WO2024081736A2 - Compositions and methods of using cell-penetrating antibodies - Google Patents

Abstract

Compositions and methods of use thereof for delivering nucleic acid cargo into cells are provided. The compositions typically include (a) a 4H2 monoclonal antibody or an antigen binding, cell-penetrating fragment thereof; a monovalent, divalent, or multivalent single chain variable fragment (scFv); or a diabody; or humanized form or variant thereof, and (b) a nucleic acid cargo including, for example, a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. Elements (a) and (b) are typically non-covalently linked to form a complex. Compositions and methods of increasing activation of immune receptors such as cGAS and TLR7 in cells of a subject are also provided. The methods typically include administering an effective amount of a 4H2 antibody to the subject. The subject can be healthy or can have a disease or disorder such cancer or an infection.

Description

COMPOSITIONS AND METHODS OF USING CELL- PENETRATING ANTIBODIES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No.68/379,121 filed on October 11, 2022, and U.S. Provisional Application No.68/379,123 filed on October 11, 2022, the contents of each of which are specifically incorporated herein in their entireties. REFERENCE TO SEQUENCE LISTING The Sequence Listing submitted as a text file named “YU8475PCT.xml” created on October 11, 2023, and having a size of 27,711 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). FIELD OF THE INVENTION The invention is generally related to the field of intracellular delivery of nucleic acids, for application including, but not limited to in vitro, ex vivo, and in vivo gene therapy and gene editing and/or enhancing immune responses, particularly through the modulation of immune receptors, and applications thereof including, but not limited to, treatment of cancer and infections and improving vaccinations. BACKGROUND OF THE INVENTION Gene Therapy Gene therapy includes a spectrum of applications ranging from gene replacement and knockdown for genetic or acquired diseases such as cancer, to vaccination. Viral vectors and synthetic liposomes have emerged as the vehicles of choice for many applications today, but both have limitations and risks, including complexity of production, limited packaging capacity, and unfavorable immunological features, which restrict gene therapy applications and hold back the potential for preventive gene therapy (Seow and Wood, Mol Ther.17(5): 767–777 (2009). In vivo uptake and distribution of nucleotide in cells and tissues has been observed (Huang, et al., FEBS Lett., 558(1-3):69-73 (2004)). Further, although, for example, Nyce, et al. have shown that antisense oligodeoxynucleotides (ODNs) when inhaled bind to endogenous surfactant (a lipid produced by lung cells) and are taken up by lung cells without a need for additional carrier lipids (Nyce, et al., Nature, 385:721-725 (1997)), small nucleic acids are taken up into T24 bladder carcinoma tissue culture cells (Ma, et al., Antisense Nucleic Acid Drug Dev., 8:415-426 (1998)), there remains a need for improved nucleic acid transfection technology, particularly for in vivo applications. AAV9, still the viral vector typically used in people was discovered in 2003 (Robbins, “Gene therapy pioneer says the field is behind – and that delivery technology is embarrassing,” Stat, November, 2019). Thus, it is an object of the invention to provided compositions and methods of use thereof for improved delivery of nucleic acids into cells. Modulating Immune Responses GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses through production of the second messenger cGAMP. In turn, cGAMP activates the adaptor STING (Chen, et al., Nat Immunol (2016) 17(10):1142–9.10.1038/ni.3558). The cGAS-STING pathway not only mediates protective immune defense against infection by a large variety of DNA-containing pathogens (e.g., microbial DNA) but also detects tumor-derived DNA and generates intrinsic antitumor immunity. The STING pathway, and its role in immune modulation and cancer develop are reviewed in, for example, Corrales, et al., Cell Res (2017) 27(1):96– 108.10.1038/cr.2016; Corrales, et al., J Clin Invest (2016) 126(7):2404– 11.10.1172/JCI86892; Rivera Vargas, et al., Eur J Cancer (2017) 75:86– 97.10.1016/j.ejca.2016.1; Qiao, et al., Curr Opin Immunol (2017) 45:16– 20.10.1016/j.coi.2016.12.005; He, et al., Cancer Lett (2017) 402:203– 12.10.1016/j.canlet.2017.05.026 For example, in the tumor microenvironment, T cells, endothelial cells, and fibroblasts, stimulated with STING agonists ex vivo produce type-I IFNs (Corrales, et al., Cell Rep (2015) 11(7):1018– 30.10.1016/j.celrep.2015.04.031). By contrast, most studies indicated that tumor cells can inhibit STING pathway activation, potentially leading to immune evasion during carcinogenesis (He, et al., Cancer Lett (2017) 402:203–12.10.1016/j.canlet.2017.05.026; Xia, et al., Cancer Res (2016) 76(22):6747–59.10.1158/0008-5472.CAN-16-1404). For example, evidence shows that activation of the STING pathway correlates with the induction of a spontaneous antitumor T-cell response involving the expression of type-I IFN genes (Chen, et al., Nat Immunol (2016) 17(10):1142–9.10.1038/ni.3558; Barber, et al., Nat Rev Immunol (2015) 15(12):760–70.10.1038/nri3921; Woo, et al., Immunity (2014) 41(5):830–42.10.1016/j.immuni.2014.10.017). Furthermore, host STING pathway is required for efficient cross-priming of tumor-Ag specific CD8+ T cells mediated by DCs (Woo, et al., Immunity (2014) 41(5):830–42.10.1016/j.immuni.2014.10.017; Deng, et al., Immunity (2014) 41(5):843–52.10.1016/j.immuni.2014.10.019). Based on these results, direct pharmacologic stimulation of the STING pathway has been explored as a cancer therapy. Beyond cancer, the development of STING agonists has been proposed for a number of different therapeutic purposes, including use as a vaccine adjuvant and for chronic viral or bacterial infections. With an expanding range of clinical applications, improved compositions and methods for modulating the cGAS-STING pathway and other immune response receptor signaling pathways are increasingly desirable. Thus, it is also an object of the present disclosure of the invention to provide improved compositions and methods of use thereof for increasing the activity of immune receptors such as cGAS and Pattern Recognition Receptors (PPRs) including toll-like receptors (e.g., TLR7). SUMMARY OF THE INVENTION Compositions and methods of use thereof for delivering nucleic acid cargo into cells are provided. The compositions typically include (a) a 4H2 monoclonal antibody or a cell-penetrating fragment thereof; a monovalent, divalent, or multivalent single chain variable fragment (scFv); or a diabody; or humanized form or variant thereof, and (b) a nucleic acid cargo including, for example, a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. Elements (a) and (b) are typically non-covalently linked to form a complex. Exemplary 4H2 antibodies and fragments and fusion protein thereof include those having (i) the CDRs of SEQ ID NO:1 (optionally SEQ ID NOS:2-4) in combination with the CDRs of SEQ ID NO:5 (optionally SEQ ID NOS:6-8); (ii) first, second, and third heavy chain CDRs selected from SEQ ID NO:1 (optionally SEQ ID NOS:2-4) in combination with first, second and third light chain CDRs selected from SEQ ID NO:5 (optionally SEQ ID NOS:5- 8); (iii) a humanized forms of (i) or (ii); (iv) a heavy chain having an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:5 in combination with a light chain having an amino acid sequence having at least 85% sequence identity to SEQ ID NO:1; (v) a humanized form of (iv). In some embodiments, the antibody or fragment or fusion protein can be bispecific, and can, for example, include a binding sequence that targets a cell type, tissue, or organ of interest. The nucleic acid cargo can be composed of DNA, RNA, modified nucleic acids, including but not limited to, PNA, or a combination thereof. 4H2 binds to guanosine. Thus, the cargo typically includes one or more guanine nucleobases, preferably one or more guanosine nucleosides. The nucleic acid cargo is typically a functional cargo, such as a functional nucleic (e.g., an inhibitory RNA), an mRNA, or a vector, for example an expression vector. The nucleic acid cargo, including vectors, can include a nucleic acid sequence encoding a polypeptide of interest operably linked to expression control sequence. The vector can be, for example, a plasmid. Typically the cargo is not, for example, randomly sheared or fragment genomic DNA. In some embodiments, the cargo includes or consists of a nucleic acid encoding a Cas endonuclease, a gRNA, or a combination thereof. In some embodiments, the cargo includes or consists of a nucleic acid encoding a chimeric antigen receptor polypeptide. In some embodiments, the cargo is a functional nucleic acid such as antisense molecules, siRNA, microRNA (miRNA), aptamers, ribozymes, RNAi, or external guide sequences, or a nucleic acid construct encoding the same. The cargo can include or consist of a plurality of a single nucleic acid molecule, or a plurality of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different nucleic acid molecules. In some embodiments, the nucleic acid molecules of cargo includes or consists of nucleic acid molecules between about 1 and about 25,000 nucleobases in length. The cargo can be single stranded nucleic acids, double stranded nucleic acids, or a combination thereof. Pharmaceutical compositions including the complexes and a pharmaceutically acceptable excipient are also provided. In some embodiments, the complexes are encapsulated in polymeric nanoparticles. A targeting moiety, a cell-penetrating peptide, or a combination thereof can be associated with, linked, conjugated, or otherwise attached directly or indirectly to the nanoparticle. Methods of delivering nucleic acid cargo into cells by contacting the cells with an effective amount of the complexes alone or encapsulated in nanoparticles are also provided. The contacting can occur in vitro, ex vivo, or in vivo. In some embodiments, an effective amount of ex vivo treated cells are administered to a subject in need thereof, e.g., in an effective amount to treat one or more symptoms of a disease or disorder. In some embodiments, the contacting occurs in vivo following administration to a subject in need thereof. The subject can have a disease or disorder, such as a genetic disorder or cancer. The compositions can be administered to the subject, for example by injection or infusion, in an effective amount to reduce one or more symptoms of the disease or disorder in the subject. Applications of the compositions and methods are also provided, and include, but are not limited to, gene therapy and CAR T cell manufacture/formation/therapy. Compositions and methods of increasing activation of cGAS and/or other immune receptors (e.g., Pattern Recognition Receptors such as TLR7) in cells of a subject in need thereof are also provided. The methods typically include administering an effective amount of a 4H2 antibody to the subject. Exemplary 4H2 antibody forms include, but are not limited to, intact monoclonal antibodies and cell-penetrating fragments thereof, such as monovalent, divalent, or multivalent single chain variable fragment (scFv), diabodies, etc. The antibody can be humanized form, chimeric form, or variant thereof. Exemplary 4H2 antibodies and fragments and fusion protein thereof include, e.g., those having (i) the CDRs of SEQ ID NO:1 (optionally SEQ ID NOS:2-4) in combination with the CDRs of SEQ ID NO:5 (optionally SEQ ID NOS:6-8); (ii) first, second, and third heavy chain CDRs selected from SEQ ID NO:1 (optionally SEQ ID NOS:2-4) in combination with first, second and third light chain CDRs selected from SEQ ID NO:5 (optionally SEQ ID NOS:5-8); (iii) a humanized forms of (i) or (ii); (iv) a heavy chain having an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:5 in combination with a light chain having an amino acid sequence having at least 85% sequence identity to SEQ ID NO:1; (v) a humanized form of (iv). In some embodiments, the subject has cancer or an infection. In some embodiments, the subject does not have cancer. Thus, method of treating subjects for cancer and infections are also provided. In some embodiments, the subject is a healthy subject. In some embodiments, the compositions and/or the methods include administering the subject, an additional agent. In some embodiments, the additional agent is a nucleic acid cargo, an immunostimulatory nucleic acid, one or more vaccine components, an immune checkpoint modulator that induces, increases, or enhances an immune response, and a combination thereof. In a particular embodiment, a method of treating cancer or an infection includes administering to a subject in need thereof an