment, the one or more therapeutic compounds comprise polyphenol therapeutics, Attorney docket No.00058-079WO1 anthracyclines, anthracenediones, camptotheca compounds, podophyllum compounds, minor groove binders, bleomycin, and/or actinomycin D. In yet a further embodiment, the one or more therapeutic compounds comprise aclarubicin, doxorubicin, daunorubicin, idarubicin, epirubicin, amrubicin, pirarubicin, valrubicin, and/or zorubicin. In another embodiment, the one or more therapeutic compounds comprise doxorubicin. In a certain embodiment, the one or more therapeutic compounds comprise mitoxantrone, topotecan, etoposide, teniposide, bleomycin, actinomycin D, and/or duocarmycin A. In another embodiment, the nucleic acid fragments comprise oligonucleotides, hydrolyzed DNA, polynucleotides, and polydeoxyribonucleotides. In yet another embodiment, the nucleic acid fragments comprise chemically synthesized DNA, RNA and/or DNA-RNA hybrids of differing nucleotide lengths. In a further embodiment, the nucleic acid fragments comprise fragments of naturally occurring DNA, RNA and/or DNA-RNA hybrids. In yet a further embodiment, the nucleic acid fragments are DNA fragments. In another embodiment, the DNA fragments are fragments of fish DNA. In yet another embodiment, the DNA fragments are fragments of fish testis or sperm DNA. In a further embodiment, the DNA fragments are fragments of DNA from fish of the family of Salmonidae, Clupeidae, Cyprinidae, Cichlidae, or Acipenseridae. In another embodiment, the DNA fragments are fragments of DNA from fish of the family of Salmonidae. In yet another embodiment, the DNA fragments are fragments of DNA from salmon or trout. In a further embodiment, the DNA fragments are fragments of DNA from salmon testis or sperm DNA. In yet a further embodiment, the DNA fragments are fragments of DNA from fish of the family of Clupeidae. In a certain embodiment, the DNA fragments are fragments of DNA from herring. In a further embodiment, the DNA fragments are fragments of DNA from fish of the family of Cyprinidae. In yet a further embodiment, the DNA fragments are fragments of DNA from carp or goldfish. In a certain embodiment, the nucleic acid fragments are from 20 nt to 10,000 nt in length. In another embodiment, the nucleic acid fragments are from 50 nt to 2,000 nt in length. In yet another embodiment, the nucleic acid fragments are from 50 nt to 500 nt in length. In a further embodiment, the nucleic acid fragments comprise a ligand that targets the nanoparticles to specific cells, tissue, organs, or tumors. In yet a further embodiment, the nanocomplexes are coated or complexed with protamine sulfate at a wt/wt ratio of 1:8 to 1:20. In another embodiment, the nanocomplexes coated or complexed with protamine sulfate are substantially monodisperse. [0008] In a particular embodiment, the disclosure also provides a pharmaceutical composition comprising a composition disclosed herein and a pharmaceutically acceptable Attorney docket No.00058-079WO1 carrier, diluent, and/or excipient. In a further embodiment, the pharmaceutical composition is formulated for parenteral delivery [0009] In a certain embodiment, the disclosure further provides a method of treating a subject having a cancer in need of treatment thereof, comprising: administering to the subject an effective amount of a pharmaceutical composition of the disclosure. In a further embodiment, the cancer is selected from acute lymphoblastic leukemia, acute myeloblastic leukemia, bone sarcoma, breast cancer, endometrial cancer, gastric cancer, head and neck cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma, liver cancer, kidney cancer, multiple myeloma, neuroblastoma, ovarian cancer, small cell lung cancer, soft tissue sarcoma, thymomas, thyroid cancer, transitional cell bladder cancer, uterine sarcoma, Wilms’ tumor, and Waldenström macroglobulinemia. In yet a further embodiment, the method further comprises administering to the subject with one or more anticancer agents selected from angiogenesis inhibitors, tyrosine kinase inhibitors, PARP inhibitors, alkylating agents, vinca alkaloids, anthracyclines, antitumor antibiotics, antimetabolites, topoisomerase inhibitors, aromatase inhibitors, mTOR inhibitors, retinoids, and HDAC inhibitors. In another embodiment, the method further comprises administering to the subject with one or more anticancer agents selected from mitoxantrone, topotecan, etoposide, teniposide, bleomycin, actinomycin D, and duocarmycin A. [0010] In a particular embodiment, the disclosure provides a composition or pharmaceutical composition or a method of use thereof as substantially described herein. [0011] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. DESCRIPTION OF DRAWINGS [0012] FIG.1A-C provides a synthesis scheme (A) and a hypothetical illustration of PS/DOX-DNA NPs’ mechanism of action (B). (C) A gel photo of a DNA degradation assay in 10% FBS/PBS. DNA was incubated with serum-containing PBS at 37 °C over time. Samples were stored in -20 °C to stop enzymatic degradation from nucleases at each time point. [DNA] = 100 μg/mL. Numbers on left indicate the base pairs in the ladder (L).0* : fresh DNA (no -20 °C storage). DNA is degraded overtime when exposed to 10% FBS/PBS. It is likely that the nucleases in the serum-containing media are contributing to this degradation. It is possible to infer a delayed release of DOX due to this degradation of DNA overtime in 10% FBS. Attorney docket No.00058-079WO1 [0013] FIG.2 presents size, PDI, and zeta-potential of PS/DOX-DNA NPs (DNA/PS ratio 10:1 or 20:1) prepared at different temperatures. [0014] FIG.3 provides size, PDI, and zeta-potential of PS/DOX-DNA NPs prepared at different DNA/PS ratios at 60 °C. [0015] FIG.4 presents size, PDI, and zeta-potential of PS/DOX-DNA NPs (DNA/PS ratio 12:1, 13:1, or 14:1) after sitting at different temperatures (4 °C for 30 min or room temperature for 90 min). [0016] FIG.5A-C provides size (A), PDI (B), and zeta-potential (C) of PS/DOX- DNA NPs. As shown, PS/DOX-DNA NPs could form self-assembled nanostructure with about 160 nm, -15.4 mV, and 0.18 PDI value. These results indicate that protamine sulfate may be well placed on the outside of the DOX-DNA NPs. [0017] FIG.6 shows a chromatogram of doxorubicin and protamine sulfate from the PS/DOX-DNA NPs. [0018] FIG.7 presents Sysmex images of DOX-DNA NPs or PS/DOX-DNA NPs. The PS/DOX-DNA NPs had a size distribution narrower than DOX-DNA NPs and a spherical morphology. [0019] FIG.8 presents TEM images of PS/DOX-DNA NPs. The PS/DOX-DNA NPs were prepared in PBS before diluting in DIW for imaging. The PS/DOX-DNA NPs were approximately 130 nm in size. [0020] FIG.9 presents SEM images of PS/DOX-DNA NPs. The PS/DOX-DNA NPs were centrifuged, the supernatant was discarded, and the pellet was resuspended in acetone, followed by centrifugation. Dried powders were sputter coated and observed. [0021] FIG.10 shows that the serum content in media resulted in DOX being released from PS/DOX-DNA NPs over time in a dose dependent manner, repeated experiments of n=3. [0022] FIG.11A-C provides the results of a study looking at in vitro cytotoxicity of PS/DOX-DNA NPs in EL4 cells at 24 h (A), 48 h (B), and 72 h (C). EL4 cells were treated by PS/DOX-DNA NPs (0 ^ [DOX] ^ 5 μg/mL), followed by cellular viability analysis via an MTT assay. PS/DOX-DNA NPs exhibited similar cytotoxicity on these cells compared to DOX at 24 h of incubation (A), as seen in the reported IC50 values: PS/DOX-DNA NPs IC50=0.059 μg/mL, DOX-DNA NPs IC50=0.076 μg/mL, and DOX IC50=0.060 μg/mL. PS/DOX-DNA NPs exhibited more cytotoxicity on these cells than that of DOX by a 1.50 or 2.53-fold difference at 48 h (B) and 72 h (C) of incubation, as seen in the reported IC50 Attorney docket No.00058-079WO1 values: PS/DOX-DNA NPs IC50=0.034 μg/mL, DOX-DNA NPs IC50=0.046 μg/mL, and DOX IC50=0.051 μg/mL at 48 h or PS/DOX-DNA NPs IC50=0.019 μg/mL, DOX-DNA NPs IC50=0.029 μg/mL, and DOX IC50=0.048 μg/mL at 72 h. PS/DOX-DNA NPs showed lower cell killing effects than DOX but quickly surpassed the efficacy of DOX at 48 h (B) and 72 h (C). [0023] FIG.12A-C presents the results of a study looking at in vitro cytotoxicity of PS/DOX-DNA NPs in HeLa cells at 24 h (A), 48 h (B), and 72 h (C). HeLa cells were treated by PS/DOX-DNA NPs (0 ^ [DOX] ^ 5 μg/mL), followed by cellular viability analysis via an MTT assay. PS/DOX-DNA NPs exhibited less cytotoxicity on these cells than that of DOX by a 1.16-fold at 24 h of incubation (A), as seen in the reported IC50 values: PS/DOX- DNA NPs IC50=0.767 μg/mL, DOX-DNA NPs IC50=0.998 μg/mL, and DOX IC50=0.662 μg/mL. PS/DOX-DNA NPs exhibited more cytotoxicity on these cells than DOX by a 1.36 or 1.55-fold difference at 48 h (B) and 72 h (C) of incubation, as seen in the reported IC50 values: PS/DOX-DNA NPs IC50=0.402 μg/mL, DOX-DNA NPs IC50=0.455 μg/mL, and DOX IC50=0.548 μg/mL at 48 h or PS/DOX-DNA NPs IC50=0.166 μg/mL, DOX-DNA NPs IC50=0.194 μg/mL, and DOX IC50=0.257 μg/mL at 72 h. PS/DOX-DNA NPs showed lower cell killing effects than DOX but quickly surpassed the efficacy of DOX at 48 h (B) and 72 h (C). [0024] FIG.13 presents the results of a study looking at in vitro time-dependent cytotoxicity of PS/DOX-DNA NP in EL4, HeLa, WM3211, and MDA-MB-468 cells (n = 12). [0025] FIG.14 demonstrates the in vitro cell killing effects of DOX in MCF7/ADR, SKOV3/ADR, and MDA-MB-231/ADR cells at 24, 48, and 72 h post-treatment. Various concentrations of DOX were used to treat the cells, and the data are expressed as the mean ± standard deviation of the mean (n=12). [0026] FIG.15 provides fluorescent images comparing intracellular distribution of PS/DOX-DNA NPs with DOX, DoxilTM, and DOX-DNA NPs. The intracellular localization of DOX and Cy5-labeled DNA was located by super resolution fluorescence microscopy at 2, 4 or 6 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. However, no significant intracellular uptake of DoxilTM was observed at 6 h in super resolution fluorescence micrographs, possibly due to inefficient endocytosis and slow DOX release from the highly stable liposomal structure and most DOX encapsulated in DoxilTM retained. Attorney docket No.00058-079WO1 [0027] FIG.16 demonstrates intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NPs. For up to 6 of incubation, free DOX rapidly accumulated in the nucleus of EL4 cells. DOX is known to freely penetrate through the cell membrane and rapidly integrate into the intracellular DNA mainly in the nucleus. while its nano-formulations are typically endocytosed via various pathways, depending on their physicochemical properties. It was clear that PS/DOX-Cy5-DNA NPs were efficiently taken up by EL4 cells via endocytosis as indicated by their decreasing localization in the lysosome as their nuclear localization increased because of protamine sulfate having nuclear transporter. [0028] FIG.17 shows the cellular uptake of PS/DOX-DNA NP via multiple endocytic pathways: Inhibited cellular uptake of PS/DOX-DNA NP by EL4 cells after exposure for 30 min to CPZ (20 ^M; clathrin-dependent pathway), Filipin III (5 ^g/mL; caveolin-dependent pathway), EIPA (20 ^M; micropinocytosis), or 4 oC (membrane fusion) at 2.5 ^g/mL DOX or DOX equivalent for 4 h incubation (n =4). [0029] FIG.18 provides for the nuclear uptake of PS/DOX-DNA NP with time- dependent (2, 4, or 6 h) and DOX (1.25, 2.5, 5, or 10 ^g/mL) or DOX equivalent concentration changes (n =4): To determine the nuclei uptake, the nuclei of free DOX or DOX equivalent in EL4 cells were isolated, per the manufacturer’s protocols with a Nuclei PURE Prep kit. The nuclei fluorescence of DOX had taken up free DOX or DOX-loaded NP was measured by fluorescence measurement (Synergy H1, BioTek, VT, USA) using excitation/emission at 497/594 nm. [0030] FIG.19 provides for the nuclear uptake of PS/DOX-DNA NP with time- dependent (2, 4, 6, 8, 10, or 12 h) changes (n =4): To determine the nuclei uptake, the nuclei of free DOX or DOX equivalent in EL4 cells were isolated, per the manufacturer’s protocols with a Nuclei PURE Prep kit. The nuclei fluorescence of DOX had taken up free DOX or DOX-loaded NP was measured by fluorescence measurement (Synergy H1, BioTek, VT, USA) using excitation/emission at 497/594 nm. [0031] FIG.20 demonstrates time-dependent cytotoxicity of PS/DOX-DNA NP in MCF7, MCF7/ADR, SKOV3, SKOV3/ADR, MDA-MB-231, and MDA-MB-231 cells with or without verapamil (n =12) [0032] FIG.21 shows the in vitro cell killing effects of PS/DOX-DNA NP in MCF7 and MCF7/ADR cells with verapamil or without verapamil at 24 h and 48 h post-treatment: Attorney docket No.00058-079WO1 Various concentrations of DOX and their NP were used to treat the cells, and the data are expressed as the mean ± standard deviation of the mean (n=12). [0033] FIG.22 presents the in vitro cell killing effects of PS/DOX-DNA NP in SKOV3 and SKOV3/ADR cells with verapamil or without verapamil at 24 h and 48 h post- treatment: Various concentrations of DOX and their NP were used to treat the cells, and the data are expressed as the mean ± standard deviation of the mean (n=12). [0034] FIG.23 presents the in vitro cell killing effects of PS/DOX-DNA NP in MDA-MB-231 and MDA-MB-231/ADR cells with verapamil or without verapamil at 24 h and 48 h post-treatment: Various concentrations of DOX and their NP were used to treat the cells, and the data are expressed as the mean ± standard deviation of the mean (n=12). [0035] FIG.24A-C shows the intracellular distributions and uptake mechanism of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in MCF7, MCF7/ADR, SKOV3, SKOV3/ADR, MDA-MB-231, and MDA-MB-231 cells with or without verapamil. (A) Cellular uptake of DOX. (B) Super resolution fluorescence for 6 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. (C) Quantified co-localization of DOX in the nuclei, lysosomes, or other locations. [0036] FIG.25A-B demonstrates the cellular uptake with verapamil or without verapamil in MDA-MB-231 and MDA-MB-231/ADR cells: (A) Quantified intracellular DOX concentrations with concentration- and time-dependent DOX changes. (B) Quantified intracellular DOX concentrations with concentration- and time-dependent DOX or DOX equivalent changes. [0037] FIG.26 demonstrates the intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in MCF7 and MCF7/ADR cells: Super resolution fluorescence micrographs with NP for 4 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. [0038] FIG.27 presents the intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in MCF7 and MCF7/ADR cells with verapamil: Super resolution fluorescence micrographs with NP for 4 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. [0039] FIG.28 shows the intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in SKOV3 and SKOV3/ADR cells: Super resolution fluorescence micrographs with NP for 4 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. Attorney docket No.00058-079WO1 [0040] FIG.29 presents the intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in SKOV3 and SKOV3/ADR cells with verapamil: Super resolution fluorescence micrographs with NP for 4 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. [0041] FIG.30 shows the intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in MDA-MB-231 and MDA-MB- 231/ADR cells: Super resolution fluorescence micrographs with