effective amount of the combination of a 4H2 antibody and an immune checkpoint modulator that induces, increases, or enhances an immune response. Immune checkpoint modulator typically induces an immune response against the cancer or infection. The immune checkpoint modulator can, for example, reduces an immune inhibitory pathway such as the PD-1 pathway. Thus, the modulator can be a PD-1 antagonist, PD-1 ligand antagonist, or CTLA4 antagonist. In some embodiments, the immune checkpoint modulator increases an immune activating pathway. The immune checkpoint modulator can be, for example, a small molecule, an antibody, a CAR-T cell, or an oncolytic virus. In another particular embodiment, a method of treating cancer or an infection includes administering to a subject in need thereof an effective amount of the combination of a 4H2 monoclonal antibody and an immunostimulatory nucleic acid. In some embodiments, the immunostimulatory nucleic acid is a STING agonist. In another particular embodiment, a method of vaccinating a subject includes administrating the subject a 4H2 antibody and one or more vaccine components. The one or more vaccine components can include, for example, an antigen, a nucleic acid encoding an antigen, an adjuvant, a nucleic acid encoding an adjuvant, or a combination thereof. The antigen can be derived from, for example, a bacteria or virus. In some embodiments, administration of the combination 4H2 and additional agent to the subject results in an additive or a more than additive increase in immune response and/or reduction in one or more symptoms of cancer or infection compared to that achieved by administering either one alone in the absence of the other. In some embodiments, 4H2 antibody is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of the additional agent. In other embodiments, the additional agent is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of 4H2 antibody. Any of the methods can further therapeutic agents or interventions such as chemotherapeutic agents, anti-infective agents, surgery, radiotherapy, or a combination thereof. A nucleic acid cargo or nucleotide, nucleoside, or nucleobase may increase cell penetration and/or activation of cGAS, and/or another Pattern Recognition Receptor such TLR7, by 4H2 antibody. Thus, any of the disclosed compositions and methods can further include a nucleic acid cargo or nucleotide, nucleoside, or nucleobase cargo. In some embodiments, the nucleic acid cargo or nucleotide, nucleoside, or nucleobase cargo is the additional agent. In some embodiments, the nucleic acid cargo or nucleotide, nucleoside, or nucleobase cargo is not the additional agent (i.e., is administered in further combination with the additional agent). In preferred embodiments, the nucleic acid cargo or nucleotide, nucleoside, or nucleobase cargo is in a complex with the 4H2 antibody. In preferred embodiments, the nucleic acid cargo or nucleotide, nucleoside, or nucleobase cargo contains guanine or guanosine and is in a complex with the 4H2 antibody. The nucleic acid cargo can be composed of, for example, DNA, RNA, PNA, phosphorodiamidate morpholino oligomers (PMO), or other modified nucleic acids, nucleic acid analogs, or modified nucleotide, nucleoside, or nucleobase analogs, or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C show 4H2 is a DP-sensitive, cell-penetrating anti- GUO autoantibody. Figure 1A is an image showing lysates of Cal12T cells treated with 0-1 mg/mL 4H2 for 24 hours analyzed by western blot probed with primary actin antibody for loading control and an anti-mouse secondary antibody to detect the actin primary and 4H2 (both murine).4H2 HC and LC ran at their expected MWs, showing the antibody is not significantly degraded 24 hours after cellular penetration. Figure 1B is an image showing lysates of Cal12T cells treated with control media, IgG control, or 4H2 for 24 hours were analyzed by total and pERK1/2 western blot. IgG control had no effect on total or pERK1/2, while 4H2 reduced pERK1/2 but not total ERK1/2. Figure 1C is a dot plot showing ImageJ quantification of 4H2 fluorescence in Cal12T cells (cellular penetration) with or without DP treatment. Figures 2A-2D show 4H2 penetrates glioma cells in a GUO- responsive manner and crosses a transwell model of the BBB. Figures 2A- 2C are plots showing the effect of supplementation of cell media with ADE or GUO on efficiency of cellular penetration into GSCs evaluated by ImageJ quantification of DX1 or 4H2 fluorescence signal. ADE enhanced DX1 penetration (Fig.2A) but had no effect on 4H2 (Fig.2B). GUO significantly enhanced 4H2 cellular penetration (Fig.2C). Figure 2D is a graph showing the results of a transwell model of the BBB using hCMEC/D3 BECs and NHAs used to evaluate 4H2 transit across the barrier from apical to basolateral chambers.4H2 crossed the barrier, and transport was suppressed by the nucleoside transport inhibitor DP. Figures 3A-3B show 4H2 localizes to orthotopic brain tumor and prolongs survival in GBM models. Figure 3A is a Kaplan-Meier survival plot of mice with GSC-derived orthotopic GBM tumors treated with IgG control (N=4) or 4H2 (N=5).4H2 increased median survival by 66% compared to mice treated with IgG control (**P<0.01, log-rank test), and survival to study completion was 40% in the group treated with 4H2 and 0% in the IgG control group. Figure 3B is a Kaplan-Meier survival plot of mice with GL261-derived orthotopic GBM tumors treated with IgG control (N=6), 4H2 (N=6), anti-PD1 (N=6), anti-PD1 + IgG control (N=7), or anti-PD1 + 4H2 (N=7).4H2 increased median survival 32% compared to IgG control (*P=0.03, log-rank test) and when combined with anti-PD1 increased median survival by 50% compared to anti-PD1 + IgG control (*P=0.02, log-rank test).4H2 alone or 4H2 + anti-PD1 yielded 33% and 29% survival to study completion, respectively, compared to 0% in all other groups. Figure 4A is a bar graph showing quantification of TUNEL staining by ImageJ showing a relative fold increase in TUNEL signal of 4.5±0.6 in mice treated with 4H2 compared to IgG control (**P<0.01). Figure 4B is a bar graph showing relative CD8 cell counts per high power field (HPF) based on ani-CD8 immunostaining of sections from GBM brain tumors in mice after treatment with IgG control or 4H2.4H2 increased CD8 content in tumors by ~53%, with relative counts of 1.53±0.15 in 4H2-treated mice compared to 1.00±0.04 in mice treated with IgG control (*P<0.03). These data demonstrate 4H2-mediated stimulation of T-cell infiltration into the GBM tumors. Figures 4C and 4D show 4H2 does not improve survival in an immunodeficient orthotopic GBM model. Kaplan-Meier survival plots of athymic nude mice with PPQ orthotopic GBM brain tumors treated with once (Fig.4C) or twice weekly (Fig.4D) cycles of IgG control (N=4 and 6, respectively) or 4H2 (N=4 and 6, respectively) are shown.4H2 did not significantly impact median survival compared to IgG control in this immunodeficient model, demonstrating the importance of a functional immune system to the 4H2 effect on survival. Figures 5A-5D are images of western blots showing 4H2 binds cGAS. Antibody content and bound proteins were isolated from IgG control or 4H2-treated GSCs using protein G beads. Western blots of input and protein G pulldown were probed for the G-proteins Ras and cGAS. No binding by IgG control or 4H2 to Ras was observed (Figure 5A), but 4H2 showed an apparent association with cGAS that was greater than background signal detected with IgG control (Figure 5B). Purified cGAS ± nucleic acid was incubated with IgG control or 4H2, and antibodies and bound protein then pulled down by protein G.4H2 showed greater binding to cGAS compared to background IgG control binding. Presence of nucleic acid reduced 4H2 binding to cGAS but did not impact nonspecific association of IgG control and cGAS (Figure 5C). Equivalent IgG control and 4H2 content in pulldown samples was confirmed by anti-IgG western blot (Figure 5D). Figures 5E and 5G are images of western blots and Figure 5F is a bar graph showing 4H2 interacts with cGAS in a nucleic acid dependent manner. Purified recombinant cGAS was incubated with IgG control or 4H2 +/- nuclease (benzonase). Antibodies and bound protein were then isolated over protein G beads, and cGAS pulldown visualized by western blot and quantified by ImageJ. In the absence of nuclease, 4H2 interaction with cGAS was demonstrated by an increase in cGAS pulldown of ~6-fold compared to IgG control (***P<0.001), while addition of nuclease eliminated this interaction. Figures 6A-6D show 4H2 enhances cGAS activity. Figure 6A is a line graph showing 4H2 causes a dose-dependent increase in cGAS activity. cGAS activity was assayed by measuring relative production of cGAMP from ATP and GTP in the presence of IgG control or 4H2. Figure 6B is an image of blot showing 4H2 induces nuclear translocation of NF-kB in GSCs. Cytoplasmic and nuclear contents of GSCs treated with IgG control or 4H2 were separated and analyzed by western blot probed NF-kB and Lamin B1 for loading control. GSCs transfected with control or cGAS siRNA were treated with IgG control or 4H2. Figure 6C is an image of a cGAS western blot confirming successful knockdown. Figure 6D is a line graph showing the results of a colony formation assay demonstrating cGAS-dependent toxicity of 4H2 to the GSCs. Figure 6E is a bar graph showing 4H2 induces nuclear translocation of NF-ĸB. Cytoplasmic and nuclear contents of PPQ cells treated with IgG control or 4H2 were analyzed by western blot probed for NF-ĸB, and Lamin B1 for loading control. Relative NF-ĸB nuclear content was quantified by ImageJ.4H2 increased relative nuclear NF-ĸB by a factor of 2.2±0.2 (*P<0.05). Figure 6F is a bar graph showing surviving fractions determined by colony formation assays in Cal12T lung cancer cells (D) transfected with control or cGAS siRNA and treated with IgG control or 4H2 demonstrated cGAS-dependent toxicity of 4H2. (*P<0.05). Figures 7A-7B show 4H2 binds DNA and RNA. Figure 7A is an image showing binding by 4H2 to circular and linearized pcDNA3 plasmid DNA evaluated by 1% agarose EMSA.4H2 but not IgG control shifted both forms of DNA consistent with binding. Figure 7B is an image showing binding by 4H2 to total and mRNA evaluated by 1% agarose EMSA.4H2 but not IgG control shifted both forms of RNA consistent with binding. Figures 8A-8B are bar graphs showing 4H2 delivers DNA and mRNA to glioma cells. pGL4.13 (luc2/SV40) complexed with DX1 or 4H2 was added to U87 glioma cells, and luciferase activity assayed 24 hours later (Figure 8A). Luc mRNA complexed with DX1 or 4H2 or encapsulated into MC3-LNP lipid nanoparticles was added to U87 glioma cells, and luciferase activity assayed 24 hours later (Figure 8B). Figures 9A-9B are images showing 4H2 mediates local gene therapy in the CNS.4H2/Cre mRNA was injected into the brain of Ai9 Cre reporter mice, and Cre recombinase activity evaluated by RFP fluorescence twenty- four hours later. RFP signal was visualized in the local area of the injection track (Fig.9A). Ai9 Cre reporter mice treated with intraocular injection of 4H2/Cre mRNA were evaluated for RFP signal after twenty-four hours. RFP signal visualized in the retina demonstrated 4H2-mediated retinal gene therapy (Fig.9B). Figures 10A-10B are images showing 4H2 delivers mRNA in vivo. Nude mice bearing H358 flank tumors received a single intratumoral injection of a mixture of DX1 or 4H2 with Luc mRNA (w/w = 3). Luc expression was evaluated by IVIS at 6, 24, and 72 hours.4H2/Luc mRNA successfully mediated Luc expression, while minimal signal was detected in tumors injected with DX1/Luc mRNA (Fig.10A). C57/BL6 mice received intramuscular injection of 4H2/Luc mRNA (left quadriceps w/w = 3, right quadriceps w/w =1). Luc expression was evaluated by IVIS at 6 and 24 hours.4H2/Luc mRNA successfully mediated Luc expression (Fig.10B). Figures 11A-11B are a series of representative IVIS images (Fig. 11A) and a corresponding bar graph (Fig.11B) of luminescence for untreated mice, and mice treated with 4H2 only, 4H2+NF2 DNA, or 4H2+NF2 mRNA in a luciferase-expressing HEI193 xenograph model. Figure 12A is a schematic showing design of the 4H2-CD5 bispecific antibody. Figures 12B and 12C are a series of representative FACS plots (Fig.12B) and corresponding bar graph (Fig.12C) showing expression of DeRed tumor cells isolated from a Ai9 mouse model bearing MC38 tumors. Figures 13A and 13B are an image of western blot and corresponding graph (determined by ImageJ) showing the results of cell lysates from glioma stem-like cells (GSCs) treated with IgG control or 4H2 and probed for TLR7. Figure 13C is an image of a western blot. Antibodies and bound proteins were pulled down from lysates of GSCs treated with IgG control or 4H2 by protein G beads and then analyzed for TLR7 western blot. Blot is representative of two independent experiments. DETAILED