NP for 4 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. [0042] FIG.31 presents the intracellular distribution of PS/DOX-DNA NP, in comparison with DOX, DoxilTM, and DOX-DNA NP in MDA-MB-231 and MDA-MB- 231/ADR cells with verapamil: Super resolution fluorescence micrographs with NP for 4 h at a concentration of 0.5 ^g/mL DOX or DOX equivalent. [0043] FIG.32A-B In vivo pharmacokinetics and biodistribution of PS/DOX-DNA NP in EL4 tumor syngeneic-bearing mice. (A) Time-dependent changes in DOX concentrations in the plasma. (B) Time-dependent changes in DOX concentrations in the lungs, liver, heart, kidneys, and spleen. [0044] FIG.33 demonstrates in vivo pharmacokinetics and biodistribution of PS/DOX-DNA NP: Time-dependent changes in DOX concentration in the brain, stomach, thyroid, large intestine, small intestine, bladder, muscle, bone, and tail. [0045] FIG.34A-B demonstrates the in vivo efficacy of PS/DOX-DNA NP. Time- dependent changes in tumor volume (A), and body weight (B). (interval 14 day) [0046] FIG.35A-C presents experiments evaluating tumor growth, body weight, and survival outcomes for EL4-challenged C57BL/6 mice (8 weeks) treated with 20 mg/kg DOX or DOX equiv. of DoxilTM, DOX-DNA NPs, or PS/DOX-DNA NPs, n=5. (A) PS/DOX-DNA NPs were more effective in suppressing tumor growth over time in comparison to Doxil and DOX-DNA NPs. (B) The body weights of the mice showed few differences between PBS- injected mice and PS/DOX-DNA NPs-injected mice. PS/DOX-DNA NPs are a safer alternative than free DOX or DOX-DNA NPs. (C) Survival for 4 weeks clearly demonstrates the best survival outcome of PS/DOX-DNA NPs-treated group compared to the DOX-treated group. The 20 mg/kg dosage led to relatively prolonged survival with slowed tumor growth and minimal toxicity when injected with PS/DOX-DNA NPs. [0047] FIG.36A-C presents additional experiments evaluating tumor growth, body weight, and survival outcomes for EL4-challenged C57BL/6 mice (8 weeks) treated with 20 Attorney docket No.00058-079WO1 mg/kg DOX or DOX equiv. of DoxilTM, or PS/DOX-DNA NPs on day 0 and day 7, n=5. (A) PS/DOX-DNA NPs were more effective in suppressing tumor growth over time in comparison to DoxilTM and DOX. (B) The body weights of the mice showed few differences between PBS-injected mice and PS/DOX-DNA NPs-injected mice. PS/DOX-DNA NPs are a safer alternative than free DOX or DoxilTM. (C) Survival for more than 40 days clearly demonstrates that the PS/DOX-DNA NPs-treated group had the best survival outcome in comparison to DOX and DoxilTM. Consequently, PS/DOX-DNA NPs treatment conferred a more promising outcome compared to free DOX and DoxilTM. [0048] FIG.37A-C presents additional experiments evaluating tumor growth, body weight, and survival outcomes for EL4-challenged C57BL/6 mice (8 weeks) treated with 20 mg/kg DOX or DOX equiv. of DoxilTM, DOX-DNA NPs, or PS/DOX-DNA NPs on day 0, day 7, and day 14, n=5. (A) PS/DOX-DNA NPs were more effective in suppressing tumor growth over time in comparison to DoxilTM and DOX-DNA NPs. (B) The body weights of the PS/DOX-DNA NPs-injected mice didn’t show noticeable toxicity. (C) Complete survival for 7 to 8 weeks clearly demonstrates the best survival outcome of PS/DOX-DNA NPs group. These results indicate that the PS/DOX-DNA NPs can effectively inhibit the growth of EL4 tumors. [0049] FIG.38A-B provides tumor growth and body weight outcomes of repeated administrations of PS/DOX-DNA NPs with 20 mg/kg on day 0, day 14, and day 21, n=5. (A) Despite increasing the drug administration interval from 7-day to 14-day, similar effects of tumor growth were observed. (B) The body weight of the test subjects generally increased over the evaluated time period. [0050] FIG.39 demonstrates sustained release and extended circulation of PS/DOX- DNA NPs. When DOX alone was administered, it was quickly cleared from circulation (t1/2- 0.1 min). However, when DOX was delivered by PS/DOX-DNA NPs, it remained in circulation for a significantly longer period (t1/2-243.5 min). Moreover, the circulation time of PS/DOX-DNA NPs was more than 5 times longer than DOX-DNA NPs. [0051] FIG.40A-C demonstrates the effects on serum cardiac troponin-I levels and body weight when animals were treated with DOX, DoxilTM, DOX-DNA NPs, or PS/DOX- DNA NPs. (A) The serum concentration of troponin-I was significantly elevated by 15 days for DOX and DoxilTM treated animals in comparison to control animals treated with PBS. In contrast, the serum concentration of troponin-I was initially elevated by day 15 for the DOX- DNA NPs and PS/DOX-DNA NP NPs-treated animals but then decreased over time. (B) The Attorney docket No.00058-079WO1 body weight of animals treated with DOX and DoxilTM significantly decreased by day 15 in comparison to control animals treated with PBS. In contrast, the body weight of the animals treated with DOX-DNA NPs and PS/DOX-DNA NPs initially decreased by day 15 but then recovered over time. (C) Animals treated with DOX-DNA NPs and PS/DOX-DNA NPs exhibited a dose-dependent effect on the serum concentration of troponin-I, with PS/DOX- DNA NPs treatment at higher concentrations causing significantly less troponin-I release in comparison to DOX-DNA NPs. DETAILED DESCRIPTION [0052] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a vector" includes a plurality of such vectors and reference to "the nucleic acid" includes reference to one or more nucleic acids and equivalents thereof known to those skilled in the art, and so forth. [0053] Also, the use of “or” means “and/or” unless stated otherwise. Similarly, “comprise,” “comprises,” “comprising” “include,” “includes,” and “including” are interchangeable and not intended to be limiting. [0054] It is to be further understood that where descriptions of various embodiments use the term “comprising,” those skilled in the art would understand that in some specific instances, an embodiment can be alternatively described using language “consisting essentially of” or “consisting of”. [0055] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although many methods and reagents are similar or equivalent to those described herein, the exemplary methods and materials are disclosed herein. [0056] All publications mentioned herein are incorporated herein by reference in full for the purpose of describing and disclosing the methodologies, which might be used in connection with the description herein. Moreover, with respect to any term that is presented in one or more publications that are similar to, or identical with, a term that has been expressly defined in this disclosure, the definition of the term as expressly provided in this disclosure will control in all respects. [0057] For purposes of the disclosure the term “cancer” will be used to encompass cell proliferative disorders, neoplasms, precancerous cell disorders and cancers, unless specifically delineated otherwise. Thus, a “cancer” refers to any cell that undergoes aberrant Attorney docket No.00058-079WO1 cell proliferation that can lead to metastasis or tumor growth. Exemplary cancers include but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non- melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, including triple negative breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell Attorney docket No.00058-079WO1 pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non- melanoma), skin cancer (melanoma), papillomas, actinic keratosis and keratoacanthomas, merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms tumor. In a particular embodiment, the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myeloblastic leukemia, bone sarcoma, breast cancer, endometrial cancer, gastric cancer, head and neck cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma, liver cancer, kidney cancer, multiple myeloma, neuroblastoma, ovarian cancer, small cell lung cancer, soft tissue sarcoma, thymomas, thyroid cancer, transitional cell bladder cancer, uterine sarcoma, Wilms tumor, and Waldenström macroglobulinemia. [0058] The term "disorder" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms. [0059] The term "non-release controlling excipient" as used herein, refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form. [0060] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" as used herein, refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component should be "pharmaceutically acceptable" in the sense of being compatible with Attorney docket No.00058-079WO1 the other ingredients of a pharmaceutical formulation. It should also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. Examples of "pharmaceutically acceptable carriers" and "pharmaceutically acceptable excipients" can be found in the following, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004. [0061] The term “therapeutics that can associate or bind with DNA or RNA” as used herein refers to small molecules that can associate or bind with DNA or RNA and can be used to treat a disorder or disease in a subject, typically cancer. Examples of “therapeutics that can associate or bind with DNA or RNA” include but are not limited to, anthracyclines or polyphenol therapeutics, such as aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin; anthracenediones, such as mitoxantrone, and pixantrone; camptotheca compounds, such as belotecan, camptothecin, cositecan, exatecan, gimatecan, irinotecan, lurtotecan, rubitecan, silatecan, and topotecan; podophyllum compounds, like etoposide, and teniposide; bleomycin; actinomycin D; minor groove binders, such as duocarmycin A, adozelesin, bizelesin, and carzelesin; purine antagonists, such as cladribine, clofarabine, nelarabine, mercaptopurine, tioguanine, and pentostatin; pyrimidine antagonists such as capecitabine, carmofur, doxifluridine, floxuridine, fluorouracil, tegafur, cytarabine, gemcitabine, azacytidine, and decitabine; folate antagonists, such as aminopterin, methotrexate, pemetrexed, and pralatrexate; alkylating agents, such as cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, chlormethine, uramustine, carmustine, fotemustine, lomustine, nimustine, ranimustine, streptozocin, mannosulfan, treosulfan, carboquone, thiotepa, triaziquone, triethylenemelamine, carboplatin, cisplatin, dicycloplatin, nedaplatin, oxaliplatin, satraplatin, temozolomide, dacarbazine, mitobronitol, pipobroman, and procarbazine. [0062] The term "release controlling excipient" as used herein, refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form. Attorney docket No.00058-079WO1 [0063] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenicity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. [0064] The terms "treat", "treating" and "treatment", as used herein, refers to ameliorating symptoms associated with a disease or disorder (e.g., cancer), including preventing or delaying the onset of the disease or disorder symptoms, and/or lessening the severity or frequency of symptoms of the disease or disorder. [0065] The term "subject" as used herein, refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like. The terms "subject" and "patient" are used interchangeably herein. For example, a mammalian subject can refer to a human patient. [0066] Therapeutics that can associate or bind with DNA or RNA have great potential for treating cancers and other diseases, but their inherent chemical structure can make them insoluble leading to poor bioavailability. Some of these therapeutics, while soluble, can lead to systemic toxicity, and can often be cleared too quickly from the body. Current solutions to these problems include delivering such compounds (e.g., anthracyclines) using a nanocarrier. Common disadvantages to these solutions, however, include very low drug loading, immunogenicity, poor therapeutic efficacy with slow clearance of the carriers, and substantial increase in cost. For example, DoxilTM, a polyethylene glycolated (PEGylated) liposomal formulation of doxorubicin (DOX), experiences all of these limitations. Although it improves the safety profile of doxorubicin, it exhibits less efficacy than DOX. DoxilTM’s prolonged circulation in the bloodstream promotes the immune system to develop antibodies against the PEGylated moieties on the particle. Thus, a major shortcoming of current solutions includes the biocompatibility of the nanocarrier. Moreover, current solutions do not have the ease of assembly. [0067] In direct contrast, the compositions and methods of the disclosure can be assembled in a straightforward manner and are more cost effective. For example, HPMA- DOX (N-(2-hydroxypropyl) methyl acrylamide polymer-doxorubicin), another DOX nanocarrier, has a reported shorter circulation time (20.1 h) than compositions described herein, and has a more involved assembly process that would be difficult to scale to a commercial level. Others have synthesized nucleic acid systems to deliver chemotherapies Attorney docket No.00058-079WO1 (e.g., click nucleic acids for DOX and cytosine deaminase delivery), but such formulations are quite cost- and time-consuming and are unlikely to reach commercial stages. Furthermore, the PEGylation of such formulations will likely lead to similar immunogenicity issues that have previously reported for other PEGylated delivery systems, like DoxilTM. [0068] Deoxyribonucleic acid (DNA) is a fully biocompatible (non-immunogenic; nontoxic), aqueous soluble, degradable, and versatile polymer found in almost all living forms. Many polyphenol cancer drugs tend to bind to DNA for their molecular actions, making DNA as a promising drug-loadable polymeric platform. DNA fragments extracted from natural resources are easy to manufacture, simple, and relatively inexpensive and lack genetic specificity without a code for specific proteins. This relatively heterogeneous DNA material contrasts with aptamer material, which is highly designed, and yet when mixed with DOX it still leads to homogenous nanocomplexes. Generally, aptamer-based systems are conjugate-based systems that must be synthetically formed. [0069] Provided herein are protamine-coated DOX-DNA nanoparticles (PS/DOX- DNA NPs) that enhance drug delivery efficiency and ensure controlled release kinetics. Protamine sulfate, a naturally occurring polycationic protein, was utilized to coat the DOX- DNA NP. Protamine offers several advantages, including the ability to stabilize nanoparticles and facilitate cellular uptake due to its positive charge. Additionally, protamine has inherent biocompatibility and can enhance the therapeutic efficacy of the nanoparticles by promoting better interaction with the negatively charged cell membranes. [0070] In direct comparison to DOX-DNA nanocomplexes that lack a protamine coating, the protamine sulfate coated nucleic acid-therapeutic nanocomplexes of the disclosure exhibited the following advantages: (1) substantially improved stability and better sustained drug release; [0071] As shown in the in vitro and in vivo studies presented herein, the protamine sulfate coated nucleic acid-therapeutic nanocomplexes of the disclosure exhibited the most pronounced reduction in tumor growth and had the best survival outcome in comparison to DOX, DoxilTM, and DOX-DNA NPs (see FIGs.35-40). The foregoing favorable outcomes are likely the result of prolonged circulation of the nanocomplexes, the monodisperse nature