DESCRIPTION OF THE INVENTION I. Definitions As used herein, the term “single chain Fv” or “scFv” as used herein means a single chain variable fragment that includes a light chain variable region (VL) and a heavy chain variable region (VH) in a single polypeptide chain joined by a linker which enables the scFv to form the desired structure for antigen binding (i.e., for the VH and VL of the single polypeptide chain to associate with one another to form a Fv). The VL and VH regions may be derived from the parent antibody or may be chemically or recombinantly synthesized. As used herein, the term “variable region” is intended to distinguish such domain of the immunoglobulin from domains that are broadly shared by antibodies (such as an antibody Fc domain). The variable region includes a “hypervariable region” whose residues are responsible for antigen binding. The hypervariable region includes amino acid residues from a “Complementarity Determining Region” or “CDR” (i.e., typically at approximately residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and at approximately residues 27-35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and/or those residues from a “hypervariable loop” (i.e., residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (H1), 53-55 (H2) and 96- 101 (H3) in the heavy chain variable domain; Chothia and Lesk, 1987, J. Mol. Biol.196:901-917). As used herein, the term “Framework Region” or “FR” residues are those variable domain residues other than the hypervariable region residues as herein defined. As used herein, the term “antibody” refers to natural or synthetic antibodies that bind a target antigen. The term includes polyclonal and monoclonal antibodies. In addition to intact immunoglobulin molecules, also included in the term “antibodies” are binding proteins, fragments, and polymers of those immunoglobulin molecules, and human or humanized versions of immunoglobulin molecules that bind the target antigen. As used herein, the term “cell-penetrating antibody” refers to an immunoglobulin protein, fragment, variant thereof, or fusion protein based thereon that is transported into the cytoplasm of living mammalian cells. As used herein, the term “cell-penetrating anti-guanosine antibody” refers to an antibody, or antigen binding fragment or molecule thereof that is transported into the cytoplasm of living mammalian cells and binds to guanosine. In some embodiments, the antibody is transported into the cytoplasm of the cells without the aid of a carrier or conjugate. In other embodiments, the antibody is conjugated to a cell-penetrating moiety, such as a cell penetrating peptide. In addition to intact immunoglobulin molecules, also included in the term “antibodies” are fragments, binding proteins, and polymers of immunoglobulin molecules, chimeric antibodies containing sequences from more than one species, class, or subclass of immunoglobulin, such as human or humanized antibodies, and recombinant proteins containing a least the idiotype of an immunoglobulin that specifically binds DNA. The antibodies can be tested for their desired activity using the in vitro assays described herein, or by analogous methods, after which their in vivo therapeutic activities are tested according to known clinical testing methods. As used herein, the term “variant” refers to a polypeptide or polynucleotide that differs from a reference polypeptide or polynucleotide, but retains essential properties. A typical variant of a polypeptide differs in amino acid sequence from another, reference polypeptide. Generally, differences are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical. A variant and reference polypeptide may differ in amino acid sequence by one or more modifications (e.g., substitutions, additions, and/or deletions). A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. A variant of a polypeptide may be naturally occurring such as an allelic variant, or it may be a variant that is not known to occur naturally. Modifications and changes can be made in the structure of the polypeptides of in disclosure and still obtain a molecule having similar characteristics as the polypeptide (e.g., a conservative amino acid substitution). For example, certain amino acids can be substituted for other amino acids in a sequence without appreciable loss of activity. Because it is the interactive capacity and nature of a polypeptide that defines that polypeptide’s biological functional activity, certain amino acid sequence substitutions can be made in a polypeptide sequence and nevertheless obtain a polypeptide with like properties. In making such changes, the hydropathic index of amino acids can be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a polypeptide is generally understood in the art. It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still result in a polypeptide with similar biological activity. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. Those indices are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (- 3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5). It is believed that the relative hydropathic character of the amino acid determines the secondary structure of the resultant polypeptide, which in turn defines the interaction of the polypeptide with other molecules, such as enzymes, substrates, receptors, antibodies, antigens, and cofactors. It is known in the art that an amino acid can be substituted by another amino acid having a similar hydropathic index and still obtain a functionally equivalent polypeptide. In such changes, the substitution of amino acids whose hydropathic indices are within ± 2 is preferred, those within ± 1 are particularly preferred, and those within ± 0.5 are even more particularly preferred. Substitution of like amino acids can also be made on the basis of hydrophilicity, particularly where the biological functional equivalent polypeptide or peptide thereby created is intended for use in immunological embodiments. The following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0 ± 1); glutamate (+3.0 ± 1); serine (+0.3); asparagine (+0.2); glutamnine (+0.2); glycine (0); proline (-0.5 ± 1); threonine (-0.4); alanine (-0.5); histidine (- 0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4). It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent, and in particular, an immunologically equivalent polypeptide. In such changes, the substitution of amino acids whose hydrophilicity values are within ± 2 is preferred, those within ± 1 are particularly preferred, and those within ± 0.5 are even more particularly preferred. As outlined above, amino acid substitutions are generally based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take various of the foregoing characteristics into consideration are well known to those of skill in the art and include (original residue: exemplary substitution): (Ala: Gly, Ser), (Arg: Lys), (Asn: Gln, His), (Asp: Glu, Cys, Ser), (Gln: Asn), (Glu: Asp), (Gly: Ala), (His: Asn, Gln), (Ile: Leu, Val), (Leu: Ile, Val), (Lys: Arg), (Met: Leu, Tyr), (Ser: Thr), (Thr: Ser), (Tip: Tyr), (Tyr: Trp, Phe), and (Val: Ile, Leu). Embodiments of this disclosure thus contemplate functional or biological equivalents of a polypeptide as set forth above. In particular, embodiments of the polypeptides can include variants having about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the polypeptide of interest. As used herein, the term “percent (%) sequence identity” is defined as the percentage of nucleotides or amino acids in a candidate sequence that are identical with the nucleotides or amino acids in a reference nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full- length of the sequences being compared can be determined by known methods. As used herein, the term “specifically binds” refers to the binding of an antibody to its cognate antigen (for example, guanosine) while not significantly binding to other antigens. Specific binding of an antibody to a target under such conditions requires the antibody be selected for its specificity to the target. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity. Preferably, an antibody “specifically binds” to an antigen with an affinity constant (Ka) greater than about 10⁵ mol^–1 (e.g., 10⁶ mol^–1, 10⁷ mol^–1, 10⁸ mol^–1, 10⁹ mol^–1, 10¹⁰ mol^–1, 10¹¹ mol^–1, and 10¹² mol^–1 or more) with that second molecule. As used herein, the term “monoclonal antibody” or “MAb” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical except for possible naturally occurring mutations that may be present in a small subset of the antibody molecules. As used herein, the term “subject” means any individual who is the target of administration. The subject can be a vertebrate, for example, a mammal. Thus, the subject can be a human. The term does not denote a particular age or sex. As used herein, the term “effective amount” means that the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination. The precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder being treated, as well as the route of administration and the pharmacokinetics of the agent being administered. As used herein, the term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. As used herein, the term “carrier” or “excipient” refers to an organic or inorganic ingredient, natural or synthetic inactive ingredient in a formulation, with which one or more active ingredients are combined. The carrier or excipient would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. As used herein, the term “treat” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. As used herein, “targeting moiety” is a substance which can direct a particle or molecule to a receptor site on a selected cell or tissue type, can serve as an attachment molecule, or serve to couple or attach another molecule. As used herein, “direct” refers to causing a molecule to preferentially attach to a selected cell or tissue type. This can be used to direct cellular materials, molecules, or drugs, as discussed below. As used herein, the term “inhibit” or “reduce” means to decrease an activity, response, condition, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. As used herein, a “fusion protein” refers to a polypeptide formed by the joining of two or more polypeptides through a peptide bond formed between the amino terminus of one polypeptide and the carboxyl terminus of another polypeptide. The fusion protein can be formed by the chemical coupling of the constituent polypeptides or it can be expressed as a single polypeptide from a nucleic acid sequence encoding the single contiguous fusion protein. A single chain fusion protein is a fusion protein having a single contiguous polypeptide backbone. Fusion proteins can be prepared using conventional techniques in molecular biology to join the two genes in frame into a single nucleic acid sequence, and then expressing the nucleic acid in an appropriate host cell under conditions in which the fusion protein is produced. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Use of the term “about” is intended to describe values either above or below the stated value in a range of approx. +/- 10%; in other embodiments the values may range in value either above or below the stated value in a range of approx. +/- 5%; in other embodiments the values may range in value either above or below the stated value in a range of approx. +/- 2%; in other embodiments the values may range in value either above or below the stated value in a range of approx. +/- 1%. The preceding ranges are intended to be made clear by context, and no further limitation is implied. All methods described herein can be performed in any suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the embodiments unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed method and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a ligand is disclosed and discussed and a number of modifications that can be made to a number of molecules including the ligand are discussed, each and every combination and permutation of ligand and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Further, each of the materials, compositions, components, etc. contemplated and disclosed as above can also be specifically and independently included or excluded from any group, subgroup, list, set, etc. of such materials. These concepts apply to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed. All methods described herein can be performed in any suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the embodiments unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. II. Compositions It has been discovered that 4H2 antibody helps deliver nucleic acids across the plasma membrane and into cell cytoplasm. Thus, compositions and methods for using 4H2 to enhance delivery of nucleic acid constructs are provided. Typically an effective amount of 4H2 antibody is contacted with a nucleic acid whose delivery into cells is desired. Typically, the contacting occurs for a sufficient amount to time for the 4H2 and the nucleic acid cargo to form a non-covalent complex. The complexes are contacted with cells for a sufficient amount of time for the nucleic acid cargo to be delivered into the cells. The cargo may accumulate in a greater quantity, greater quality (e.g., more intact, functional, etc.), or a faster rate, or combination thereof, than if the cells were contacted with the nucleic acid cargo in the absence of the antibody. Because the antibody serves as the delivery means, the delivery systems are typically non-viral. Multiple cell-penetrating anti-DNA autoantibodies have been isolated from murine models of SLE. While most of these antibodies penetrate live cell nuclei, the anti-GUO autoantibody 4H2 is distinguished by its cytoplasmic localization. The epitope on GUO to which 4H2 binds maps to the site to which G-proteins bind, matching reports on anti-GUO autoantibody binding in human SLE patient serum (Colburn, et al., Journal of Rheumatology 30(5): 993-97 (2003)). Additionally, 4H2 penetrates and reduces cAMP concentrations in cultured cells, consistent with interference with G-protein signaling (Colburn & Green, Clin Chim Acta 370: 9-16 (2006)). The results presented below show that 4H2 cytoplasmic penetration is linked to nucleoside transport, and that 4H2 binds and mediates delivery of nucleic acids, and binds and enhances the activity of cGAS to cause cGAS- dependent toxicity to tumor cells. Results also show that 4H2 causes activation of TLR7 as seen by induction of TLR7 by 4H2 (it is the cleaved form of TLR7 that is active). Further, pulldown assay shows that 4H2 binds that cleaved form of TLR7. Thus, compositions and methods of modulating cGAS and other Pattern Recognition Receptors such as TLR7 are also provided. A. 4H2 Antibodies Although generally referred to herein as “4H2,” “4H2 antibody,” or “4H2 antibodies,” it will be appreciated that unless otherwise specified (e.g., the experimental examples) not only whole immunoglobulins, but also fragments and binding proteins, including antigen-binding fragments, variants, and fusion proteins such as scFv, di-scFv, tri-scFv, and other single chain variable fragments, chimeric and humanized forms, and other cell- penetrating, nucleic acid transporting molecules disclosed herein are encompassed by the phrase “4H2”, “4H2 antibody,” and “4H2 antibodies,” and are also expressly provided for use in the compositions and methods disclosed herein. The antibodies are also referred to herein as cell- penetrating and binding proteins. In preferred embodiments, the 4H2 antibody is transported into the cytoplasm of the cells without the aid of a carrier or conjugate. Antibodies that can be used in the compositions and methods include whole immunoglobulin (i.e., an intact antibody) of any class, fragments thereof, and synthetic proteins containing at least the antigen binding variable domain of an antibody. The variable domains differ in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not usually evenly distributed through the variable domains of antibodies. It is typically concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies. Therefore, the antibodies typically contain at least the CDRs necessary to maintain guanosine binding. A 4H2 hybridoma was previously generated from the MRLmpj/lpr lupus mouse model. 4H2 does not localize to lysosomes or endosomes, where cargo molecules often get destroyed in the case of other delivery vehicles like TAT peptide. 4H2 is a cell-penetrating lupus anti-guanosine antibody that can reduce phosphorylation of ERK and Akt in cells, is toxic to cancer cells harboring a range of mutations in the small GTPase K-Ras and is not significantly toxic to cells with WT K-Ras. See published International Application WO 2015/134607 and WO 2017/218824, each of which are specifically incorporated by references in their entireties. The 4H2 antibody is typically a monoclonal 4H2, or a variant, derivative, fragment, fusion, or humanized form thereof that binds the same or different epitope(s) as 4H2. 1. Antibody Sequences a. 4H2 Light Chain Variable Region An amino acid sequence for the kappa light chain variable region (VL) of mAb 4H2 is: DIVLTQSPATLSVTPGDRVSLSCRASQSISNYLHWYQQKSHESPRLLIKYA SQSISGIPSRFSGSGSGTDFTLSIISVETEDFGMYFCQQSNSWPLTFGAGT KLELK (SEQ ID NO:1). The complementarity determining regions (CDRs) are shown with underlining, including CDR L1:RASQSISNYLH (SEQ ID NO:2); CDR L2: YASQSIS (SEQ ID NO:3); CDR L3: QQSNSWPLT (SEQ ID NO:4). b. 4H2 Heavy Chain Variable Region An amino acid sequence for the heavy chain variable region (VH) of mAb 4H2 is: EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGRV NPSNGGISYNQKFKGKATLTVDKSLSTAYMQLNSLTSEDSAVYYCARGPYT MYYWGQGTSVTVSS (SEQ ID NO:5). The complementarity determining regions (CDRs) are shown with underlining, including CDR H1 : DYYMN (SEQ ID NO:6); CDR H2: RVNPSNGGISYNQKFKG (SEQ ID NO:7); CDR H3: GPYTMYY (SEQ ID NO:8). 2. Form of the Antibody Exemplary antibodies that can be used include whole immunoglobulin (i.e., an intact antibody) of any class, fragments thereof, and synthetic proteins containing at least the antigen binding variable domain of an antibody. The variable domains differ in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not usually evenly distributed through the variable domains of antibodies. It is typically concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR). The variable domains of native heavy and light chains each include four FR regions, largely adopting a beta-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies. Therefore, the antibodies can contain the components of the CDRs necessary to penetrate cells and bind guanosine. The antibody can be a humanized or chimeric antibody, or a fragment, variant, or fusion protein thereof. Methods for humanizing non- human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Antibody humanization techniques generally involve the use of recombinant DNA technology to manipulate the DNA sequence encoding one or more polypeptide chains of an antibody molecule. The 4H2 antibody can be composed of an antibody fragment or fusion protein that includes one or more CDR(s) that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of the CDR(s) of 4H2 or a variant or humanized form thereof (e.g., CDR(s) of any of SEQ ID NOS:1 and 5 such as SEQ ID NOS:2-4 and 6-8. respectively). The determination of percent identity of two amino acid sequences can be determined by BLAST protein comparison. In some embodiments, the antibody includes one, two, three, four, five, or all six of the CDRs of the above-described preferred variable domains (e.g., SEQ ID NOS:1 and 5), without any changes, or with up to 0 1, 2, 3, 4, or 5 changes per CDR (i.e., independently selected per CDR) or total across all CDRs. The 4H2 antibody can be composed of an antibody fragment or fusion protein including an amino acid sequence of a variable heavy chain and/or variable light chain that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of the variable heavy chain and/or light chain of 4H2 or a humanized form thereof (e.g., SEQ ID NOS:5 and 1). Preferably, the antibody includes a heavy chain CDR1, CDR2, and CDR3 in combination with a light chain CDR1, CDR2, and CDR3. Thus, in some embodiments, the cell-penetrating antibody contains the CDRs, or the entire heavy and light chain variable regions, of SEQ ID NOS:5 and 1; or a humanized form thereof. Many non-human antibodies (e.g., those derived from mice, rats, or rabbits) are naturally antigenic in humans, and thus can give rise to undesirable immune responses when administered to humans. Therefore, humanized 4H2 antibodies, antibody fragments and fusions are provided. The humanized antigen binding molecules may lessen the chance that the antibodies or antibody fragments or scFv will evoke an undesirable immune response when administered to a human. Humanized forms of non-human (e.g., murine) antibodies include chimeric immunoglobulins, immunoglobulin chains or fragments thereof which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient antibody are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also contain residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will contain substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. A humanized antibody can optimally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Antibody humanization techniques generally involve the use of recombinant DNA technology to manipulate the DNA sequence encoding one or more polypeptide chains of an antibody molecule. Humanization can be essentially performed by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, a humanized form of a non-human antibody (or a fragment thereof) is a chimeric antibody or fragment, wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is very important in order to reduce antigenicity. According to the “best-fit” method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable domain sequences. The human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody. Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies. It is further important that antibodies be humanized with retention of high affinity for the antigen and other favorable biological properties. To achieve this goal, humanized antibodies are preferably prepared by a process of analysis of the parental sequences and various conceptual humanized products using three dimensional models of the parental and humanized sequences. Three dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the consensus and import sequence so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Also included are fragments of antibodies which have bioactivity. The fragments, whether attached to other sequences or not, include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the nonmodified antibody or antibody fragment. Techniques can also be adapted for the production of single-chain antibodies specific to an antigenic protein of the present disclosure. Methods for the production of single-chain antibodies are well known to those of skill in the art. A single chain antibody can be created by fusing together the variable domains of the heavy and light chains using a short peptide linker, thereby reconstituting an antigen binding site on a single molecule. Single- chain antibody variable fragments (scFvs) in which the C-terminus of one variable domain is tethered to the N-terminus of the other variable domain via e.g., a 15 to 25 amino acid peptide or linker have been developed without significantly disrupting antigen binding or specificity of the binding. The linker is chosen to permit the heavy chain and light chain to bind together in their proper conformational orientation. The 4H2 antibodies can be modified to improve their therapeutic potential. For example, in some embodiments, the cell-penetrating 4H2 antibody is conjugated to another antibody specific for a second e.g., therapeutic target in the cytoplasm and/or nucleus of a target cell. For example, the cell-penetrating 4H2 antibody can be a fusion protein containing 4H2 Fv and a single chain variable fragment of a monoclonal antibody that specifically binds the second target. In other embodiments, the cell-penetrating 4H2 antibody is a bispecific antibody having a first heavy chain and a first light chain from 4H2 and a second heavy chain and a second light chain from a monoclonal antibody that specifically binds the second target. In some embodiments, the second target is specific for a target cell- type, tissue, organ etc. Thus, the second heavy chain and second light chain can serve as a targeting moiety that targets the complex to the target cell- type, tissue, organ. In some embodiments, the second heavy chain and second light chain target hematopoietic stem cells, CD34⁺ cells, T cells, cancer or infected cells, or any another preferred cell type, e.g., by targeting a receptor or ligand expressed on the preferred cell type. In some embodiments, the second heavy chain and second light chain target the thymus, spleen, or cancer cells. In some embodiments, particularly those for targeting T cell in vivo, for example, for in vivo production of CAR T cells, immune cell or T cell markers such as CD3, CD5, CD7, or CD8 can be targeted. For example, anti-CD8 antibodies and anti-CD3 Fab fragments have both been used to target T cells in vivo (Pfeiffer, et al., EMBO Mol Med., 10(11) (2018). pii: e9158. doi: 10.15252/emmm.201809158., Smith, et al., Nat Nanotechnol., 12(8):813-820 (2017). doi: 10.1038/nnano.2017.57). Thus, in some embodiments, the 4H2 antibody or antigen binding fragment or fusion protein is a bispecific antibody part of which can bind specifically to CD3, CD5, CD7, CD8, or another immune cell (e.g., T cell) marker, or a marker for a specific tissue such as the thymus, spleen, or