Attorney docket No.00058-079WO1 of the nanocomplexes, the nuclear localization of the nanocomplexes, and the sustained release of therapeutics from the nanocomplexes, as evidenced by the 24 h, 48 h, and 72 h in vitro cytotoxicity studies and by the in vivo blood circulation study. Accordingly, the protamine sulfate coated nucleic acid-therapeutic nanocomplexes of the disclosure exerted a chemotherapeutic effect that was far superior to DOX treatment alone, and superior to DoxilTM treatment and DOX-DNA NPs treatment. DoxilTM has been shown to be effective in reducing systemic toxicity effects but does not result in an improved treatment outcome. Moreover, the PEGylation of DoxilTM and the repeated administration of this chemotherapy formulation has been shown to result in immunogenicity. The production of the protamine sulfate coated nucleic acid-therapeutic nanocomplexes of the disclosure can be made in a rapid and facile manner. Further, therapeutics, nucleic acids, and protamine sulfate are already manufactured at commercial scale. Thus, unlike other therapeutic/nucleic acid formulations, preparations and compositions comprising the protamine sulfate coated nucleic acid-therapeutic nanocomplexes of the disclosure are easy to produce and are commercially scalable. [0072] In a particular embodiment, the disclosure provides for a composition, preparation or formulation comprising one or more therapeutics that have been complexed with nucleic acids to form nanoparticles. Examples of therapeutics that can be complexed with nucleic acids to form nanoparticles include, but are not limited to, norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepam; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; low molecular weight heparins, such as enoxaparin; Factor VIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. pitavastatin, itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as Attorney docket No.00058-079WO1 rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichlormethiazide, polythiazide, benzothiazine, benzthiazide ethacrynic acid, tricrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiazolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as folate antagonists, purine analogues, and pyridine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant- derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; polyphenol compounds; polyketide compounds; prenyl-protein transferase inhibitors; and cyclosporines; cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunomide; and cyclooxygenase-2 (COX- 2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin. While the exemplary Attorney docket No.00058-079WO1 studies presented herein, clearly indicate that DOX-nucleic acid nanoparticles disclosed herein can be used to effectively treat cancer, it should be understood that any disease or disorder that is treatable by therapeutic agents is encompassed by this disclosure. [0073] In a particular embodiment, the disclosure provides for a therapeutic composition, preparation, or formulation comprising polyphenols that have been complexed with nucleic acids to form nanoparticles. Polyphenols are a structural class of mainly natural, but also synthetic or semisynthetic, organic chemicals characterized by the presence of large multiples of phenol structural units. The number and characteristics of these phenol structures underlie the unique physical, chemical, and biological (metabolic, toxic, therapeutic, etc.) properties of particular members of the class. Many polyphenols are micronutrients produced as secondary metabolites by dietary plants. Although these compounds display poor bioavailability (only a proportion of ingested amounts are absorbed and excretion is rapid), and complex pharmacodynamics and metabolism, they present therapeutic properties. A substantial body of evidence (epidemiological studies, animal studies, and human clinical trials) indicate that polyphenols reduce a range of pathologies associated with cardiovascular disease including thrombosis (Navarro-Nuñez et al., J Agric Food Chem.2008; 56:2970–2976.), atherosclerosis (Chiva-Blanch et al., Am J Clin Nutr. 2012; 95:326–334.) and inflammation (Rieder et al., Br J Pharmacol.2012; 167:1244– 1258.), as well as displaying anti-cancer (Gali et al., Cancer Res. 1991; 51:2820–2825.) and neuroprotective (Gatson et al., J Trauma Acute Care Surg.2013; 74:470–475) properties. The activities of these compounds are achieved via a range of mechanisms including their well-characterized antioxidant effects (Pignatelli et al., Atherosclerosis. 2006; 188:77–83), inhibition of intracellular kinase activity (Wright et al., Regen Med.2012;7:295–307), binding to cell surface receptors (Jacobson et al., Adv Exp Med Biol.2002; 505:163–171) and disrupting the integrity of cell plasma membranes (Pawlikowska-Pawlega et al., Biochim Biophys Acta. 2007; 1768:2195–2204). Research on the application of polyphenols has increased especially in functional foods, nutraceutical, and pharmaceutical industries. However, one problem in human health is related to the effectiveness of polyphenols, which depends on preserving the stability, bioactivity, and bioavailability of the bioactive compounds. Additionally, the unpleasant taste of some phenolic compounds limits their use in pharmaceutical applications. The encapsulation or complexation of polyphenols with nucleic acids disclosed herein, can effectively help to solve some of the drawbacks seen with the free polyphenol compounds. As the compositions and methods disclosed herein are Attorney docket No.00058-079WO1 directed to a platform-based polyphenol delivery system, it is expected that any type of polyphenol can be complexed or encapsulated by the nucleic acids disclosed herein. Exemplary examples of such polyphenol compounds, include but are not limited to, xanthohumols; flavanols, such as epicatechin, epigallocatechin, EGCG, and procyanidins; flavanones, such as hesperidin, and naringenin; flavones, such as apigenin, chrysin, and luteolin; flavonols, such as quercetin, kaempferol, myricetin, isorhamnetin, and galangin; isoflavonoids, such as genistein, and daidzein; phenolic acids, such as ellagic acid, gallic acid, ferulic acid, and chlorogenic acid; lignans, such as sesamin, and secoisolariciresinol diglucoside; stilbenes, such as resveratrol, pterostilbene, and piceatannol. Accordingly, the disclosure provides a platform technology that provides for formulations, compositions, or preparations that allow for safe, efficient, and controlled delivery of polyphenols in a subject to treat any number of diseases or disorders that are treatable by polyphenolic compounds. For example, numerous studies have demonstrated that polyphenols limit the incidence of coronary heart diseases (Renaud et al., Lancet.1992; 339:1523–1526; Dubick et al., J Nutraceut Functional & Med Foods.2001; 3:67–93; Nardini et al., Platelets.2007; 18:224– 243; and Vita et al., Am J Clin Nutr. 2005; 81:292–297); type II diabetes (Rizvi et al., Clin Exp Pharmacol Physiol.2005;32:70–75; Matsui et al., J Agric Food Chem. 2002; 50:7244– 7248; Dembinska-Kiec et al., Br J Nutr 20.2008; 99:109–117; and Chen et al., Eur J Pharmacol.2007; 568:269–277); obstructive lung disease (Tabak et al., Am J Respir Crit Care Med.2001; 164:61–64; and Woods et al., Am J Clin Nutr.2003; 78:414–421); and neurodegenerative diseases (Ajami et al., Neuoroscience & Biobehavioral Reviews 2007; 73:39-47; and Mandel et al., Free Radical Biology and Medicine 2004; 37(3):304-317). It should be further noted that the preparations, compositions, or formulations disclosed herein are not just limited to the delivery of one particular polyphenol compound, as any number of polyphenol compounds can be complexed with nucleic acids disclosed herein to make polyphenol/nucleic acid nanoparticles. [0074] Additionally, polyketide compounds can be complexed with the nucleic acids disclosed herein, or alternatively both polyketide and polyphenol compounds can be complexed with the nucleic acids disclosed herein. Polyketides are a large group of secondary metabolites which either contain alternating carbonyl and methylene groups (-CO- CH2-), or are derived from precursors which contain such alternating groups. Many polyketides have antimicrobial and immunosuppressive properties. Like with polyphenol Attorney docket No.00058-079WO1 compounds, polyketide compounds can form pi-pi stacking interactions with the nucleic acid species disclosed herein to form polyketide/nucleic acid nanoparticles. [0075] In a particular embodiment, the disclosure provides for a composition, preparation, or formulation comprising one or more therapeutics that can associate or bind with DNA or RNA disclosed are complexed with nucleic acids to form nanoparticles. Examples of therapeutics that can be complexed with nucleic acids to form nanoparticles include, but are not limited to, anthracyclines, such as aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin; anthracenediones, such as mitoxantrone, and pixantrone; camptotheca compounds, such as belotecan, camptothecin, cositecan, exatecan, gimatecan, irinotecan, lurtotecan, rubitecan, silatecan, and topetecan; podophyllum compounds, like etoposide, and teniposide; bleomycin; actinomycin D; minor groove binders, such as duocarmycin A, adozelesin, bizelesin, and carzelesin; purine antagonists, such as cladribine, clofarabine, nelarbine, mercptopurine, tioguanine, and pentostatin; pyrimidine antagonists such as capecitabine, carmofur, doxifluridine, floxuridine, fluorouracil, tegafur, cytarabine, gemcitabine, azacytidine, and decitabine; folate antagonists, such as aminopterin, methotrexate, pemetrexed, and pralatrexate; alkylating agents, such as cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, chlormethine, uramustine, carmustine, fotemustine, lomustine, nimustine, ranimustine, streptozocin, mannosulfan, treosulfan, carboquone, thiotepa, triaziquone, triethylenemelamine, carboplatin, cisplatin, dicycloplatin, nedaplatin, oxaliplatin, satraplatin, temozolomide, dacarbazine, mitobronitol, pipobroman, and procarbazine. In a certain embodiment, one or more therapeutics that can associate or bind with DNA or RNA is selected from anthracyclines, such as aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin; anthracenediones, such as mitoxantrone, and pixantrone; camptotheca compounds, such as belotecan, camptothecin, cositecan, exatecan, gimatecan, irinotecan, lurtotecan, rubitecan, silatecan, and topotecan; podophyllum compounds, like etoposide, and teniposide; bleomycin; actinomycin D; minor groove binders, such as duocarmycin A, adozelesin, bizelesin, and carzelesin. In a further embodiment, one or more therapeutics that can associate or bind with DNA or RNA comprise aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and/or zorubicin. In another embodiment, one or more therapeutics that can associate or bind with DNA or RNA comprise mitoxantrone, topotecan, etoposide, teniposide, bleomycin, actinomycin D, and/or duocarmycin A. Attorney docket No.00058-079WO1 [0076] As the compositions and methods disclosed herein are directed to a platform- based therapeutic delivery system, it is expected that any type of therapeutic compound that associates or binds with DNA or RNA can be complexed or encapsulated by the nucleic acids disclosed herein. Exemplary examples of such therapeutic compounds, include but are not limited to, anthracyclines, such as aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin; anthracenediones, such as mitoxantrone, and pixantrone; camptotheca compounds, such belotecan, camptothecin, cositecan, exatecan, gimatecan, irinotecan, lurtotecan, rubitecan, silatecan, and topotecan; podophyllum compounds, like etoposide, and teniposide; bleomycin; and actinomycin D. Accordingly, the disclosure provides for a platform technology that can be used for formulations, compositions, or preparations for safe, efficient, and controlled delivery of therapeutics that can associate or bind with DNA or RNA in a subject to treat any number of diseases or disorders that are treatable by such therapeutics. While the exemplary studies presented herein, clearly indicate that DOX/nucleic acid nanoparticles disclosed herein can be used to effectively treat cancer, any disease or disorder that is treatable by therapeutics that can associate or bind with DNA or RNA is encompassed by this disclosure. It should be further noted that the preparations, compositions, or formulations disclosed herein are not just limited to the delivery of a therapeutic that associates or binds with DNA or RNA, as any number of therapeutics that can associate or bind with DNA or RNA can be complexed with nucleic acids disclosed herein to make therapeutic/nucleic acid nanoparticles. [0077] In regard to the nucleic acid component of the therapeutic/nucleic acid nanoparticles, any type and length of nucleic acid species may be used to complex with the therapeutics that can associate or bind with DNA or RNA. Namely, the nucleic acid species should be capable of forming pi-pi stacking interactions with therapeutics that can associate or bind with DNA or RNA. While DNA was used in the studies presented herein, it is envisaged DNA, RNA, DNA-RNA hybrids, or mixtures thereof could be used to form therapeutic/nucleic acid nanoparticles disclosed herein. Moreover, for purposes of this disclosure “nucleic acids” include nucleic acid analogues. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pentose sugar, either ribose or deoxyribose, and one of four nucleobases. A nucleic acid analogue may have any of these altered. [0078] DNA, abbreviation of deoxyribonucleic acid, is an organic chemical of complex molecular structure that is found in all prokaryotic and eukaryotic cells and in many Attorney docket No.00058-079WO1 viruses. DNA codes genetic information for the transmission of inherited traits. Each strand of a DNA molecule is composed of a long chain of monomer nucleotides. The nucleotides of DNA consist of a deoxyribose sugar molecule to which is attached a phosphate group and one of four nitrogenous bases: two purines (adenine and guanine) and two pyrimidines (cytosine and thymine). The nucleotides are joined together by covalent bonds between the phosphate of one nucleotide and the sugar of the next, forming a phosphate-sugar backbone from which the nitrogenous bases protrude. One strand is held to another by hydrogen bonds between the bases; the sequencing of this bonding is specific—i.e., adenine bonds only with thymine, and cytosine only with guanine. The configuration of the DNA molecule is highly stable, allowing it to act as a template for the replication of new DNA molecules, as well as for the production (transcription) of the related RNA (ribonucleic acid) molecule. In a particular embodiment, the DNA is be selected from oligonucleotides, hydrolyzed DNA, polynucleotides, and polydeoxyribonucleotides. [0079] RNA, abbreviation of ribonucleic acid, is a complex compound of high molecular weight that functions in cellular protein synthesis and replaces DNA (deoxyribonucleic acid) as a carrier of genetic codes in some viruses. RNA consists of ribose nucleotides (nitrogenous bases appended to a ribose sugar) attached by phosphodiester bonds, forming strands of varying lengths. The nitrogenous bases in RNA are adenine, guanine, cytosine, and uracil, which replace thymine in DNA. The ribose sugar of RNA is a cyclical structure consisting of five carbons and one oxygen. The presence of a chemically reactive hydroxyl (íOH) group attached to the second carbon group in the ribose sugar molecule makes RNA prone to hydrolysis. This chemical lability of RNA, compared with DNA, which does not have a reactive íOH group in the same position on the sugar moiety (deoxyribose), is thought to be one reason why DNA evolved to be the preferred carrier of genetic information in most organisms. In a particular embodiment, this reactive -OH group of RNA may be replaced by a less reactive -O-alkyl group or halide group, to make the RNA resistant to the action of RNAses. [0080] DNA-RNA hybrids are abundant in human cells. They form during transcription when nascent RNA is near its DNA template. The resulting RNA/DNA hybrids and the displaced single-stranded (ss) DNA are called R-loops. RNA/DNA hybrids are structurally different and more stable than the corresponding double-stranded DNAs. RNA/DNA hybrids are found in origins of replication, immunoglobulin class-switch regions, Attorney docket No.00058-079WO1 and transcription complexes. RNA/DNA hybrids do not adopt the traditional B-conformation of DNA or A-conformation of RNA but occur as mixtures or heterogenous duplexes. [0081] For purposes of this disclosure, fragments of nucleic acids can result from the enzymatic cleavage or physical breakage of naturally occurring nucleic acids; chemical synthesis of various sizes of nucleic acids; or some combination thereof. Examples of methos to physically break naturally occurring nucleic acids, include but are not limited, to nebulization, sonication, and hydrodynamic shearing. Examples of enzymes used for enzymatic cleaving naturally occurring nucleic acids include but are not limited to, restriction enzymes, DNase I, and transposases. Additionally, the fragments of nucleic acids are of various lengths and sizes, unless indicated otherwise. [0082] Any naturally occurring nucleic acid may be used, including nucleic acids from any species, from prokaryotes, from eukaryotes, from fungi, etc. In a particular embodiment, the nucleic acid fragments are isolated from fish. In yet a further embodiment, the nucleic acid fragments are isolated from fish testis or sperm. Examples of fish that can be used as a source of nucleic acid fragments, include fish from a family selected from Salmonidae, Clupeidae, Cyprinidae, Cichlidae, and Acipenseridae. In a further embodiment, the nucleic acid fragments are from fish from Salmonidae family. Fish from the Salmonidae family include, but are not limited to, salmon, trout, char, freshwater whitefishes, graylings, taimens, and lenoks. In yet a further embodiment, the nucleic acid fragments are isolated from salmon or trout. In another embodiment, the nucleic acid fragments are isolated from salmon testis and/or sperm. In yet another embodiment, the nucleic acid fragments are from fish from Clupeidae family. Fish from the Clupeidae family include, but are not limited to, herring and sprats. In yet a further embodiment, the nucleic acid fragments are isolated from herring. In another embodiment, the nucleic acid fragments are isolated from herring testis and/or sperm. In yet another embodiment, the nucleic acid fragments are from fish from Cyprinidae family. Fish from the Cyprinidae family include, but are not limited to, carp, minnow, and goldfish. In yet a further embodiment, the nucleic acid fragments are isolated from carp. In another embodiment, the nucleic acid fragments are isolated from carp testis and/or sperm. The sizes/lengths of nucleic acid fragments can have a specific size or range, or can be varied to suit the therapeutic being used. For example, fragments of nucleic acids can have a length of 20 nt, 30 nt, 40 nt, 50 nt, 60 nt, 70 nt, 80 nt, 90 nt, 100 nt, 110 nt, 120 nt, 130 nt, 140 nt, 150 nt, 160 nt, 170 nt, 180 nt, 190 nt, 200 nt, 250 nt, 300 nt, 350 nt, 400 nt, 450 nt, 500 nt, 550 nt, 600 nt, 650 nt, 700 nt, 750 nt, 800 nt, 850 nt, 900 nt, 950 nt, 1,000 nt, Attorney docket No.00058-079WO1 1,500 nt, 2,000 nt, 2,500 nt, 3,000 nt, 3,500 nt, 4,000 nt, 4,500 nt, 5,000 nt, 5,500 nt, 6,000 nt, 6,500 nt, 7,000 nt, 7,500 nt, 8,000 nt, 8,500 nt, 9,000 nt, 9,500 nt, 10,000 nt, 15,000 nt or a range of lengths that is between or includes any two of the foregoing lengths (e.g., 20 nt to 15,000 nt, 50 nt to 10,000 nt, 50 nt to 2,000 nt, 50 nt to 500 nt, etc.). In a particular embodiment, the sequence of the nucleic acid may be random or be selected to have a desired sequence. In the latter case, sequences may be selected to target transcription factors (TFs), TLRs, or other DNA or RNA-binding proteins; or are aptamers. In such a case, the therapeutic/nucleic acid nanoparticles may be targeted to certain tissue, organs, or tumors, via selection of a particular sequence or a ligand to tumor-specific antigens. Ligands to tumor- specific antigens are commercially available from a variety of vendors, and therefore do not have to be generated de novo (e.g., see Elabscience, Santa Cruz biotechnology, Biospacific, Novus Biologicals, etc.). In a particular embodiment, the ligand attached to the therapeutic agent/nucleic acid nanoparticles binds to a tumor specific antigen selected from alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, CA15-3, CA19-9, MUC- 1, epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), abnormal products of ras or p53, CTAG1B, MAGEA1, and HER2/neu. The ligand that binds to the tumor-specific antigen should have bind to the target antigen with high affinity (Kd < 10 nM) for efficient uptake into target tumor cells and it should be minimally immunogenic. In a further embodiment, the ligand that binds to the tumor-specific antigen is attached to a therapeutic agent/nucleic acid nanoparticle disclosed herein via a use of a cleavable linker (acid-labile linkers, protease cleavable linkers, and disulfide linkers). Acid-labile linkers are designed to be stable at pH levels encountered in the blood, but become unstable and degrade when the low pH environment in lysosomes is encountered. Protease-cleavable linkers are also designed to be stable in blood/plasma, but rapidly release free drug inside lysosomes in cancer cells upon cleavage by lysosomal enzymes. They take advantage of the high levels of protease activity inside lysosomes and include a peptide sequence that is recognized and cleaved by these proteases, as occurs with a dipeptide Val-Cit linkage that is rapidly hydrolyzed by cathepsins. A third type of linker that can be used to attach the ligand to the therapeutic agent/nucleic acid nanoparticle contains a disulfide linkage. This linker exploits the high level of intracellular reduced glutathione to release free drug inside the cell. Reagents, like Traut’s reagent (2-iminothiolane), MBS (3-maleimidobenzoic acid N- hydroxysuccinimide ester), and SATA (N-succinimidyl S-acetylthioacetate) can convert such primary amine groups to sulfhydryls, which can then form disulfide bonds with ligands Attorney docket No.00058-079WO1 comprising cysteine residues. Other reagents, like SPDP (N-succinimidyl 3-(2-pyridyldithio) propionate), SMCC (succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate), and Sulfo-SMCC can be used as linkers for attaching ligands to nucleic acids of the therapeutic agent/nucleic acid nanoparticles. Examples of how to use of such groups for attaching ligands to the therapeutic agent/nucleic acid nanoparticles can be found on the worldwide web at labome.com/method/Antibody-Conjugation.html, and the references cited therein, including Safdari et al., Monoclon Antib Immunodiagn Immunother. 201332:409-12; Joosten V et al., Microb Cell Fact.20032:1; Winter et al., Trends Pharmacol Sci.199314:139-43; Arbabi et al., Front Immunol.20178:1589; Brinkley et al., Bioconjug Chem.19923:2-13; Vlasak et al., MAbs.20113:253-63; Ducancel et al., MAbs.20124:445-57; McCombs et al., AAPS J.2015;17:339-51; Hondal R., Protein Pept Lett.200512:757-64; Zimmerman et al., Bioconjug Chem.201425:351-61; Traut et al., Biochemistry.197312:3266-73; Knight P., Biochem J.1979179:191-7; Carlsson et al., Biochem J.1978173:723-37; Peeters J et al., J Immunol Methods. 1989120:133-43; Hashida et al., J Appl Biochem.19846:56-63; Avrameas et al., Immunochemistry.19718:1175-9; Richards et al., J Mol Biol.196837:231- 3; Chandler et al., J Immunol Methods. 198253:187-94; Coulepis et al., J Clin Microbiol. 198522:119-24; White et al., J Clin Microbiol.198927:2300-4; Liu et al., J Immunol Methods.2000234:P153-67; Tian et al., Bioconjug Chem.201526:1144-55; Vira et al., Anal Biochem.2010402:146-50; Szabó et al., Biophys J.2018114:688-700; Hagan et al., Lanthanide- Anal Bioanal Chem. 2011400:2847-64; Han et al. Nat Protoc.201813:2121- 2148; Bottrill et al., Chem Soc Rev.200635:557-71; Ye et al., J Clin Lab Anal.201428:335- 40; Fernández Moreira et al., Analyst.2010135:42-52; Brouwers et al., J Nucl Med.2004 45:327-37; Vera et al., Nucl Med Biol.201239:3-13; Stein et al., J Nucl Med.200142:967- 74; Bratthauer G., Methods Mol Biol.2010588:257-70; Engle et al., Science.2019364:1156- 1162; Sano et al., Science.1992258:120-2; Malou et al., Trends Microbiol.201119:295-302; Cardoso et al., Curr Med Chem. 2012;19:3103-27; East et al., Methods Mol Biol.2014 1199:67-83; Tan et al., Nanomaterials (Basel).20155:1297-1316; Geng et al., Bioconjug Chem.201627:2287-2300; Pecanha et al., J Immunol.1991146:833-9; Pecanha et al., J Immunol.1993150:2160-8; and Chen Y., Methods Mol Biol.20131045:267-73, the disclosures of which are incorporated herein. [0083] The therapeutics may be complexed with nucleic acids at a certain weight to weight (wt/wt) ratio to form nanoparticles. For example, the nucleic acid fragments are complexed with one or more therapeutic compounds at a wt/wt ratio of about 1:20, 1:15, Attorney docket No.00058-079WO1 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, or a range that includes or is between any two of the foregoing ratios, including fractional increments thereof (e.g., 2:1 to 10:1, 4:1 to 7:1, 4.5:1 to 6.5:1, etc.). In a particular embodiment, the nucleic acid fragments are complexed with one or more therapeutic compounds at a wt/wt ratio of about 6:1. [0084] Protamine sulfate, an FDA-approved antidote to heparin-induced anticoagulation, is small, arginine-rich polypeptide (MW 4000–4250) that is extracted from a natural source such as mature testes of fish, usually salmon. The cationic protamine electrostatically binds with anionic nucleic acids, forming a compact structure that assists intracellular trafficking to the nucleus. Protamine sulfate complexed with insulin (also known as NPH) extends the systemic circulation of insulin upon administration. The extensive history of using long-acting NPH insulin as a diabetic therapy minimizes potential concerns of toxicity and immunogenicity. The disclosure provides for protamine sulfate coated therapeutic/nucleic acid nanocomplexes for the delivery of therapeutics. The protamine sulfate coated therapeutic/nucleic acid nanocomplexes of the disclosure exhibited improved stability and nucleus-targeting capabilities in comparison to therapeutic/nucleic acid nanoparticles that were not protamine sulfate coated. The protamine sulfate coated therapeutic/nucleic acid nanocomplexes can be used therapeutic applications. Additionally, the protamine sulfate coated therapeutic/nucleic acid nanocomplexes can be used in cosmetic applications. [0085] The therapeutic/nucleic acid nanocomplexes disclosed herein are complexed or coated with protamine sulfate. In yet a further embodiment, the protein sulfate is complexed with therapeutic/nucleic acid nanocomplexes at a wt/wt ratio of 1:1, 2:1, 3:1, 4:1, 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, 21:1, 22:1, 23:1, 24:1, 25:1, or a range that includes or is between any two of the foregoing ratios, including fractional increments thereof (e.g., 1:1 to 25:1, 5:1 to 20:1, 7:1 to 15:1, etc.). [0086] The size of the protamine sulfate coated therapeutic/nucleic acid nanocomplexes can also be controlled based upon the concentration of the starting materials, reaction parameters (e.g., temperature, time, etc.), and addition of agents (e.g., surfactants, salts, etc.). In a particular embodiment, the size of the protamine sulfate coated therapeutic/nucleic acid nanocomplexes are about 20 nm, 30 nm, 40 nm, 50 nm, 70 nm, 80 nm, 90 nm, 9100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 Attorney docket No.00058-079WO1 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 370 nm, 380 nm, 390 nm, 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 550 nm, 600 nm or a range that includes or is between any two of the foregoing ratios, including fractional increments thereof (e.g., 25 nm to 500 nm, 100 nm to 150 nm, etc.). In a particular embodiment, the size of the protamine sulfate coated therapeutic/nucleic acid nanocomplexes are about 130 nm. The protamine sulfate coated therapeutic/nucleic acid nanocomplexes are substantially spherical in shape. [0087] In the exemplary studies presented herein, doxorubicin (DOX) was intercalated with a mixture of nucleic acid fragments ranging from 50 to 2,000 nucleotides and protamine sulfate (PS) was further used to coat the surface of the DOX-nucleic acid nanocomplexes (PS/DOX-DNA NPs). PS/DOX-DNA NPs exhibited improved stability and enhanced nucleus-targeted intracellular localization in comparison to DOX-nucleic acid nanocomplexes lacking PS (DOX-DNA NPs). PS/DOX-DNA NPs were more monodispersed than DOX-DNA NPs. As indicated in the studies herein, the therapeutic delivery efficacy and safety were significantly improved in vitro and in vivo by coating DOX- nucleic acid nanocomplexes with protamine sulfate. Additionally, the hygroscopic nature of nucleic acids making up the nanocomplexes can be utilized to make therapeutic-loaded hydrogels; and the nucleic acids can be conjugated with proteins (e.g., thymosin-Į 1) to provide for multi-modal approaches in treating a disease or disorder with the protamine sulfate coated therapeutic/nucleic acid nanocomplexes disclosed herein. For example, the protamine sulfate coated therapeutic/nucleic acid nanocomplexes can be conjugated with an immune enhancing protein such as thymosin-Į 1 for a multi-modal approach by priming the immune system to fight against cancer while at the same time delivering an anticancer therapeutic compound. [0088] In a certain embodiment, the disclosure provides for a pharmaceutical composition which comprises a protamine sulfate coated therapeutic/nucleic acid nanocomplex disclosed herein. The pharmaceutical composition can be formulated into a form suitable for administration to a subject including the use of carriers, excipients, additives, or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol, and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. Preservatives include antimicrobials, Attorney docket No.00058-079WO1 antioxidants, chelating agents, cryoprotectants, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975), and The National Formulary XIV., 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See Goodman and Gilman's, The Pharmacological Basis for Therapeutics (7th ed.). [0089] The pharmaceutical compositions according to the disclosure may be administered at a therapeutically effective amount either locally or systemically. As used herein, "administering a therapeutically effective amount" is intended to include methods of giving or applying a pharmaceutical composition of the disclosure to a subject that allows the composition to perform its intended therapeutic function. The therapeutically effective amounts will vary according to factors, such as the degree of infection in a subject, the age, sex, and weight of the individual. Dosage regimes can be adjusted to provide the optimum therapeutic response. For example, several divided doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation. [0090] The pharmaceutical composition can be administered in a convenient manner, such as by injection (e.g., subcutaneous, intravenous, and the like), oral administration, inhalation, transdermal application, or rectal administration. Depending on the route of administration, the pharmaceutical composition can be coated with a material to protect the pharmaceutical composition from the action of enzymes, acids, and other natural conditions that may inactivate the pharmaceutical composition. The pharmaceutical composition can also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. [0091] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The composition will typically be sterile and fluid to the extent that easy syringeability exists. Typically, the composition will be stable under the conditions of manufacture and storage and preserved Attorney docket No.00058-079WO1 against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size, in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride are used in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin. [0092] Sterile injectable solutions can be prepared by incorporating the pharmaceutical composition in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the pharmaceutical composition into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. [0093] The pharmaceutical composition can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The pharmaceutical composition and other ingredients can also be enclosed in a hard or soft-shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the pharmaceutical composition can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 1% by weight of active compound. The percentage of the compositions and preparations can, of course, be varied and can conveniently be between about 5% to about 80% of the weight of the unit. [0094] The tablets, troches, pills, capsules, and the like can also contain the following: a binder, such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid, and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin, or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it can contain, in addition to Attorney docket No.00058-079WO1 materials of the above type, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar, or both. A syrup or elixir can contain the agent, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the pharmaceutical composition can be incorporated into sustained- release preparations and formulations. [0095] Thus, a “pharmaceutically acceptable carrier” is intended to include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the pharmaceutical composition, use thereof in the therapeutic compositions and methods of treatment is contemplated. Supplementary active compounds can also be incorporated into the compositions. [0096] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein, refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of pharmaceutical composition is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure is related to the characteristics of the pharmaceutical composition and the particular therapeutic effect to be achieved. [0097] The principal pharmaceutical composition is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. [0098] In a particular embodiment, the protamine sulfate coated therapeutic/nucleic acid nanocomplexes disclosed herein can be administered in combination with anti-cancer agents known in the art to treat a subject with cancer. The protamine sulfate coated therapeutic/nucleic acid nanocomplexes disclosed herein can be administered, concurrently or sequentially, with anti-cancer agents to treat a subject with cancer. Use of the protamine Attorney docket No.00058-079WO1 sulfate coated therapeutic/nucleic acid nanocomplexes of the disclosure with the anti-cancer agents provides a multimodal therapy that can provide a more effective treatment of a cancer than use of the anticancer agent alone or use of the protamine sulfate coated therapeutic/nucleic acid nanocomplexes alone. Examples, of anticancer agents that can be used with the therapeutic/nucleic acid nanoparticles disclosed herein include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and tiimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; vinca alkaloids; epipodophyllotoxins; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall; L-asparaginase; anthracenedione substituted urea; methyl hydrazine derivatives; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as Attorney docket No.00058-079WO1 ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitiaerine; pentostatin; phenamet; pirarubicin; losoxantione; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,22''- trichlorotiiethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel) (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids such as retinoic acid; capecitabine; leucovorin (LV); irenotecan; adrenocortical suppressant; adrenocorticosteroids; progestins; estrogens; androgens; gonadotropin-releasing hormone analogs; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included anticancer agents are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON- toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® megestrol acetate, AROMASL® exemestane, formestanie, fadrozole, Attorney docket No.00058-079WO1 RIVISOR® vorozole, FEMARA® letrozole, and ARTMIDEX® anastrozole; and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; ribozymes such as a VEGF-A expression inhibitor (e.g., ANGIOZYME® ribozyme) and a HER2 expression inhibitor; vaccines such as gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; PROLEUKIN® rJL-2; LURTOTECAN® topoisomerase 1 inhibitor; ABARELLX® rmRH; antibodies such as trastuzumab and pharmaceutically acceptable salts, acids or derivatives of any of the above. In a particular embodiment, the therapeutic/nucleic acid nanoparticles disclosed herein are used in combination of one or more anticancer agents selected from cyclophosphamide, tamoxifen, tegafur, paclitaxel, apatinib, cisplatin, docetaxel, 5-fluorouracil, capecitabine, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, ifosfamide, rituximab, vincristine, prednisone, bleomycin, and dacarbazine. [0099] For use in the therapeutic or biological applications described herein, kits and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. [00100] For example, the container(s) can comprise one or more protamine sulfate coated therapeutic/nucleic acid nanocomplexes described herein, optionally in a composition or in combination with another agent (e.g., mRNA and/or ssRNA) as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise an identifying description or label or instructions relating to its use in the methods described herein. [00101] A kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but are not limited to, buffers, Attorney docket No.00058-079WO1 diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. [00102] A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. These other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. [00103] The disclosure further provides that the methods and compositions described herein can be further defined by the following aspects (aspects 1 to 35): 1. A composition comprising nanocomplexes that have been coated or complexed with protamine sulfate to form protamine sulfate coated nanocomplexes, wherein the nanocomplexes comprise one or more therapeutic compounds that have been complexed with nucleic acid fragments of varying lengths and sizes, and wherein the one or more therapeutic compounds are small molecule drugs that can associate or bind with DNA or RNA, preferably, wherein the nanocomplexes are electrostatically coated with protamine sulfate, preferably, wherein the surface zeta potential of the nanocomplexes is lower than the surface zeta potential of the protamine sulfate coated nanocomplexes, preferably, wherein the protamine sulfate coated nanocomplexes are nanoparticles, more preferably, the protamine sulfate coated nanocomplexes are nanoparticles that have a spherical morphology, preferably, wherein the protamine sulfate coated nanocomplexes are less than 200 nm in size, preferably, wherein the one or more therapeutic compounds are small molecule drugs that are used to treat cancer or have anticancer properties, preferably, wherein only a single therapeutic compound is complexed with nucleic acid fragments of varying lengths and sizes, and Attorney docket No.00058-079WO1 preferably, wherein the small molecule drugs bind with DNA. 2. The composition of aspect 1, wherein the nucleic acid fragments are complexed with the one or more therapeutic compounds at a wt/wt ratio of 2:1 to 10:1. 3. The composition of aspect 1 or aspect 2, wherein the nucleic acid fragments are complexed with the one or more therapeutic compounds at a wt/wt ratio of 4:1 to 7:1. 4. The composition of any one of aspects 1 to 3, wherein the protamine sulfate coated nanocomplexes are from 20 nm to 500 nm in size. 5. The composition of any one of aspects 1 to 4, wherein the protamine sulfate coated nanocomplexes are from 100 nm to 200 nm in size, preferably, 120 nm to 180 nm in size. 6. The composition of any one of aspects 1 to 5, wherein the one or more therapeutic compounds comprise polyphenol therapeutics, anthracyclines, anthracenediones, camptotheca compounds, podophyllum compounds, minor groove binders, bleomycin, and/or actinomycin D. 7. The composition of any one of aspects 1 to 6, wherein the one or more therapeutic compounds comprise aclarubicin, doxorubicin, daunorubicin, idarubicin, epirubicin, amrubicin, pirarubicin, valrubicin, and/or zorubicin. 8. The composition of any one of aspects 1 to 7, wherein the one or more therapeutic compounds comprise doxorubicin. 9. The composition of any one of aspects 1 to 8, wherein the one or more therapeutic compounds comprise mitoxantrone, topotecan, etoposide, teniposide, bleomycin, actinomycin D, and/or duocarmycin A, preferably, wherein the one or more therapeutics comprise mitoxantrone. 10. The composition of any one of aspects 1 to 9, wherein the nucleic acid fragments comprise oligonucleotides, hydrolyzed DNA, polynucleotides, and polydeoxyribonucleotides. 11. The composition of any one of aspects 1 to 10, wherein the nucleic acid fragments comprise chemically synthesized DNA, RNA and/or DNA-RNA hybrids of differing nucleotide lengths, preferably, wherein the nucleic acid fragments comprise chemically synthesized DNA of differing nucleotide lengths. 12. The composition of any one of aspects 1 to 10, wherein the nucleic acid fragments comprise fragments of naturally occurring DNA, RNA and/or DNA-RNA hybrids, Attorney docket No.00058-079WO1 preferably, wherein the nucleic acid fragments comprise naturally occurring DNA of differing nucleotide lengths. 13. The composition of any one of aspects 1 to 12, wherein the nucleic acid fragments are DNA fragments of varying lengths and sizes, preferably, wherein the DNA fragments are generated from physical breakage or enzymatic cleavage of naturally occurring DNA. 14. The composition of any one of aspects 1 to 13, wherein the DNA fragments are fragments of fish DNA. 15. The composition of any one of aspects 1 to 14, wherein the DNA fragments are fragments of fish testis or fish sperm DNA. 16. The composition of any one of aspects 1 to 15, wherein the DNA fragments are fragments of DNA from fish of the family of Salmonidae, Clupeidae, Cyprinidae, Cichlidae, or Acipenseridae. 17. The composition of any one of aspects 1 to 16, wherein the DNA fragments are fragments of DNA from fish of the family of Salmonidae. 18. The composition of any one of aspects 1 to 17, wherein the DNA fragments are fragments of DNA from salmon or trout. 19. The composition of any one of aspects 1 to 18, wherein the DNA fragments are fragments of DNA from salmon testis or sperm DNA. 20. The composition of any one of aspects 1 to 16, wherein the DNA fragments are fragments of DNA from fish of the family of Clupeidae. 21. The composition of aspect 20, wherein the DNA fragments are fragments of DNA from herring, preferably, wherein the DNA fragments are fragments of DNA from herring testis or sperm DNA. 22. The composition of any one of aspects 1 to 16, wherein the DNA fragments are fragments of DNA from fish of the family of Cyprinidae. 23. The composition of aspect 22, wherein the DNA fragments are fragments of DNA from carp or goldfish, preferably, wherein the DNA fragments are fragments of DNA from carp testis or sperm DNA. 24. The composition of any one of aspects 1 to 23, wherein the nucleic acid fragments are from 20 nt to 10,000 nt in length. 25. The composition of any one of aspects 1 to 24, wherein the nucleic acid fragments are from 50 nt to 2,000 nt in length. Attorney docket No.00058-079WO1 26. The composition of any one of aspects 1 to 25, wherein the nucleic acid fragments are from 50 nt to 500 nt in length. 27. The composition of any one of aspects 1 to 26, wherein the nucleic acid fragments comprise a ligand that targets the nanoparticles to specific cells, tissue, organs, or tumors. 28. The composition of any one of aspects 1 to 27, wherein the nanocomplexes are coated or complexed with protamine sulfate at a wt/wt ratio of 1:8 to 1:20, preferably, wherein the nanocomplexes are coated or complexed with protamine sulfate at a wt/wt ratio of 1:10 to 1:15. 29. The composition of any one of aspects 1 to 28, wherein the nanocomplexes coated or complexed with protamine sulfate are substantially monodisperse, preferably, wherein the protamine sulfate coated nanocomplexes have a polydispersity index of less than 0.30, more preferably, wherein the protamine sulfate coated nanocomplexes have a polydispersity index of less than 0.20. 30. A pharmaceutical composition comprising the composition any one of aspects 1 to 29 and a pharmaceutically acceptable carrier, diluent, and/or excipient, preferably, wherein the pharmaceutically acceptable carrier is buffered saline. 31. The pharmaceutical composition of aspect 30, wherein the pharmaceutical composition is formulated for parenteral delivery, preferably, wherein the pharmaceutical composition is formulated as an injectable solution, and preferably, wherein the pharmaceutical composition is sterile and pyrogen-free. 32. A method of treating a subject having a cancer in need of treatment thereof, comprising: administering to the subject an effective amount of the composition of any one of aspects 1 to 29 and the pharmaceutical composition of aspect 30 of aspect 31, preferably, wherein the one or more therapeutic compounds are small molecule drugs that have been approved treat cancer. 33. The method of aspect 32, wherein the cancer is selected from acute lymphoblastic leukemia, acute myeloblastic leukemia, bone sarcoma, breast cancer, endometrial cancer, gastric cancer, head and neck cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma, liver cancer, kidney cancer, multiple myeloma, neuroblastoma, ovarian cancer, small cell lung cancer, soft tissue sarcoma, thymomas, thyroid cancer, transitional cell bladder cancer, uterine sarcoma, Wilms’ tumor, and Waldenström macroglobulinemia. Attorney docket No.00058-079WO1 34. The method of aspect 32 or aspect 33, wherein the method further comprises administering to the subject with one or more anticancer agents selected from angiogenesis inhibitors, tyrosine kinase inhibitors, PARP inhibitors, alkylating agents, vinca alkaloids, anthracyclines, antitumor antibiotics, antimetabolites, topoisomerase inhibitors, aromatase inhibitors, mTOR inhibitors, retinoids, and HDAC inhibitors. 35. The method of any one of aspects 32 to 34, wherein the method further comprises administering to the subject with one or more anticancer agents selected from metformin, bortezomib, cyclophosphamide, taxotere, bleomycin, vinblastine, adriamycin, dacarbazine, vincristine, prednisone, 5-fluorouracil, mitoxantrone, topotecan, etoposide, teniposide, actinomycin D, and duocarmycin A, preferably, wherein the one or more anticancer agents selected from metformin, bortezomib, cyclophosphamide, taxotere, bleomycin, vinblastine, adriamycin, dacarbazine, vincristine, prednisone, and 5-fluorouracil. [00104] The following examples are intended to illustrate but not limit the disclosure. While they are typical of those that might be used, other procedures known to those skilled in the art may alternatively be used. EXAMPLES [00105] Materials. Doxorubicin (DOX), and ethidium bromide are purchased from Thermo Fisher Scientific (Waltham, MA). Deoxyribonucleic acid (DNA) fragments (50- 2000 base pair fragments with a MW range of 33.75-1350kDA) from DNA isolated from sperm of salmon testis was provided by Pharma Research Co., Ltd. (Seongnam, Korea). 3- (4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) is purchased from Millipore Sigma (Burlington, MA). was a generic (Dr. Reddy’s Laboratories Inc., Princeton, NJ) purchased from UCI health Outpatient Pharmacy (Orange, CA). Hoechst 33342, phosphate buffered saline, SpectrumTM Spectra/PorTM Float-A-LyzerTM G2 Dialysis Devices (MWCO: 3.5kDA), and LysoTrackerTM Red DND-99 dye were purchased from Thermo Fisher Scientific (Waltham, MA). Label IT® Nucleic Acid Labeling Kit® cy5 was purchased from Mirus Bio (Madison, WI). Dulbecco’s modification of Eagle’s medium (DMEM) and penicillin-streptomycin were purchased from Gibco (Grand Island, NY). Ca2+- free and Mg2+-free Dulbecco’s phosphate-buffered saline (DPBS), fetal bovine serum (FBS), and trypsin-EDTA were purchased from Corning (Glendale, AZ). EL4 cells and HeLa cells (ATCC, Rockville, MD) were cultured in Dulbecco’s modification of Eagle’s medium (DMEM) (MediaTech, Manassas, VA) with 10% fetal bovine serum (FBS) (Atlanta Biologicals, Flowery Branch, GA) and 1% antibiotics (100 units/mL penicillin; 100 μg/mL Attorney docket No.00058-079WO1 streptomycin) (Gibco, Grand Island, NY). Nuclei PURE Prep kit and protamine sulfate were purchased from Sigma-Aldrich Company (St. Louis, MO). C57BL/6 mice (6-8-week-old female) was purchased from Charles River Laboratories (Wilmington, MA) was used in all animal studies. [00106] Preparation of protamine sulfate coated DOX-DNA nanoparticles (PS/DOX-DNA NPs). DOX (0.6 mg; 8mg/mL) and DNA (3.6 mg; 48mg/mL) were separately dissolved in a deionized water (DIW) and then two solutions were heated up to 70 °C. The DOX solution was added to DNA and vigorously vortexed for on minute. The resulting mixture solution was immediately incubated at ice for 30 min to allow for self- assembly. Then, the mixture solution was heated at 70 °C for 1min before an equal volume of 2x PBS (150 ^L) was pipetted into the mixture, and vigorously vortexed for 1 min. After immediately allowing 30min-rest in an ice bath, the formed DOX-DNA NP (100 ^L) was further added to protamine sulfate solution (0.12 mg; 0.3 mg/mL in PBS) to coat the surface of PS/DOX-DNA NP. [00107] The size and zeta-potential characterization of PS/DOX-DNA NPs. The size and zeta-potential of PS/DOX-DNA NP was measured using a dynamic light scattering (DLS) particle analyzer, Zetasizer Nano ZS (Malvern Panalytical, Malvern, UK), with a refractive index of 1.59 and an absorption of 0.01 at room temperature in a series of 10 runs per measurement for size and 100 runs per measurement for zeta-potential. Briefly, 100 ^L of PS/DOX-DNA NP (0.4 mg DOX/mL) was dispersed in 900 ^L deionized water, then size was measured using the disposable cuvettes (ZEN0040, Malvern Panalytical, Ltd). Then, 100 ^L of the diluted solution was dispensed in the DTS1070 folded capillary cells (Malvern Panalytical, Ltd), while a remaining 600 ^L volume of DIW was dispersed on either side of the cell to prevent any burning of the electrodes during zeta-potential measurement. [00108] Morphology of PS/DOX-DNA NPs. The morphology of PS/DOX-DNA NP was observed using Scanning Electron Microscopy (SEM) (Sigma, Carl Zeiss), Transmission Electron Microscopy (TEM) (Talos L120C, Thermo Fisher Scientific), and a single molecule fluorescence microscope HM-1000 (NanoresoTM, Sysmex Corporation, Kobe, Japan). To observe the SEM images, the PS/DOX-DNA NP was centrifuged at 13,500 rpm for 10 min, and the supernatant was discarded. The pellet was resuspended in acetone and centrifuged again at 13,500 rpm for 10 min. After removing the supernatant, the remaining pellet was dried at room temperature. The samples were mounted on aluminum stubs using carbon tape and sputter-coated with platinum. The morphology and size of the PS/DOX-DNA NP were Attorney docket No.00058-079WO1 then observed under a field-emission scanning electron microscope. To obtain the TEM images, the PS/DOX-DNA NP was diluted in PBS and subsequently blotted and vitrified using an automated plunge-freezing device (Vitrobot, Thermo Fisher Scientific). The vitrified grids were then transferred into the microscope under cryogenic conditions for observation. [00109] DOX release test of PS/DOX-DNA NP. Two milliliters of the PS/DOX- DNA NP dispersion ([DOX] = 5 ^g/mL) was transferred to a floating dialysis cup (MWCO 3.5 kDa) in a shaker incubation at 37 °C to estimate DOX release from the PS/DOX-DNA NP. The PS/DOX-DNA NP was exposed to PBS, FBS-containing PBS, or FBS only. During the release experiment, the sample in the receiver was measured at predetermined time points, after which fresh buffer was added to fill the receiver. Fluorescence was measured using a Synergy H1 Microplate Fluorescence Reader (BioTek, Winooski, VT) at excitation/emission 482 nm/596 nm wavelengths by comparing to a DOX standard at varying concentrations and incubated for the same periods of time under the same conditions. [00110] Effects of Dox on multiple drug resistance cells. To understand the effect of doxorubicin on the development of drug resistance in tumors, MCF7, SKOV3, and MDA- MB-231 cells were gradually treated with exponential concentrations of doxorubicin to test the strength of resistance to doxorubicin. Briefly, MCF7/WT, SKOV3/WT, and MDA-MB- 231/WT cells were repeatedly treated with doxorubicin to establish a series of cell line exerting different strengths of resistance. Resistant cells were selected by doxorubicin starting at 1 nM. The drug concentration was doubled until the cells acquired resistance. Followed by repeated treatments, 4 cell lines were established with incremental strength of resistance to doxorubicin ranging from 10 nM to 80 nM. The series of resistant cells were named MCF7/ADR, SKOV3/ADR, and MDA-MB-231/ADR (DOX n-nM). The 4 cell lines were cultured with DOX at concentrations to maintain the resistance strength. Cytotoxicity of the 4 cell lines was measured by the MTT assay. [00111] Method to determine Cytotoxicity of PS/DOX-DNA NP in various cell lines. Using the well-established MTT assay, the cytotoxicity of PS/DOX-DNA NP was evaluated in various cancer cell lines such as EL4, HeLa, WM3211, and MDA-MB-468, supplemented with 10% FBS and D-glucose (2 g/L for RPMI 1640 and 4.5 g/L for DMEM) in humidified air with 5% CO2 at 37 °C. EL4, HeLa, WM3211, and MDA-MB-468 cells were seeded in 96-well plates at a density of 2,000 cells per well, respectively, in their respective culture medium (0.1 mL) and then incubated for 24 h. After exposure to PS-DOX-DNA NP (0 ^ [DOX] ^ 5 ^g/mL), the cells were incubated for 24, 48, 72 h. Four hours before the Attorney docket No.00058-079WO1 experiments were complete, MTT solution (10 ^L, 5 mg/mL) was added to the NP-treated cells. When the cytotoxicity test was completed, the MTT-containing culture medium was discarded, and DMSO (0.1 mL) was added to the wells to dissolve the formazan crystals produced by the live cells. The absorbance of formazan was measured at 570 nm using a microplate reader (SpectraMax M5; Molecular Devices, Sunnyvale, CA, USA). These data were used to estimate the effect of NP on cell viability with Eq.1: Cell 100 (1) [00112] Intracellular distribution of PS/DOX-DNA NP. The intracellular distribution of DOX delivered by PS/DOX-DNA NP was evaluated using a NanoresoTM Super Resolution Fluorescence Microscope (Sysmex Corporation, Kobe, Japan). Briefly, 20,000 of EL4, MCF7, SKOV3, and MDA-MB-231 cells were inoculated in a 8-well chamber dish (Thermo Fisher Scientific, Walham, MA) and incubated for 24 h. After incubation with PS/DOX-DNA NP at a DOX concentration of 0.5 μg/mL for 2, 4, and 6 h, the cells were stained with LysoTrackerTM Red DND-99 at a concentration of 100 nM for 20 min order to locate acidic intracellular organelles, while their nuclei were stained with Hoechst 33342 at a concentration of 1 μg/mL for 10 min. The cells were rinsed with DPBS twice and the fluorescence of DOX in the cells was captured in 10,000 frames per image. The locations of intracellular DOX and other fluorophores were precisely determined by analyzing the obtained images using ThunderSTORM for image filtering with a wavelet filter (B-Spline) and result visualization by normalized Gaussian method and colocalized fluorescence, located in the same location, was quantified (% volume colocalized) by Image J software (National Institutes of Health, Bethesda, MD; https://imagej.nih.gov/ij/.) in analysis mode. [00113] In vivo antitumor efficacy and toxicity of PS/DOX-DNA NP. All animal studies were conducted using IACUC-approved procedures. EL4 tumors were established in the right rear flank of five-week-old athymic nude mice or in in the right rear flank of 6-12 week old female C57BL/6/027 mice (Charles River Laboratories, Wilmington, MA, USA) by subcutaneously injecting 1×106 EL4 cells in approximately 100 μL of PBS or DPBS. Tumor size was measured using a digital caliper, and the tumor volume was calculated using the following equation: V=W2L/2, where V is tumor volume, W is the width of the tumor, and L is the length of the tumor. Mice were given food and water ad libitum. When the tumor volume reached approximately 60 to 80 mm3, the tumor-bearing mice were randomly Attorney docket No.00058-079WO1 allocated into one of the following five groups (n = 5 mice per group). The tumor volumes and body weights were measured every 2 d. [00114] In vivo pharmacokinetics of PS/DOX-DNA NP. The samples obtained from the tissue distribution study were analyzed by LC-MS/MS. The LC-MS/MS system was comprised of an The AB SCIEX 6500 triple quadrupole tandem mass spectrometer (AB Sciex, Toronto, Canada) with an Agilent 1290 UPLC system (Agilent, CA, USA). Instrument control and data acquisition were performed using the Analyst® software (Version.1.7. AB SCIEX). The electrospray ionization (ESI) source was used in a positive ion mode with multiple reaction monitoring. The instrument parameters were set as follows: gas temperature of 250 °C, ion source gas 1 of 15 psi, ion source gas 2 of 10 psi, ionspray voltage of 5500 V, curtain gas 20 psi, and collision gas of 9 psi. The fragmentor voltages were set as 86 V(doxorubicin), 76 V(daunorubicin, IS). The collision energy was 17 V (doxorubicin), 39 V (daunorubicin, IS), respectively. The precursor to product ion transitions used for quantification were m/z 544.1 ĺ 396.9 for doxorubicin, m/z 528.1 ĺ 321.0 for IS. Sample preparation was conducted as follows. Aliquots of 20-^L(serum) or 50-^L(tissue) methanol (in 1% formic acid) containing 100 ng/mL of daunorubicin B (IS) was added to 20-^L (serum) or 50-^L(tissue) plasma samples. After adding to 20-^L 1M Tris buffer and 500 -^L of extraction mixture solution [chloroform: methanol (4:1, v/v)] vortex and mixing for 10 min. Following centrifugation (14000× g, 10 min), the supernatant was transferred into a new amber polypropylene tube. The organic layer was evaporated to dryness at 2000rpm, 4 °C over 120 min using a vacuum evaporator (HyperVAC-MAX, Labogene). The residues were dissolved in 50-^L of 10% formic acid in 40% methanol and centrifuged. An aliquot was injected directly onto a reversed-phase ACQUITYY UPLC BEH C18 column (2.1 mm i.d. × 50 mm, 1.7 ^m, Waters) connected to Security Guard Pre-Column (C18, 2.1 × 5 mm; Waters). The gradient elution of mobile phase, 0.1% formic acid in distilled water (A) and 0.1% formic acid in methanol (B), was run through the column at a flow rate of 0.4 mL/min as follows: [B%; 0í1 min, 5%; 1í1.5 min, 95%; 1.5í2 min, 95%; 2.0í2.1 min, 95 % to 5 %; 2.1í4.0 min, 5 %]. The column and autosampler temperature were set at 30°C and 4°C, respectively. The injection volume was 5 ^L and total run time was 4.0 min. The calibration curves were linear over the concentration range of 100 ^200000 ng/mL for Serum, 20^10000 ng/mL for Tissue. The mean intra- and inter-day coefficients of variation (CV) of the analysis on 5 consecutive days were below 12.82 %, and the assay accuracies ranged from 87.2– 114.0%. Attorney docket No.00058-079WO1 [00115] Statistical analysis. All data were analyzed for statistical significance using unpaired Student’s t-test for single comparison. *p < 0.05, **p < 0.01, or ***p < 0.001. [00116] Preparation and characterization of PS/DOX-DNA NP. In an aqueous solution, the PS/DOX-DNA NP was easily prepared by two steps; the DOX-DNA NP was prepared by intercalating DOX into DNA through self-assembly and then the NP was electrostatically coated with protamine sulfate, thereby forming NP of §60 and §160 nm with a -28.3 and -15.4 zeta potential, respectively, as determined by dynamic light scattering (DLS) (see FIG. 5A). Protamine, an arginine-rich polypeptide, possesses abundant positive charges, which facilitate its complexation with the negatively charged DOX-DNA NP. These results indicate an increase in zeta potential of the PS/DOX-DNA NP, and PS is localized on the surface of the DOX-DNA NP. This self-assembly of PS/DOX-DNA NP was also confirmed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) for the size and spherical morphology with a narrow distribution (polydispersity index [PDI]: §0.18) (see FIG.5B and 5C). These results indicate that the PS/DOX-DNA NP was successfully prepared