liver. Exemplary fragments and fusions include, but are not limited to, single chain antibodies, single chain variable fragments (scFv), di-scFv, tri- scFv, diabody, triabody, tetrabody, disulfide-linked Fvs (sdFv), Fab', F(ab')2, Fv, and single domain antibody fragments (sdAb). For example, divalent single-chain variable fragments (di-scFvs) can be engineered by linking two scFvs. This can be done by producing a single peptide chain with two VH and two VL regions, yielding tandem scFvs. ScFvs can also be designed with linker peptides that are too short for the two variable regions to fold together (about five amino acids), forcing scFvs to dimerize. This type is known as diabodies. Diabodies have been shown to have dissociation constants up to 40-fold lower than corresponding scFvs, meaning that they have a much higher affinity to their target. Still shorter linkers (one or two amino acids) lead to the formation of trimers (triabodies or tribodies). Tetrabodies have also been produced. They exhibit an even higher affinity to their targets than diabodies. In some embodiments, the 4H2 antibody may contain two or more linked single chain variable fragments of 4H2 (e.g., 4H2 di-scFv, 4H2 tri-scFv), or conservative variants thereof. In some embodiments, the 4H2 antibody is a diabody or triabody (e.g., 4H2 diabody, 4H2 triabody). In some embodiments, the antibody is conjugated or fused to a cell- penetrating moiety, such as a cell-penetrating peptide, to facilitate entry into the cell. Examples of cell-penetrating peptides include, but are not limited to, Polyarginine (e.g., R₉), Antennapedia sequences, TAT, HIV-Tat, Penetratin, Antp-3A (Antp mutant), Buforin II, Transportan, MAP (model amphipathic peptide), K-FGF, Ku70, Prion, pVEC, Pep-1, SynB1, Pep-7, HN-1, BGSC (Bis-Guanidinium-Spermidine-Cholesterol, and BGTC (Bis-Guanidinium- Tren-Cholesterol). In other embodiments, the antibody is modified using TransMabs™ technology (InNexus Biotech., Inc., Vancouver, BC). The function of the antibody may be enhanced by coupling the antibody or a fragment thereof with a therapeutic agent. Such coupling of the antibody or fragment with the therapeutic agent can be achieved by making an immunoconjugate or by making a fusion protein, or by linking the antibody or fragment to a nucleic acid such as DNA or RNA (e.g., siRNA), comprising the antibody or antibody fragment and the therapeutic agent. A recombinant fusion protein is a protein created through genetic engineering of a fusion gene. This typically involves removing the stop codon from a cDNA sequence coding for the first protein, then appending the cDNA sequence of the second protein in frame through ligation or overlap extension PCR. The DNA sequence will then be expressed by a cell as a single protein. The protein can be engineered to include the full sequence of both original proteins, or only a portion of either. If the two entities are proteins, often linker (or “spacer”) peptides are also added which make it more likely that the proteins fold independently and behave as expected. In some embodiments, the cell-penetrating antibody is modified to alter its half-life. In some embodiments, it is desirable to increase the half- life of the antibody so that it is present in the circulation or at the site of treatment for longer periods of time. For example, it may be desirable to maintain titers of the antibody in the circulation or in the location to be treated for extended periods of time. In other embodiments, the half-life of the 4H2 antibody is decreased to reduce potential side effects. Antibody fragments, such as 4H2Fv may have a shorter half-life than full size antibodies. Other methods of altering half-life are known and can be used in the described methods. For example, antibodies can be engineered with Fc variants that extend half-life, e.g., using Xtend™ antibody half-life prolongation technology (Xencor, Monrovia, CA). a. Linkers The term “linker” as used herein includes, without limitation, peptide linkers. The peptide linker can be any size provided it does not interfere with the binding of the epitope by the variable regions. In some embodiments, the linker includes one or more glycine and/or serine amino acid residues. Monovalent single-chain antibody variable fragments (scFvs) in which the C-terminus of one variable domain are typically tethered to the N-terminus of the other variable domain via a 15 to 25 amino acid peptide or linker. The linker is chosen to permit the heavy chain and light chain to bind together in their proper conformational orientation. Linkers in diabodies, triabodies, etc., typically include a shorter linker than that of a monovalent scFv as discussed above. Di-, tri-, and other multivalent scFvs typically include three or more linkers. The linkers can be the same, or different, in length and/or amino acid composition. Therefore, the number of linkers, composition of the linker(s), and length of the linker(s) can be determined based on the desired valency of the scFv as is known in the art. The linker(s) can allow for or drive formation of a di-, tri-, and other multivalent scFv. For example, a linker can include 4-8 amino acids. In a particular embodiment, a linker includes the amino acid sequenceGQSSRSS (SEQ ID NO:10). In another embodiment, a linker includes 15-20 amino acids, for example, 18 amino acids. In a particular embodiment, the linker includes the amino acid sequenceGQSSRSSSGGGSSGGGGS (SEQ ID NO:11). Other flexible linkers include, but are not limited to, the amino acid sequences Gly- Ser, Gly-Ser-Gly-Ser (SEQ ID NO:12), Ala-Ser, Gly-Gly-Gly-Ser (SEQ ID NO:13), (Gly₄-Ser)₂ (SEQ ID NO:14) and (Gly₄-Ser)₄ (SEQ ID NO:15), and (Gly-Gly-Gly-Gly-Ser)3 (SEQ ID NO:16). Other exemplary linkers include, for example, RADAAPGGGGSGGGGSGGGGS (SEQ ID NO:17) and ASTKGPSVFPLAPLESSGS (SEQ ID NO:18). b. Exemplary 4H2 scFv Sequences One of skill in the art will appreciate that the exemplary fusion proteins, or domains thereof, can be utilized to construct fusion proteins discussed in more detail above. For example, in some embodiments, the scFv includes an scFv including a Vk variable region (SEQ ID NO:1, or a functional variant or fragment thereof), linked to a VH variable domain (e.g., SEQ ID NO:5, or a functional variant or fragment thereof). In some embodiments, the di-scFv includes a first scFv including a Vk variable region (SEQ ID NO:1, or a functional variant or fragment thereof), linked to a VH variable domain (e.g., SEQ ID NO:5, or a functional variant or fragment thereof), linked to a second scFv including a Vk variable region (e.g., SEQ ID NO:1, or a functional variant or fragment thereof), linked to a VH variable domain (e.g., SEQ ID NO:5, or a functional variant or fragment thereof). In some embodiments, a tri-scFv includes a di-scFv linked to a third scFv domain including a Vk variable region (e.g., SEQ ID NO:1, or a functional variant or fragment thereof), linked to a VH variable domain (e.g., SEQ ID NO:5, or a functional variant or fragment thereof). The Vk variable regions can be linked to VH variable domains by, for example, a linker (e.g., (GGGGS)3 (SEQ ID NO:19) alone or in combination with a (6 aa) of light chain CH1 (e.g., RADAAP (SEQ ID NO:20)). Other suitable linkers are discussed above and known in the art. scFv can be linked by a linker (e.g., human IgG CH1 initial 13 amino acids (e.g.,ASTKGPSVFPLAP (SEQ ID NO:21)) alone or in combination with a swivel sequence (e.g., LESSGS (SEQ ID NO:22)). Other suitable linkers are discussed above and known in the art. In some embodiments, the fusion proteins include additional domains. For example, in some embodiments, the fusion proteins include sequences that enhance solubility. In some embodiments that fusion proteins include one or more domains that enhance purification, isolation, capture, identification, separation, etc., of the fusion protein. Exemplary domains include, for example, Myc tag and/or a His tag. Other substitutable domains and additional domains are discussed in more detail above. Exemplary scFv molecules are also provided. DIVLTQSPATLSVTPGDRVSLSCRASQSISNYLHWYQQKSHESPRLLIKYA SQSISGIPSRFSGSGSGTDFTLSIISVETEDFGMYFCQQSNSWPLTFGAGT

of SEQ ID NO:9, or the C-terminus of the 4H2 VH sequence of SEQ ID NO:9 linked to the N-terminal sequence of the 4H2 VL of SEQ ID NO:9. The linker of SEQ ID NO:9 can be substituted with an alternative linker including, but not limited to, the alternative linkers disclosed herein. Typically, the linker is about 10 to about 25 amino acids and is typically includes glycines. The His₆ tag of SEQ ID NO:9 can be replaced with another tag, moved to the N-terminus of the scFv, or deleted completely. In some embodiments, the 4H2 VL, the 4H2 VH, or a combination thereof are variants or humanized forms of the 4H2 VL and/or 4H2 VH of SEQ ID NO:9. In some embodiments, the 4H2 VL and/or 4H2 VH domains are truncated at the N-terminal end, the C-terminal end of both compared to the 4H2 VL and/or 4H2 VH of SEQ ID NO:9. The scFv can includes the 3 CDRs of the 4H2 VL and/or 4H2 VH of SEQ ID NO:9, or humanized forms thereof. In some embodiments the antibody, or fragment, or fusion thereof has at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99 percent sequence identity to SEQ ID NO:9. In some embodiments, the antibody, or fragment, or fusion thereof has a VL domain at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99 percent sequence identity to the 4H2 VL domain of SEQ ID NO:9. In some embodiments, the antibody, or fragment, or fusion thereof has a VH domain at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99 percent sequence identity to the 4H2 VH domain of SEQ ID NO:9. The SEQ ID NO:9 and humanized form and variants thereof can be used in any of the compositions and methods disclosed herein. In some embodiments, SEQ ID NO:9, or a humanized form or variant thereof is used in a therapeutic method, such as the methods disclosed herein, without being conjugated to a nanocarrier or therapeutic agent. Thus, in some embodiments, SEQ ID NO:9, or a humanized form or variant thereof is only therapeutic agent. In some embodiments, SEQ ID NO:9, or a humanized form or variant thereof is not a therapeutic agent (e.g., only a targeting moiety), or is one of two or more therapeutic agents. c. Exemplary 4H2 Bispecific Antibodies An exemplary bispecific antibody is utilized in Example 13 below. The antibody has the format according to Figure 12A and the heavy and light chain variable region sequences: 4H2 sequences VL: DIVLTQSPATLSVTPGDRVSLSCRASQSISNYLHWYQQKSHESPRLLIKYA SQSISGIPSRFSGSGSGTDFTLSIISVETEDFGMYFCQQSNSWPLTFGAGT KLELK (SEQ ID NO:1) VH: EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGRV NPSNGGISYNQKFKGKATLTVDKSLSTAYMQLNSLTSEDSAVYYCARGPYT MYYWGQGTSVTVSS (SEQ ID NO:5) CD5 sequences VL: NIVMTQSPSSLSASVGDRVTITCQASQDVGTAVAWYOQKPDQSPKLLIYWT STRHTGVPDRFTGSGSGTDFTLTISSLOPEDIATYFCHQYNSYNTFGSGTK LEIK (SEQ ID NO:23) VH: QVTLKESGPVLVKPTETLTLTCTFSGFSLSTSGMGVGWIRQAPGKGLEWVA HIWWDDDVYYNPSLKSRLTITKDASKDQVSLKLSSVTAADTAVYYCVRRRA TGTGFDYWGQGTLVTVSS (SEQ ID NO:24) This antibody is only exemplary, and it will be appreciated that other formats, alternative sequences, particularly the framework sequences, and even other second-arm binding domain that target antigens other than CD5 are also expressly provided. For example, in some embodiments, the CDRs of SEQ ID NOS:1, 5, 23, and 24, or humanized forms thereof (e.g., with 1, 2, 3, mutations, e.g., conservative substitutions per CDR or in total) are also provided as a chimeric or humanized bispecific antibody with human heavy and light chain variable region frameworks and optionally constant domains. The predicted CDRs for 4H2 are underlined and expressly provided above. The predicted CDRs for anti-CD5 are underlined above and expressly provided as: CDR L1 : QASQDVGTAVA (SEQ ID NO:25); CDR L2: YWTSTRHT (SEQ ID NO:26); HQYNSYNT CDR L3: (SEQ ID NO:27). CDR H1 : TFSGFSLSTSGMGVG (SEQ ID NO:28); CDR H2: HIWWDDDVY (SEQ ID NO:29); CDR H3: RRATGTGFDY (SEQ ID NO:30). For example, the 4H2-CD5 bispecific antibody can be composed of an antibody fragment or fusion protein that includes one or more CDR(s) that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of the CDR(s) of 4H2 or a variant or humanized form thereof (e.g., CDR(s) of any of SEQ ID NOS:1 and 5 such as SEQ ID NOS:2-4 and 6-8, respectively) in combination with an anti-CD5 antibody fragment or fusion protein or a variant or humanized form thereof (e.g., CDR(s) of any of SEQ ID NOS:23 and 24 such as SEQ ID NOS:25-27 and 28-30, respectively). The determination of percent identity of two amino acid sequences can be determined by BLAST protein comparison. In some embodiments, the antibody includes one, two, three, four, five, or all six of the CDRs of the above-described preferred variable domains (e.g., SEQ ID NOS:1 and 5 and/or 23 and 24), without any changes, or with up to 01, 2, 