and circulated throughout the blood stream due to its negative zeta potential. [00117] DOX release kinetics from PS/DOX-DNA NPs in serum containing media. PBS buffer, 10% FBS buffer, 25% FBS buffer, 50% FBS buffer, or 100% FBS buffer were added to the NP. Subsequently, the solution was transferred to Spectra-Por® Float-A-Lyzer® G2 dialysis devices (MWCO; 3.5 kDa, Sigma-Aldrich) in a shaker incubator at 37 °C. During the release experiment, the sample in the receiver was measured at predetermined time points, after which fresh buffer was added to fill the receiver. The concentration of fluorescence was calculated by fluorescence measurement (Synergy H1, BioTek, VT, USA) at excitation and emission wavelength (DOX: 483/596). Serum contents greatly facilitated DOX release from the NP. Also, PS/DOX-DNA NPs exhibited slower release than DOX- DNA NPs because protamine sulfate can reduce dissociation from serum (see FIG.10). [00118] Drug release from the carriers plays a pivotal role in therapeutic efficacy because it determines the rate and extent to which a drug is available to the action site. The release of DOX from the DOX-DNA NP and PS/DOX-DNA NP in serum was measured over time to assess its stability in a biological environment. In addition, the DoxilTM formulation, a clinically approved liposomal DOX, was used as a positive control to compare the effects of drug release rate. As shown in FIG.10, serum contents greatly facilitated DOX release from DOX/DNA NP and PS/DOX-DNA NP. In only PBS to stimulate normal physiological Attorney docket No.00058-079WO1 conditions, only a very small amount of DOX was released from the DoxilTM, DOX/DNA NP, and PS/DOX-DNA NP in a very slow fashion; the cumulative release of DOX was only about 11% within 72 h. However, the presence of FBS only in the biological conditions, caused different drug release rates from three carriers: DOX-DNA NP > PS/DOX-DNA NP > DoxilTM in the fastest-to-slowest order. DOX release rates of DOX-DNA NP and PS/DOX- DNA NP could be related with serum proteins. It is likely that the serum proteins are interfering with the molecular interaction among PS, DOX, and DNA. [00119] Cytotoxicity of PS/DOX-DNA NPs in EL4 and HeLa cells. EL4 cells and HeLa cells (ATCC, Rockville, MD) were plated at 10 k cells per well in a 96-well plate. The plated cells are treated in triplicate for 24, 48, or 72 hours with a range of concentrations of 0.001 μg/mL DOX, DOX-DNA NPs, or PS/DOX-DNA NPs to 5 μg/mL, followed by cellular viability analysis via MTT assay. Cells were incubated at 37 °C, 5% CO2, and 95% humidity. Absorbance was read at 571 nm. [00120] For EL4 cells, PS/DOX-DNA NPs exhibited similar cytotoxicity on these cells compared to DOX at 24 h of incubation, as seen in the reported IC50 values: PS/DOX-DNA NPs IC50=0.059 μg/mL, DOX-DNA NPs IC50=0.076 μg/mL, and DOX IC50=0.060 μg/mL. PS/DOX-DNA NPs exhibited more cytotoxicity on these cells than that of DOX by a 1.50 or 2.53-fold difference at 48 h and 72 h of incubation, as seen in the reported IC50 values: PS/DOX-DNA NPs IC50=0.034 μg/mL, DOX-DNA NPs IC50=0.046 μg/mL, and DOX IC50=0.051 μg/mL at 48 h or PS/DOX-DNA NPs IC50=0.019 μg/mL, DOX-DNA NPs IC50=0.029 μg/mL, and DOX IC50=0.048 μg/mL at 72 h. PS/DOX-DNA NPs showed lower cell killing effects than DOX but quickly surpassed the efficacy of DOX at 48 h and 72 h (see FIG.11A-C). [00121] For HeLa cells, PS/DOX-DNA NPs exhibited less cytotoxicity on these cells than that of DOX by a 1.16-fold at 24 h of incubation, as seen in the reported IC50 values: PS/DOX-DNA NPs IC50=0.767 μg/mL, DOX-DNA NsP IC50=0.998 μg/mL, and DOX IC50=0.662 μg/mL. PS/DOX-DNA NPs exhibited more cytotoxicity on these cells than DOX by a 1.36 or 1.55-fold difference at 48 h and 72 h of incubation, as seen in the reported IC50 values: PS/DOX-DNA NPs IC50=0.402 μg/mL, DOX-DNA NPs IC50=0.455 μg/mL, and DOX IC50=0.548 μg/mL at 48 h or PS/DOX-DNA NPs IC50=0.166 μg/mL, DOX-DNA NPs IC50=0.194 μg/mL, and DOX IC50=0.257 μg/mL at 72 h. PS/DOX-DNA NPs showed lower cell killing effects than DOX but quickly surpassed the efficacy of DOX at 48 h and 72 h (see FIG.12A-C). Attorney docket No.00058-079WO1 [00122] Cytotoxicity of PS/DOX-DNA NP in cancer cells. Next was investigated the cytotoxicity and therapeutic effect of PS/DOX-DNA NP in comparison to free DOX, DoxilTM, and DOX-DNA NP to confirm the potential utility of PS/DOX-DNA NP as drug delivery system in various cancer cells. The PS/DOX-DNA NP was evaluated by the MTT- based dose-dependent cytotoxicity test in EL4 (mouse lymphoma), HeLa (human cervical cancer), WM3211 (human melanoma), and MDA-MB-468 cells (human breast cancer) at 24, 48, or 72 h. When treating EL4 cells with free DOX, DoxilTM, DOX-DNA NP, or PS/DOX- DNA NP, the dose-dependent viability revealed that PS/DOX-DNA NP had greater cell- killing effect than did free DOX, DoxilTM, or DOX-DNA NP, respectively. After 72 h of incubation with EL4 cells, PS/DOX-DNA NP exhibited 2.4-fold, 10.9-fold, and 2.1-fold higher cell-killing effect than did free DOX, DoxilTM, or DOX-DNA NP, respectively, because the IC50 values were § 0.043 ^g/mL for free DOX, 0.196 ^g/mL for DoxilTM, and 0.038 ^g/mL for DOX-DNA NP (see FIG.13). Similarly, in HeLa cells at 72 h incubation, PS/DOX-DNA NP had 3.1-fold, 34.1-fold, and 2.8-fold better anti-tumor activity than free DOX, DoxilTM, and DOX-DNA NP, whereas PS/DOX-DNA NP had IC50 § 0.111 ^g/mL. Also, in WM3211 cells at 72 h incubation, PS/DOX-DNA NP had 2.3-fold, 18.0-fold, and 2.0-fold the potency, as quantitatively demonstrated by lowered IC50 values about § 0.048 ^g/mL. In MDA-MB-468 cells, PS/DOX-DNA NP exhibited 1.5-fold lower cytotoxicity at 24 h incubation than DOX but surpassed 1.6-fold higher cell killing effect than DOX at 72 h incubation. The comparable therapeutic effects of PS/DOX-DNA NP indicate that PS/DOX- DNA NP significantly enhances the cytotoxic effect against various cancer cell. [00123] Intracellular delivery of PS/DOX-DNA NP in cancer cells. Next was investigated whether the designed PS/DOX-DNA NP showed potential for cellular internalization, endo-lysosomal escape, cytosolic DOX release, and ultimately, whether the released DOX could reach the nucleus. Thus, to image the intracellular distribution of the DOX and DNA, and quantify their intracellular fluorescent intensity, PS/DOX-DNA NP- containing EL4 cells were analyzed by confocal microscopy. The intracellular DOX fluorescence intensity in EL4 cells treated with free DOX was much stronger than that in cells treated with the PS/DOX-DNA NP and similar preferences for nuclei (see FIG.15). [00124] Furthermore, the concentrations of therapeutic compounds within cells and their rate of internalization play pivotal roles in determining the resulting therapeutic effects. The cellular entry of free DOX was taken up primarily diffusion-driven membrane penetration, whereas DOX/DNA NP and PS/DOX-DNA NP could enable via clathrin- and Attorney docket No.00058-079WO1 caveolin-mediated endocytosis. However, the strongly repellant character of the DoxilTM with PEG chains could significantly inhibit or reduce the uptake, resulting in slow fluid-phase endocytosis. Thus, to understand why PS/DOX-DNA NP has similar uptake than free DOX, the cellular uptake of PS/DOX-DNA was monitored by Fluorescence Reader using fluorescent character of the delivered DOX. The cellular uptake of PS/DOX-DNA NP was 1.1-fold lower than that of free DOX, 2.9-fold higher than that of DoxilTM, and 1.4-fold higher than that of DOX-DNA NP (see FIG.16). These results indicate that the amount of DOX delivered by the PS/DOX-DNA NP was much higher than that by free DOX, likely because PS can enhance the permeability of cell membranes, allowing NP to pass through more effectively into the cells. [00125] As mentioned above, although the cellular uptake of DOX significantly influences its therapeutic effects, the amount of DOX delivered to the nucleus could be much more important because the nucleus is the final action site of DOX. Thus, to determine the amount of DOX molecules delivered by the PS/DOX-DNA NP into the nucleus, the nuclear delivery efficiency of PS/DOX-DNA NP was evaluated by monitoring the nuclei uptake by isolated nuclei after treatment. The PS/DOX-DNA NP exhibited 1.0-fold similar than that of free DOX, 11.8-fold and 2.9-fold higher than those of DoxilTM and DOX-DNA NP, respectively (see FIG.19). PS contains a nuclear localization signal; it and its binding partners can be transported into the nucleus, improving the efficiency of exogenous substances into the cell nucleus. The nuclei uptake results helped to explain why the PS/DOX-DNA NP exhibited strong cell cytotoxicity. [00126] Cytotoxicity and intracellular delivery in multi-drug resistance cell. Intrinsic or acquired multidrug resistance (MDR) poses a significant challenge in the clinical treatment of cancers, undermining the effectiveness of chemotherapy and limiting therapeutic options for patients. Mounting evidence implicates the ATP-binding cassette (ABC) transporter family as key contributors to drug resistance, owing to their remarkable ability to actively efflux drugs from cancer cells, thereby reducing intracellular drug concentrations and rendering chemotherapy less effective. Among the various ABC transporters implicated in MDR, P-glycoprotein (P-gp) stands out for its prominent role in mediating drug efflux and conferring resistance to a broad spectrum of chemotherapeutic agents. The overexpression of P-gp in cancer cells has been extensively documented as a major mechanism underlying resistance to chemotherapy. P-gp acts as a transmembrane efflux pump that actively transports a diverse array of substrates, including chemotherapeutic drugs, out of cancer cells, Attorney docket No.00058-079WO1 thereby diminishing their cytotoxic effects. Consequently, tumors with high levels of P-gp expression often exhibit reduced intracellular accumulation of drugs, leading to diminished therapeutic efficacy and treatment failure. Doxorubicin (DOX), a widely used chemotherapeutic agent in the treatment of various cancers, including breast cancer, is particularly susceptible to P-gp-mediated drug efflux. Despite its potent cytotoxic effects, the clinical utility of DOX is often hampered by the development of MDR, attributed in part to the upregulation of P-gp expression in tumor cells. Consequently, tumors with elevated P-gp levels display reduced sensitivity to DOX, necessitating alternative strategies to overcome MDR and enhance therapeutic efficacy. To determine whether PS/DOX-DNA NP could reverse MDR, the cytotoxicity of PS/DOX-DNA NP evaluated against MCF7, SKOV3, and MDA-MB-231 cells with or without verapamil. Verapamil is a calcium channel blocker vasodilator which has been recognized as a potent P-gp inhibitor. In MCF7 with or without verapamil and MCF7/ADR cells with verapamil, DOX, DoxilTM, DOX-DNA NP, PS/DOX-DNA NP all showed dose-dependent toxicity. After 72 h of incubation, IC50 of free DOX, DoxilTM, DOX-DNA NP, and PS/DOX-DNA NP was 0.115-0.135, 0.778-0.851, 0.141- 0.146, and 0.048-0.066 ^g/mL, respectively. However, in MCF7/ADR cells without verapamil, free DOX did not exhibit visible cytotoxicity from 24 to 48 h due to the overexpression of P-gp on the cell membrane of MCF7/ADR to pump the drug out. The toxicity of free DOX occurred only when the incubation was extended to 72 h, and the cell viability was still over 50% after treatment with 2.616 ^g/mL, which proved the strong resistance of MCF7/ADR cells to DOX. In contrast to free DOX, DoxilTM, DOX-DNA NP, and PS/DOX-DNA NP showed remarkable cytotoxicity, and the cytotoxicity was dependent on the treatment time (see FIG.20). When treating SKOV3 with or without verapamil and SKOV3/ADR cells with or without verapamil for PS/DOX-DNA NP, the dose-dependent viability revealed that PS/DOX-DNA NP had greater cell-killing effect than did free DOX, DoxilTM, or DOX-DNA NP, respectively. After 72 h of incubation, IC50 of free DOX, DoxilTM, DOX-DNA NP, and PS/DOX-DNA NP had 0.249-0.251, not determined, 0.217- 0.234, and 0.097-0.108 ^g/mL, respectively. However, in SKOV3/ADR cells without verapamil, free DOX did not exhibit visible cytotoxicity from 24 h. The toxicity of free DOX occurred when the incubation was extended 48 to 72 h, and the cell viability was still over 50% after treatment with 3.882 and 3.712 ^g/mL, which proved the strong resistance of SKOV3/ADR cells to DOX. In contrast to free DOX, DOX-DNA NP and PS/DOX-DNA NP showed remarkable cytotoxicity, and the cytotoxicity was dependent on the treatment time Attorney docket No.00058-079WO1 (see FIG.20). Also, in MDA-MB-231 with or without verapamil and MDA-MB-231/ADR cells with verapamil after 72 h of incubation, the IC50 values were 0.228-0.241, not determined, 0.144-0.150, and 0.069-0.075 ^g/mL for DOX, DoxilTM, DOX-DNA NP, and PS/DOX-DNA NP, respectively. In MDA-MB-231/ADR without verapamil, free DOX did not exhibit visible cytotoxicity from 24 h. The toxicity of free DOX was found to be at the 48 to 72 h mark, and the IC50 values were 2.832 and 1.937 ^g/mL, respectively. Furthermore, in contrast to free DOX, DOX-DNA NP and PS/DOX-DNA NP showed remarkable cytotoxicity, and the cytotoxicity was dependent on the treatment time (see FIG.20). These results indicate that PS/DOX-DNA NP did not affect P-gp on the cell membrane, indicating that the NP would be appropriate for clinical use. Clinical trials using MDR inhibitors have had limited success; with the exception of cyclosporine that was used to inhibit P-gp in patients with low-risk acute myeloid leukemia, resulting in significant gains in overall survival and no relapse. Difficulties in clinical trials with inhibitors are mainly due to inhibitor toxicities, drug interactions and clinical trial design problems. Verapamil is the prototype P-gp blocker, and it is known to cause serious and devastating immunosuppressive and cardiovascular effects. P-gp has been a target for drug discovery for almost 40 years and despite these complications in the use of inhibitors, it does not diminish the impact or the importance that the search for effective P-gp modulators would have, which can be used in chemotherapies against cancer with favorable results in patients. PS/DOX-DNA NP, as a candidate for effective treatment in P-gp expression tumor cell, increases the intracellular accumulation of doxorubicin. [00127] The intracellular distribution of the PS/DOX-DNA NP was monitored by super resolution fluorescence microscopy because both the intracellular intensity and location of the DOX fluorescence could strongly influence the antitumor effects of DOX. When applying free DOX to MCF7 with or without verapamil and MCF7/ADR with verapamil, the intracellular fluorescence intensity of the free DOX was intense, however in MCF7/ADR cells without verapamil, free DOX didn’t exhibit any fluorescence intensity (see FIG.24 and FIG.26). Also, cellular uptake mechanisms showed same results. In particular, when overlapping the fluorescence of the free DOX with the stained subcellular organelles, the majority of the free DOX was localized in the nucleus, while a minor portion was detected in the mitochondria. However, interestingly, it seems that the PS/DOX-DNA NP didn’t affect intracellular distribution and uptake mechanisms. Also, the NP was much stronger than free DOX with regards to nuclear localization. Attorney docket No.00058-079WO1 [00128] In vivo circulation time of PS/DOX-DNA NP. One of the obvious advantages of formulating a small molecule drug in a larger delivery platform is to avoid rapid clearance and extend circulation in vivo. Upon tail vein intravenous injection in EL4 tumor-challenged C57BL/6 mice, blood in an amount of 0.5 mL was collected into a Z Serum Separator (Greiner Bio-One, Monroe, NC) from the saphenous vein of the mice at each time point, spun down, and the resultant supernatant was analyzed for DOX concentration after mixing with acidified alcohol (0.075 N HCl in 90% isopropanol), brought up to 100 μL, pipette-mixed 15 times, and measured within 1 h of collection by measuring fluorescence measurement (Synergy H1, BioTek, VT, USA). DOX was quickly cleared (t1/2-0.1 min) but exhibited a much slower clearance when delivered by PS/DOX-DNA NPs (t1/2-243.5 min) (see FIG.32A). These results indicate that the PS/DOX-DNA NPs attributed to DOX-DNA NPs shielding by protamine sulfate for sustainable release. [00129] In vivo pharmacokinetic and biodistribution of PS/DOX-DNA NP. NP was intravenously injected into C57BL/6 mice, and time-dependent changes in DOX concentrations were monitored in the plasma, liver, spleen, heart, kidney, lung, and brain to understand the pharmacokinetics and biodistribution of PS/DOX-DNA NP in vivo (see FIG. 32B and FIG.33). This understanding is important for optimizing the therapeutic efficacy and safety profile of PS/DOX-DNA NP for clinical applications. The mean plasma DOX concentration-time profile of DOX-DNA NP was not significantly different from that of free DOX, but DoxilTM and PS/DOX-DNA NP were increased in the plasma. The observed increase in plasma DOX concentrations with DoxilTM and PS/DOX-DNA NP highlights the distinct pharmacokinetic behavior of these formulations. DoxilTM is designed to prolong the circulation time of DOX and enhance its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect. The similarity in increased plasma levels between DoxilTM and PS/DOX-DNA NP suggests that the latter may also benefit from a similar mechanism, potentially offering prolonged circulation and improved tumor targeting. The biodistribution data across various organs are particularly telling. For instance, the liver and spleen are known to be major organs for nanoparticle accumulation due to the presence of the mononuclear phagocyte system (MPS). High concentrations of DOX in these organs could indicate significant uptake by the MPS, which is a common challenge for nanoparticle-based drug delivery systems. Strategies to reduce MPS uptake could further enhance the therapeutic index of PS/DOX-DNA NP by increasing the proportion of the drug that reaches the target tumor sites. Conversely, the relatively low DOX concentrations observed in the heart with Attorney docket No.00058-079WO1 PS/DOX-DNA NP are promising, as they suggest a potential reduction in cardiotoxicity, a major side effect associated with DOX therapy. This finding supports the hypothesis that nanoparticle formulations can alter the tissue distribution of DOX in a way that mitigates its adverse effects while maintaining or enhancing its therapeutic efficacy. [00130] In vivo antitumor effects of PS/DOX-DNA NP. In evaluating therapeutic efficacy in C57BL/6 mice with subcutaneous EL4 solid tumors, a single intravenous dose of PS/DOX-DNA NP significantly suppressed tumor growth and improved survival rates. PS/DOX-DNA NP notably extended survival, slowed tumor progression, and exhibited minimal toxicity. Repeated administration of candidate drugs in preclinical studies simulates the conditions of clinical cancer therapy, where patients often receive multiple doses of chemotherapy over a period of time. This approach allows researchers to evaluate the long- term efficacy and safety of potential treatments, which are critical considerations for clinical translation. To simulate repeated clinical treatments, EL4 tumor-bearing mice were given weekly intravenous doses of DOX, DoxilTM, DOX-DNA NP, and PS/DOX-DNA NP at 20 mg DOX or DOX equivalent per kg for two and three weeks. Among these, repeated administration of PS/DOX-DNA NP was most effective at inhibiting tumor growth with low associated toxicity (see FIG.34). Importantly, there were negligible differences in body weight between PBS-injected and PS/DOX-DNA NP-injected mice, indicating a favorable safety profile (see FIG. 34). These findings clearly demonstrate that PS/DOX-DNA NPs are more efficient and safer than DOX, DoxilTM, and DOX-DNA NP, supporting PS/DOX-DNA NPs potential for clinical translation. This suggests that PS/DOX-DNA NP maintains its therapeutic efficacy over multiple dosing cycles, which is essential for chronic cancer treatment. Importantly, the repeated administration of PS/DOX-DNA NP was associated with low toxicity, as evidenced by the minimal differences in body weight between PBS-injected mice and PS/DOX-DNA NP-injected mice. Body weight is a general indicator of overall health and systemic toxicity in preclinical studies. The fact that PS/DOX-DNA NP-treated mice maintained their body weight similar to control mice (PBS-injected) highlights the safety profile of this nanoparticle formulation. This low toxicity is an important advantage, as it suggests that PS/DOX-DNA NP can deliver therapeutic doses of DOX without compromising the health and wellbeing of the patient. [00131] Tumor growth and survival. Tumor growth and survival of EL4-challenged mice were tracked regularly for 8 weeks after i.v. treatment with 20 mg/kg of DOX, DoxilTM, DOX-DNA NPs, or PS/DOX-DNA NPs on day 0, day 7, and/or day 14, n=5. Initial tumor Attorney docket No.00058-079WO1 challenge consisted of 1×106 EL4 cells injected subcutaneously in the right rear flank of the mice. When tumor growth of 4-5 mm in diameter is measurable, the treatment was administered in the tail vein. Mice are euthanized when tumors exceeded 15 mm, when tumor lesions appeared, or when weight fell below 75% initial weight. [00132] PS/DOX-DNA NPs were more effective in suppressing tumor growth over time in comparison to DoxilTM and DOX-DNA NPs (see FIG.35A, FIG.36A, and FIG. 37A). The body weights of the mice showed few differences between PBS-injected mice and PS/DOX-DNA NPs-injected mice (see FIG.35B, FIG.36B, and FIG.37B). Complete survival for 7 to 8 weeks clearly demonstrates the best survival outcome of PS/DOX-DNA NPs group (see FIG.35C, FIG.36C, and FIG.37C). These results indicate that the PS/DOX-DNA NPs can effectively inhibit the growth of EL4 tumors (see also FIG.38). [00133] Cardiac toxicity of PS/DOX-DNA NP. DOX is renowned for its potent anti- cancer properties and is widely used in treating various malignancies including breast cancer, lymphoma, leukemia, and sarcomas. However, its clinical utility is limited by the onset of severe cardiovascular complications, which can occur shortly after initial administration or even years following the completion of chemotherapy. These complications, collectively termed as DOX cardiotoxicity, encompass a spectrum of adverse effects such as left ventricular dysfunction, myocardial ischemia, conduction disturbances, hypertension, and venous thromboembolism. The incidence of these complications can be substantial, affecting up to 28% of treated patients, with variability depending on factors like dosage, treatment duration, and concomitant use of other anti-cancer agents. Monitoring cardiac biomarkers, particularly cardiac troponin-I (cTnI), is crucial for the early detection and management of DOX-induced myocardial injury. Elevated serum cTnI levels serve as a sensitive indicator of myocardial damage, reflecting the severity of cardiac toxicity associated with DOX and its formulations. Studies in animal models, including mice, have consistently demonstrated that both DOX and a liposomal formulation of DOX, lead to significant increases in serum cTnI levels as early as 24 hours post-administration, with further elevation observed up to 168 hours. These findings underscore the potential of DOX to induce myocardial dysfunction, highlighting the need for strategies to mitigate its cardiotoxic effects. DOX and DoxilTM -induced myocardial dysfunction has been reported in mice, and it was demonstrated that DOX and DoxilTM induced elevated serum levels of cardiac Troponin-I in mouse serum. However, PS/DOX-DNA NPs showed a similar value to PBS (see FIG.40C). In contrast to traditional DOX formulations, recent research has explored the use of PS/DOX-DNA NP as a Attorney docket No.00058-079WO1 novel approach to improve the safety profile of DOX therapy. The study presented herein demonstrated that PS/DOX-DNA NP administration resulted in serum cTnI levels comparable to those observed in mice treated with PBS, indicating minimal myocardial injury. This suggests that PS/DOX-DNA NP may offer a promising strategy to mitigate DOX- induced cardiotoxicity while maintaining its anti-cancer efficacy. [00134] A number of embodiments have been described herein. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of this disclosure. Accordingly, other embodiments are within the scope of the following claims.

Claims

Attorney docket No.00058-079WO1 WHAT IS CLAIMED IS: 1. A composition comprising nanocomplexes that have been coated or complexed with protamine sulfate to form protamine sulfate coated nanocomplexes, wherein the nanocomplexes comprise one or more therapeutic compounds that have been complexed with nucleic acid fragments of varying lengths and sizes, and wherein the one or more therapeutic compounds are small molecule drugs that can associate or bind with DNA or RNA. 2. The composition of claim 1, wherein the nucleic acid fragments are complexed with the one or more therapeutic compounds at a wt/wt ratio of 2:1 to 10:1. 3. The composition of claim 2, wherein the nucleic acid fragments are complexed with the one or more therapeutic compounds at a wt/wt ratio of 4:1 to 7:1. 4. The composition of claim 1, wherein the protamine sulfate coated nanocomplexes are from 20 nm to 500 nm in size. 5. The composition of claim 4, wherein the protamine sulfate coated nanocomplexes are from 100 nm to 200 nm in size. 6. The composition of claim 1, wherein the one or more therapeutic compounds comprise polyphenol therapeutics, anthracyclines, anthracenediones, camptotheca compounds, podophyllum compounds, minor groove binders, bleomycin, and/or actinomycin D. 7. The composition of claim 1, wherein the one or more therapeutic compounds comprise aclarubicin, doxorubicin, daunorubicin, idarubicin, epirubicin, amrubicin, pirarubicin, valrubicin, and/or zorubicin. 8. The composition of claim 7, wherein the one or more therapeutic compounds comprise doxorubicin. Attorney docket No.00058-079WO1 9. The composition of claim 1, wherein the one or more therapeutic compounds comprise mitoxantrone, topotecan, etoposide, teniposide, bleomycin, actinomycin D, and/or duocarmycin A. 10. The composition of claim 1, wherein the nucleic acid fragments comprise oligonucleotides, hydrolyzed DNA, polynucleotides, and polydeoxyribonucleotides. 11. The composition of claim 1, wherein the nucleic acid fragments comprise chemically synthesized DNA, RNA and/or DNA-RNA hybrids of differing nucleotide lengths. 12. The composition of claim 1, wherein the nucleic acid fragments comprise fragments of naturally occurring DNA, RNA and/or DNA-RNA hybrids. 13. The composition of claim 1, wherein the nucleic acid fragments are DNA fragments. 14. The composition of claim 13, wherein the DNA fragments are fragments of fish DNA. 15. The composition of claim 13, wherein the DNA fragments are fragments of fish testis or sperm DNA. 16. The composition of claim 14, wherein the DNA fragments are fragments of DNA from fish of the family of Salmonidae, Clupeidae, Cyprinidae, Cichlidae, or Acipenseridae. 17. The composition of claim 16, wherein the DNA fragments are fragments of DNA from fish of the family of Salmonidae. 18. The composition of claim 17, wherein the DNA fragments are fragments of DNA from salmon or trout. 19. The composition of claim 18, wherein the DNA fragments are fragments of DNA from salmon testis or sperm DNA. Attorney docket No.00058-079WO1 20. The composition of claim 16, wherein the DNA fragments are fragments of DNA from fish of the family of Clupeidae. 21. The composition of claim 20, wherein the DNA fragments are fragments of DNA from herring. 22. The composition of claim 16, wherein the DNA fragments are fragments of DNA from fish of the family of Cyprinidae. 23. The composition of claim 22, wherein the DNA fragments are fragments of DNA from carp or goldfish. 24. The composition of claim 1, wherein the nucleic acid fragments are from 20 nt to 10,000 nt in length. 25. The composition of claim 24, wherein the nucleic acid fragments are from 50 nt to 2,000 nt in length. 26. The composition of claim 25, wherein the nucleic acid fragments are from 50 nt to 500 nt in length. 27. The composition of claim 1, wherein the nucleic acid fragments comprise a ligand that targets the nanoparticles to specific cells, tissue, organs, or tumors. 28. The composition of claim 1, wherein the nanocomplexes are coated or complexed with protamine sulfate at a wt/wt ratio of 1:8 to 1:20. 29. The composition of claim 1, wherein the protamine sulfate coated nanocomplexes are substantially monodisperse by having a polydispersity index of less than 0.20. 30. A pharmaceutical composition comprising the composition of any one of claims 1 to 29 and a pharmaceutically acceptable carrier, diluent, and/or excipient. Attorney docket No.00058-079WO1 31. The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is formulated for parenteral delivery. 32. A method of treating a subject having a cancer in need of treatment thereof, comprising: administering to the subject an effective amount of the pharmaceutical composition of claim 30. 33. The method of claim 32, wherein the cancer is selected from acute lymphoblastic leukemia, acute myeloblastic leukemia, bone sarcoma, breast cancer, endometrial cancer, gastric cancer, head and neck cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma, liver cancer, kidney cancer, multiple myeloma, neuroblastoma, ovarian cancer, small cell lung cancer, soft tissue sarcoma, thymomas, thyroid cancer, transitional cell bladder cancer, uterine sarcoma, Wilms’ tumor, and Waldenström macroglobulinemia. 34. The method of claim 32, wherein the method further comprises administering to the subject with one or more anticancer agents selected from angiogenesis inhibitors, tyrosine kinase inhibitors, PARP inhibitors, alkylating agents, vinca alkaloids, anthracyclines, antitumor antibiotics, antimetabolites, topoisomerase inhibitors, aromatase inhibitors, mTOR inhibitors, retinoids, and HDAC inhibitors. 35. The method of claim 32, wherein the method further comprises administering to the subject with one or more anticancer agents selected from mitoxantrone, topotecan, etoposide, teniposide, bleomycin, actinomycin D, and duocarmycin A.
EP24857117.6A 2023-08-18 2024-08-17 Protamine-coated nucleic acid/therapeutic agent complexes, and uses thereof Pending EP4727589A1 (en)

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