3, 4, or 5 changes per CDR (i.e., independently selected per CDR) or total across all CDRs. The 4H2-CD5 bispecific antibody can be composed of an antibody fragment or fusion protein including an amino acid sequence of a variable heavy chain and/or variable light chain that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of the variable heavy chain and/or light chain of 4H2 or a humanized form thereof (e.g., SEQ ID NOS:5 and 1) and variable heavy chain and/or light chain of anti-CD5 or a humanized form thereof (e.g., SEQ ID NOS:24 and 23). Preferably, the bispecific antibody includes a heavy chain CDR1, CDR2, and CDR3 in combination with a light chain CDR1, CDR2, and CDR3 of each of 4H2 in combination with those of anti-CD5. Thus, in some embodiments, the cell-penetrating bispecific antibody contains the CDRs, or the entire heavy and light chain variable regions, of SEQ ID NOS:5 and 1 and 24 and 23; or a humanized form thereof. B. Additional Agents Results below show that extracellular nucleic acids promote cellular penetration by 4H2. Furthermore, cGAS activation by cytosolic DNA leads to endogenous generation of cyclic GMP–AMP, a unique second messenger, which binds to stimulator of interferon genes (STING), leading to activation of TANK-binding kinase 1 (TBK1) and IRF3, resulting in the transcription of genes encoding type I interferons (Pesiridis and Fitzgerald, Nature Reviews Genetics volume 20, pages 657–674 (2019)). The experimental results below show that 4H2 activates cGAS and other Pattern Recognition Receptor (PPR) such as TLR7. Such activation may be by direct binding and activation by 4H2 or indirect binding through simultaneous interactions between the immune receptor, 4H2, and cytoplasmic nucleic acid and/or GTP. Thus, the disclosed compositions can be used to facilitate delivery of nucleic acid cargo. Additionally or alternatively, 4H2 antibodies can be used to modulate immune responses with or without the assistance of nucleic acid cargo. For example, in some embodiments, the compositions and methods include nucleic acids and/or GTP (also referred to as nucleic acid cargo) to facilitate 4H2 cellular penetration and/or activation of cGAS and/or another PRR such as TLR7. Additionally, STING agonists has been proposed for a number of different therapeutic purposes, including use for the treatment of cancer, infections, and as a vaccine adjuvant. See, e.g., Pesiridis and Fitzgerald, Nature Reviews Genetics volume 20, pages 657–674 (2019), which is specifically incorporated by reference herein it its entirety. Thus, in some embodiments, the disclosed compositions and methods include an additional agent to further these applications. Non-limiting examples of additional agents included, but are not limited to, additional STING agonists, vaccine compositions, and immune checkpoint inhibitors, each of which is discussed in more detail below. In some embodiments, the additional agent are nucleic acids (e.g., immunostimulatory oligonucleotides, nucleic acids encoding vaccine components such as peptide antigens, etc.). Such nucleic acid additional agents can be nucleic acid cargo, or additionally or alternatively separately administered to the subject. Thus, any of the additional agents can be in the same or different admixture as the 4H2 antibody, and can be administered at the same or a different time from the 4H2 antibody. In some embodiments, such as where the additional agent is a nucleic acid cargo, the additional agent and 4H2 antibody are contacted and form a complex prior to administration to the subject. The interaction between the antibody and the nucleic acid cargo is non-covalent. In such embodiments, the complex can be administered to the subject. Although referred to as cargo, as disclosed herein the cargo nucleic acids can also be separately administered and thus are not necessarily cargo of 4H2 antibodies under these conditions. 1. Cargo Nucleic acid cargos are also provided. As discussed in more detail below, the disclosed 4H2 antibodies can be used to deliver nucleic acid cargos to cells for any purpose. In particular embodiments, cargo can also be used to increase cell penetration of 4H2 antibodies and/or increase activation of cGAS and/or another PRR such as TLR7. As used in the methods of nucleic acid delivery provided herein, the 4H2 is typically contacted with cells in complex with a nucleic acid cargo. The interaction between the antibody or binding protein and the nucleic acid cargo is non-covalent. Nucleic acid cargos can be single stranded or double stranded, or a single nucleotide, nucleoside, or nucleobase, or a plurality thereof. In some embodiments, the cargo is GTP, GDP, GMP, cGAMP, or cGMP. The nucleic acid cargo can be or include DNA, RNA, nucleic acid analogs, or a combination thereof. As discussed in more detail below, nucleic acid analogs can be modified at the base moiety, sugar moiety, or phosphate backbone. Such modification can improve, for example, stability, hybridization, or solubility of the nucleic acid. 4H2 binds to guanosine. Thus, the cargo typically includes one or more guanine nucleobases, preferably one or more guanosine nucleosides. The nucleic acid cargo can be functional in the sense that is or encodes an agent that is biologically active once delivered into cells, or can be non-functional and merely facilitate delivery of 4H2 into the cytoplasm and/or its activation of cGAS and/or another PRR such as TLR7. Exemplary cargo is discussed in more detail below, but includes, for example, mRNA or DNA encoding polypeptides of interest including, for example expression constructs and vectors, inhibitory nucleic acids such as siRNA, or nucleic acid encoding the inhibitory nucleic acid including, for example expression constructs and vectors, or non-coding RNA or DNA. The disclosed compositions can include a plurality of a single nucleic acid cargo molecule. In some embodiments, the compositions include a plurality of a multiplicity (e.g., 2, 3, 4, 5, 6, 7, 8, 910, or more) of different nucleic acid molecules. In some embodiments, the cargo molecules are 0.001, 0.01, 1, 10’s 100’s, 1,000’s, 10,000’s, and/or 100,000’s of kilobases in length. In some embodiments, e.g., the cargo may be between 0.001 kb and 100 kb, or between 0.001 kb kb and 50 kb, or between 0.001 kb kb and 25 kb, or between 0.001 kb and 12.5 kb, or between 0.001 kb and 10 kb, or between 0.001 kb and 8 kb, or 0.001 kb and 5 kb, or between 0.001 kb and 2.5 kb, or between 0.001 kb and 1 kb, or between 0.01 kb and 100 kb, or between 0.01 kb kb and 50 kb, or between 0.01 kb kb and 25 kb, or between 0.01 kb and 12.5 kb, or between 0.01 kb and 10 kb, or between 0.01 kb and 8 kb, or 0.01 kb and 5 kb, or between 0.01 kb and 2.5 kb, or between 0.01 kb and 1 kb, or between 0.1 kb and 100 kb, or between 0.1 kb kb and 50 kb, or between 0.1 kb kb and 25 kb, or between 0.1 kb and 12.5 kb, or between 0.1 kb and 10 kb, or between 0.1 kb and 8 kb, or 0.1 kb and 5 kb, or between 0.1 kb and 2.5 kb, or between 0.1 kb and 1 kb, or between 1 kb and 100 kb, or between 1 kb kb and 50 kb, or between 1 kb kb and 25 kb, or between 1 kb and 12.5 kb, or between 1 kb and 10 kb, or between 1 kb and 8 kb, or 1 kb and 5 kb, or between 1 kb and 2.5 kb, each inclusive. In some embodiments, e.g., the cargo may be between 0.2 kb and 10 kb, or between 0.2 kb and 5 kb, or between 0.2 kb and 2.5 kb, or between 0.2 kb and 1 kb, or between 0.2 kb and 0.5 kb, or between 0.2 kb and 0.25 kb, or between 0.5 kb and 10 kb, or between 0.5 kb and 5 kb, or between 1 kb and 5 kb, or between 1 kb and 3 kb, or between 2 kb and 10 kb, or between 3 kb and 5 kb. It will be appreciated that for specific application the nucleic acid cargo may be one or more discrete lengths that, for example, falls within one of the foregoing ranges (inclusive), the specific values for each are expressly disclosed. For example, the size can be as small as a single nucleotide or nucleobase. In an exemplary application the cargo is a cyclic dinucleotide like cGAMP, which is a STING agonist. In other embodiments, the cargo is a short oligomer. For example, oligomers as short as 8-mers can be used for anti-sense or splice switching. Slightly longer ones (e.g., 18 to 20 mers) can be used for gene editing. a. Forms of the Cargo The nucleic acid cargo is a nucleic acid and can be an isolated nucleic acid composition. As used herein, “isolated nucleic acid” refers to a nucleic acid that is separated from other nucleic acid molecules that are present in a mammalian genome, including nucleic acids that normally flank one or both sides of the nucleic acid in a mammalian genome. The term “isolated” as used herein with respect to nucleic acids also includes the combination with any non-naturally-occurring nucleic acid sequence, since such non-naturally- occurring sequences are not found in nature and do not have immediately contiguous sequences in a naturally-occurring genome. An isolated nucleic acid can be, for example, a DNA molecule, provided one of the nucleic acid sequences normally found immediately flanking that DNA molecule in a naturally-occurring genome is removed or absent. Thus, an isolated nucleic acid includes, without limitation, a DNA molecule that exists as a separate molecule independent of other sequences (e.g., a chemically synthesized nucleic acid, or a cDNA or genomic DNA fragment produced by PCR or restriction endonuclease treatment), as well as recombinant DNA that is incorporated into a vector, an autonomously replicating plasmid, a virus (e.g., a retrovirus, lentivirus, adenovirus, or herpes virus), or into the genomic DNA of a prokaryote or eukaryote. In addition, an isolated nucleic acid can include an engineered nucleic acid such as a recombinant DNA molecule that is part of a hybrid or fusion nucleic acid. A nucleic acid existing among hundreds to millions of other nucleic acids within, for example, a cDNA library or a genomic library, or a gel slice containing a genomic DNA restriction digest, is not to be considered an isolated nucleic acid. The nucleic acid sequences encoding polypeptides include genomic sequences. Also disclosed are mRNA/cDNA sequence wherein the exons have been deleted. Other nucleic acid sequences encoding polypeptides, such polypeptides that include the above-identified amino acid sequences and fragments and variants thereof, are also disclosed. Nucleic acids encoding polypeptides may be optimized for expression in the expression host of choice. Codons may be substituted with alternative codons encoding the same amino acid to account for differences in codon usage between the organism from which the nucleic acid sequence is derived and the expression host. In this manner, the nucleic acids may be synthesized using expression host-preferred codons. Nucleic acids can be in sense or antisense orientation, or can be, for example, complementary to a reference sequence encoding a polypeptide. i. Vectors The cargo can be a vector, for example, a vector encoding a polypeptide(s) and/or functional nucleic acid(s). Nucleic acids, such as those described above, can be inserted into vectors for expression in cells. As used herein, a “vector” is a replicon, such as a plasmid, phage, virus or cosmid, into which another DNA segment may be inserted so as to bring about the replication of the inserted segment. Vectors can be expression vectors. An “expression vector” is a vector that includes one or more expression control sequences, and an “expression control sequence” is a DNA sequence that controls and regulates the transcription and/or translation of another DNA sequence. Nucleic acids in vectors can be operably linked to one or more expression control sequences. For example, the control sequence can be incorporated into a genetic construct so that expression control sequences effectively control expression of a coding sequence of interest. Examples of expression control sequences include promoters, enhancers, and transcription terminating regions. A promoter is an expression control sequence composed of a region of a DNA molecule, typically within 100 nucleotides upstream of the point at which transcription starts (generally near the initiation site for RNA polymerase II). To bring a coding sequence under the control of a promoter, it is necessary to position the translation initiation site of the translational reading frame of the polypeptide between one and about fifty nucleotides downstream of the promoter. Enhancers provide expression specificity in terms of time, location, and level. Unlike promoters, enhancers can function when located at various distances from the transcription site. An enhancer also can be located downstream from the transcription initiation site. A coding sequence is “operably linked” and “under the control” of expression control sequences in a cell when RNA polymerase is able to transcribe the coding sequence into mRNA, which then can be translated into the protein encoded by the coding sequence. Suitable expression vectors include, without limitation, plasmids, cosmids, and viral vectors derived from, for example, bacteriophage, baculoviruses, tobacco mosaic virus, herpes viruses, cytomegalo virus, retroviruses, vaccinia viruses, adenoviruses, and adeno-associated viruses. Numerous vectors and expression systems are commercially available from such corporations as Novagen (Madison, WI), Clontech (Palo Alto, CA), Stratagene (La Jolla, CA), and Invitrogen Life Technologies (Carlsbad, CA). In some embodiments, the cargo is delivered into the cell and remains extrachromosomal. In some embodiments, the cargo is introduced into a host cell and is integrated into the host cell’s genome. As discussed in more detail below, the compositions can be used in methods of gene therapy. Methods of gene therapy can include the introduction into the cell of a polynucleotide that alters the genotype of the cell. Introduction of the polynucleotide can correct, replace, or otherwise alter the endogenous gene via genetic recombination. Methods can include introduction of an entire replacement copy of a defective gene, a heterologous gene, or a small nucleic acid molecule such as an oligonucleotide. For example, a corrective gene can be introduced into a non-specific location within the host’s genome. In some embodiments, the cargo is a vector. Methods to construct expression vectors containing genetic sequences and appropriate transcriptional and translational control elements are well known in the art. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Expression vectors generally contain regulatory sequences and necessary elements for the translation and/or transcription of the inserted coding sequence, which can be, for example, the polynucleotide of interest. The coding sequence can be operably linked to a promoter and/or enhancer to help control the expression of the desired gene product. Promoters used in biotechnology are of different types according to the intended type of control of gene expression. They can be generally divided into constitutive promoters, tissue-specific or development-stage-specific promoters, inducible promoters, and synthetic promoters. For example, in some embodiments, a polynucleotide of interest is operably linked to a promoter or other regulatory elements known in the art. Thus, the cargo can be a vector such as an expression vector. The engineering of polynucleotides for expression in a prokaryotic or eukaryotic system may be performed by techniques generally known to those of skill in recombinant expression. An expression vector typically includes one of the disclosed compositions under the control of one or more promoters. To bring a coding sequence “under the control of” a promoter, one positions the 5' end of the translational initiation site of the reading frame generally between about 1 and 50 nucleotides “downstream” of (i.e., 3' of) the chosen promoter. The “upstream” promoter stimulates transcription of the inserted DNA and promotes expression of the encoded recombinant protein or functional nucleic acid. This is the meaning of “recombinant expression” in the context used here. Many standard techniques are available to construct expression vectors containing the appropriate nucleic acids and transcriptional/translational control sequences in order to achieve protein or peptide or functional nucleic acid expression in a variety of host-expression systems. Expression vectors for use in mammalian cells ordinarily include an origin of replication (as necessary), a promoter located in front of the gene to be expressed, along with any necessary ribosome binding sites, RNA splice sites, polyadenylation site, and transcriptional terminator sequences. The origin of replication may be provided either by construction of the vector to include an exogenous origin, such as may be derived from SV40 or other viral (e.g., Polyoma, Adeno, VSV, BPV) source, or may be provided by the host cell chromosomal replication mechanism. If the vector is integrated into the host cell chromosome, the latter is often sufficient. The promoters may be derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Further, it is also possible, and may be desirable, to utilize promoter or control sequences normally associated with the desired gene sequence, provided such control sequences are compatible with the host cell systems. A number of viral based expression systems may be utilized, for example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40 (SV40). The early and late promoters of SV40 virus are useful because both are obtained easily from the virus as a fragment which also contains the SV40 viral origin of replication. Smaller or larger SV40 fragments may also be used, provided there is included the approximately 250 bp sequence extending from the HindIII site toward the BglI site located in the viral origin of replication. In cases where an adenovirus is used as an expression vector, the coding sequences may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing proteins in infected hosts. Specific initiation signals may also be required for efficient translation of the disclosed compositions. These signals include the ATG initiation codon and adjacent sequences. Exogenous translational control signals, including the ATG initiation codon, may additionally need to be provided. One of ordinary skill in the art would readily be capable of determining this need and providing the necessary signals. It is well known that the initiation codon must be in-frame (or in-phase) with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements or transcription terminators. In eukaryotic expression, one will also typically desire to incorporate into the transcriptional unit an appropriate polyadenylation site if one was not contained within the original cloned segment. Typically, the poly A addition site is placed about 30 to 2000 nucleotides “downstream” of the termination site of the protein at a position prior to transcription termination. For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines that stably express constructs encoding proteins may be engineered. Rather than using expression vectors that contain viral origins of replication, host cells can be transformed with vectors controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched medium, and then are switched to a selective medium. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci, which in turn can be cloned and expanded into cell lines. ii. mRNAs The cargo can be mRNA. Chemical structures with the ability to promote stability and/or translation efficiency may also be used. For example, the RNA can have 5’ and 3’ UTRs. The length of the 3’ UTR can, for example, exceed 100 nucleotides. In some embodiments the 3’ UTR sequence is between 100 and 5000 nucleotides. In some embodiments, the 5’ UTR is between zero and 3000 nucleotides in length. The length of 5’ and 3’ UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5’ and 3’ UTR lengths required to achieve optimal translation efficiency following delivery of the transcribed RNA. The 5’ and 3’ UTRs can be the naturally occurring, endogenous 5’ and 3’ UTRs for the gene of interest. Alternatively, UTR sequences that are not endogenous to the gene of interest can be added by incorporating the UTR sequences into the forward and reverse primers or by any other modifications of the template. The use of UTR sequences that are not endogenous to the gene of interest can be useful for modifying the stability and/or translation efficiency of the RNA. For example, it is known that AU- rich elements in 3’ UTR sequences can decrease the stability of mRNA. Therefore, 3’ UTRs can be selected or designed to increase the stability of the transcribed RNA based on properties of UTRs that are well known in the art. In some embodiments, the 5’ UTR contains the Kozak sequence of the endogenous gene. Alternatively, when a 5’ UTR that is not endogenous to the gene of interest is being added by PCR as described above, a consensus Kozak sequence can be redesigned by adding the 5’ UTR sequence. Kozak sequences can increase the efficiency of translation of some RNA transcripts, but does not appear to be required for all RNAs to enable efficient translation. The requirement for Kozak sequences for many mRNAs is known in the art. In other embodiments the 5’ UTR can be derived from an RNA virus whose RNA genome is stable in cells. In other embodiments various nucleotide analogues can be used in the 3’ or 5’ UTR to impede exonuclease degradation of the mRNA. In some embodiments, the mRNA has a cap on the 5' end, a 3' poly(A) tail, or a combination thereof which determine ribosome binding, initiation of translation and stability mRNA in the cell. 5’caps provide stability to RNA molecules. The 5' cap may, for example, be m⁷G(5')ppp(5')G, m⁷G(5')ppp(5')A, G(5')ppp(5')G or G(5')ppp(5')A cap analogs, which are all commercially available. The 5’ cap can also be an anti-reverse-cap-analog (ARCA) (Stepinski, et al., RNA, 7:1468-95 (2001)) or any other suitable analog. The 5’ cap can be incorporated using techniques known in the art (Cougot, et al., Trends in Biochem. Sci., 29:436-444 (2001); Stepinski, et al., RNA, 7:1468-95 (2001); Elango, et al., Biochim. Biophys. Res. Commun., 330:958-966 (2005)). The RNAs can also contain an internal ribosome entry site (IRES) sequence. The IRES sequence may be any viral, chromosomal or artificially designed sequence which initiates cap-independent ribosome binding to mRNA and facilitates the initiation of translation. Generally, the length of a poly(A) tail positively correlates with the stability of the transcribed RNA. In one embodiment, the poly(A) tail is between 100 and 5000 adenosines. A polyA segment can be produced during PCR by using a reverse primer containing a polyT tail, such as 100T tail (size can be, e.g., 50-5000 T), or after PCR by any other method, including, but not limited to, DNA ligation or in vitro recombination. Poly(A) tails also provide stability to RNAs and reduce their degradation. Poly(A) tails of RNAs can additionally or alternatively be extended following in vitro transcription with the use of a poly(A) polymerase, such as E. coli polyA polymerase (E-PAP). Additionally, the attachment of different chemical groups to the 3' end can increase mRNA stability. Such attachment can contain modified/artificial nucleotides, aptamers and other compounds. For example, ATP analogs can be incorporated into the poly(A) tail using poly(A) polymerase. ATP analogs can further increase the stability of the RNA. Suitable ATP analogs include, but are not limited to, cordiocipin and 8- azaadenosine. b. Sequence of the Cargo i. Polypeptide of Interest The cargo can encode one or more proteins. The cargo can be a polynucleotide that can be monocistronic or polycistronic. In some embodiments, polynucleotide is multigenic. The polynucleotide can be, for example, an mRNA or a expression construct such as a vector. The cargo can encode one or more polypeptides of interest. The polypeptide can be any polypeptide. For example, the polypeptide encoded by the polynucleotide can be a polypeptide that provides a therapeutic or prophylactic effect to an organism or that can be used to diagnose a disease or disorder in an organism. For example, for treatment of cancer, autoimmune disorders, parasitic, viral, bacterial, fungal or other infections, the polynucleotide(s) to be expressed may encode a polypeptide that functions as a ligand or receptor for cells of the immune system, or can function to stimulate or inhibit the immune system of an organism. In some embodiments, the polynucleotide supplements or replaces a polynucleotide that is defective in the organism. In particular embodiments, the polynucleotide encodes dystrophin, utrophin, or a combination thereof. Such compositions may be administered in an effective amount to treat a subject from a dystrophy, particularly a muscular dystrophy, for example, Duchenne's muscular dystrophy. In another particular embodiment, the polynucleotide encodes antigen, e.g., an antigen that can be utilized in a vaccine formulation and associated methods. In a particular embodiment, polynucleotide encodes a viral antigen(s), for example, a SARS-CoV-2 antigen(s). Thus, compositions and methods of use thereof for protection against, and the treatment of, SARS-CoV-2 virus and viral infections and disease associate therewith including COVID19 are provided. In some embodiments, the polynucleotide includes a selectable marker, for example, a selectable marker that is effective in a eukaryotic cell, such as a drug resistance selection marker. This selectable marker gene can encode a factor necessary for the survival or growth of transformed host cells grown in a selective culture medium. Typical selection genes encode proteins that confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, kanamycin, gentamycin, Zeocin, or tetracycline, complement auxotrophic deficiencies, or supply critical nutrients withheld from the media. In the working Example 12 below, a nucleic acid (i.e., NF2) that encodes wildtype Merlin, a protein mutated in Neurofibromatosis type 2, reduces tumor growth. Thus, in some embodiments, the nucleic acid encodes a wildtype or other compensatory variant of an oncogenic protein such as Merlin. In some embodiments, the polynucleotide includes a reporter gene. Reporter genes are typically genes that are not present or expressed in the host cell. The reporter gene typically encodes a protein which provides for some phenotypic change or enzymatic property. Examples of such genes are provided in Weising et al. Ann. Rev. Genetics, 22, 421 (1988). Preferred reporter genes include glucuronidase (GUS) gene and GFP genes. ii. Functional Nucleic Acids The cargo can be or encode a functional nucleic acid. Functional nucleic acids are nucleic acid molecules that have a specific function, such as binding a target molecule or catalyzing a specific reaction. As discussed in more detail below, functional nucleic acid molecules can be divided into the following non-limiting categories: antisense molecules, siRNA, miRNA, aptamers, ribozymes, RNAi, and external guide sequences, and cyclic dinucleotides. The functional nucleic acid molecules can act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional nucleic acid molecules can possess a de novo activity independent of any other molecules. Functional nucleic acid molecules can interact with any macromolecule, such as DNA, RNA, polypeptides, or carbohydrate chains. Thus, functional nucleic acids can interact with the mRNA or the genomic DNA of a target polypeptide or they can interact with the polypeptide itself. Often functional nucleic acids are designed to interact with other nucleic acids based on sequence homology between the target molecule and the functional nucleic acid molecule. In other situations, the specific recognition between the functional nucleic acid molecule and the target molecule is not based on sequence homology between the functional nucleic acid molecule and the target molecule, but rather is based on the formation of tertiary structure that allows specific recognition to take place. Therefore the compositions can include one or more functional nucleic acids designed to reduce expression of a gene, or a gene product thereof. For example, the functional nucleic acid or polypeptide can be designed to target and reduce or inhibit expression or translation of an mRNA; or to reduce or inhibit expression, reduce activity, or increase degradation of a protein. In some embodiments, the composition includes a vector suitable for in vivo expression of the functional nucleic acid. (1) Antisense The functional nucleic acids can be or encode antisense molecules. Antisense molecules are designed to interact with a target nucleic acid molecule through either canonical or non-canonical base pairing. The interaction of the antisense molecule and the target molecule is designed to promote the destruction of the target molecule through, for example, RNAse H mediated RNA-DNA hybrid degradation. Alternatively the antisense molecule is designed to interrupt a processing function that normally would take place on the target molecule, such as transcription or replication. Antisense molecules can be designed based on the sequence of the target molecule. There are numerous methods for optimization of antisense efficiency by finding the most accessible regions of the target molecule. Exemplary methods include in vitro selection experiments and DNA modification studies using DMS and DEPC. It is preferred that antisense molecules bind the target molecule with a dissociation constant (Kd) less than or equal to 10^-6, 10^-8, 10^-10, or 10^-12. (2) RNA Interference In some embodiments, the functional nucleic acids induce gene silencing through RNA interference. Gene expression can also be effectively silenced in a highly specific manner through RNA interference (RNAi). This silencing was originally observed with the addition of double stranded RNA (dsRNA) (Fire, et al. (1998) Nature, 391:806-11; Napoli, et al. (1990) Plant Cell 2:279-89; Hannon, (2002) Nature, 418:244-51). Once dsRNA enters a cell, it is cleaved by an RNase III –like enzyme, Dicer, into double stranded small interfering RNAs (siRNA) 21-23 nucleotides in length that contains 2 nucleotide overhangs on the 3’ ends (Elbashir, et al. (2001) Genes Dev., 15:188-200; Bernstein, et al. (2001) Nature, 409:363-6; Hammond, et al. (2000) Nature, 404:293-6). In an ATP dependent step, the siRNAs become integrated into a multi-subunit protein complex, commonly known as the RNAi induced silencing complex (RISC), which guides the siRNAs to the target RNA sequence (Nykanen, et al. (2001) Cell, 107:309-21). At some point the siRNA duplex unwinds, and it appears that the antisense strand remains bound to RISC and directs degradation of the complementary mRNA sequence by a combination of endo and exonucleases (Martinez, et al. (2002) Cell, 110:563-74). However, the effect of iRNA or siRNA or their use is not limited to any type of mechanism. Short Interfering RNA (siRNA) is a double-stranded RNA that can induce sequence-specific post-transcriptional gene silencing, thereby decreasing or even inhibiting gene expression. In one example, a siRNA triggers the specific degradation of homologous RNA molecules, such as mRNAs, within the region of sequence identity between both the siRNA and the target RNA. For example, WO 02/44321 discloses siRNAs capable of sequence-specific degradation of target mRNAs when base-paired with 3' overhanging ends, herein incorporated by reference for the method of making these siRNAs. Sequence specific gene silencing can be achieved in mammalian cells using synthetic, short double-stranded RNAs that mimic the siRNAs produced by the enzyme dicer (Elbashir, et al. (2001) Nature, 411:494498) (Ui-Tei, et al. (2000) FEBS Lett 479:79-82). siRNA can be chemically or in vitro-synthesized or can be the result of short double-stranded hairpin-like RNAs (shRNAs) that are processed into siRNAs inside the cell. Synthetic siRNAs are generally designed using algorithms and a conventional DNA/RNA synthesizer. Suppliers include Ambion (Austin, Texas), ChemGenes (Ashland, Massachusetts), Dharmacon (Lafayette, Colorado), Glen Research (Sterling, Virginia), MWB Biotech (Esbersberg, Germany), Proligo (Boulder, Colorado), and Qiagen (Vento, The Netherlands). siRNA can also be synthesized in vitro using kits such as Ambion’s SILENCER® siRNA Construction Kit. The production of siRNA from a vector is more commonly done through the transcription of a short hairpin RNAse (shRNAs). Kits for the production of vectors having shRNA are available, such as, for example, Imgenex’s GENESUPPRESSOR™ Construction Kits and Invitrogen’s BLOCK-IT™ inducible RNAi plasmid and lentivirus vectors. In some embodiment, the functional nucleic acid is siRNA, shRNA, miRNA. In some embodiments, the composition includes a vector expressing the functional nucleic acid. (3) Aptamers The functional nucleic acids can be or encode an aptamer. Aptamers are molecules that interact with a target molecule, preferably in a specific way. Typically aptamers are small nucleic acids ranging from 15-50 bases in length that fold into defined secondary and tertiary structures, such as stem- loops or G-quartets. Aptamers can bind small molecules, such as ATP and theophiline, as well as large molecules, such as reverse transcriptase and thrombin. Aptamers can bind very tightly with Kd’s from the target molecule of less than 10^-12 M. It is preferred that the aptamers bind the target molecule with a Kd less than10^-6, 10^-8, 10^-10, or 10^-12. Aptamers can bind the target molecule with a very high degree of specificity. For example, aptamers have been isolated that have greater than a 10,000 fold difference in binding affinities between the target molecule and another molecule that differ at only a single position on the molecule. It is preferred that the aptamer have a K_d with the target molecule at least 10, 100, 1000, 10,000, or 100,000 fold lower than the Kd with a background binding molecule. It is preferred when doing the comparison for a molecule such as a polypeptide, that the background molecule be a different polypeptide. (4) Ribozymes The functional nucleic acids can be or encode ribozymes. Ribozymes are nucleic acid molecules that are capable of catalyzing a chemical reaction, either intramolecularly or intermolecularly. It is preferred that the ribozymes catalyze intermolecular reactions. There are a number of different types of ribozymes that catalyze nuclease or nucleic acid polymerase type reactions which are based on ribozymes found in natural systems, such as hammerhead ribozymes. There are also a number of ribozymes that are not found in natural systems, but which have been engineered to catalyze specific reactions de novo. Preferred ribozymes cleave RNA or DNA substrates, and more preferably cleave RNA substrates. Ribozymes typically cleave nucleic acid substrates through recognition and binding of the target substrate with subsequent cleavage. This recognition is often based mostly on canonical or non-canonical base pair interactions. This property makes ribozymes particularly good candidates for target specific cleavage of nucleic acids because recognition of the target substrate is based on the target substrates sequence. (5) External Guide Sequences The functional nucleic acids can be or encode external guide sequences. External guide sequences (EGSs) are molecules that bind a target nucleic acid molecule forming a complex, which is recognized by RNase P, which then cleaves the target molecule. EGSs can be designed to specifically target a RNA molecule of choice. RNAse P aids in processing transfer RNA (tRNA) within a cell. Bacterial RNAse P can be recruited to cleave virtually any RNA sequence by using an EGS that causes the target RNA:EGS complex to mimic the natural tRNA substrate. Similarly, eukaryotic EGS/RNAse P-directed cleavage of RNA can be utilized to cleave desired targets within eukaryotic cells. Representative examples of how to make and use EGS molecules to facilitate cleavage of a variety of different target molecules are known in the art. Methods of making and using vectors for in vivo expression of functional nucleic acids such as antisense oligonucleotides, siRNA, shRNA, miRNA, EGSs, ribozymes, and aptamers are known in the art. (6) Cyclic Dinucleotides In some embodiments, the 4H2 antibody is co-administered in combination with an immunostimulatory oligonucleotide. The immunostimulatory oligonucleotide can be cargo, and thus administered in complex with the antibody, or separately administered. In some embodiments, the immunostimulatory oligonucleotide is cyclic dinucleotide. The functional nucleic acids can be or encode a cyclic dinucleotide. Cyclic dinucleotides bind directly to the STING adaptor protein, resulting in production of IFN-β (Zhang, et al., Mol Cell., 51(2):226-35 (2013). doi: 10.1016/j.molcel.2013.05.022.). Several canonical and noncanonical dinucleotides are known in the art, and include, but are not limited to, GMP– AMP (cGAS), 2'3'-cGAMP , 2'3'-cGAMP , 3'3'-cGAMP, c-di-GMP, 2’2’- cGAMP, 2’3’-cGAM(PS)2 (Rp/Sp), 3'3'-cGAMP Fluorinated, c-di-GMP Fluorinated, or 2’3’-c-di-GMP, c-di-AMP, c-di-GMP, cAIMP (CL592), cAIMP Difluor (CL614), cAIM(PS)2 Difluor (Rp/Sp) (CL656), c-di-AMP Fluorinated, 2'3'-c-di-AMP, 2’3’-c-di-AM(PS)2 (Rp,Rp), 2'3'-c-di-AM(PS)2 (Rp,Rp), c-di-GMP Fluorinated, 2’3’-c-di-GMP, c-di-IMP, and DMXAA. (7) Immunostimulatory Oligonucleotides In some embodiments, the immunostimulatory oligonucleotide is or encodes an oligonucleotide ligand. Examples include, but are not limited to, pattern recognition receptors (PRRs) ligands. Examples of PRRs include the Toll-like family of signaling molecules that play a role in the initiation of innate immune responses and also influence the later and more antigen specific adaptive immune responses. Therefore, the oligonucleotide can serve as a ligand for a Toll- like family signaling molecule, such as Toll-Like Receptor 9 (TLR9). For example, unmethylated CpG sites can be detected by TLR9 on plasmacytoid dendritic cells and B cells in humans (Zaida, et al., Infection and Immunity, 76(5):2123-2129, (2008)). Therefore, the sequence of oligonucleotide can include one or more unmethylated cytosine-guanine (CG or CpG, used interchangeably) dinucleotide motifs. The ‘p’ refers to the phosphodiester backbone of DNA, however, in some embodiments, oligonucleotides including CG can have a modified backbone, for example a phosphorothioate (PS) backbone. In some embodiments, an oligonucleotide can contain more than one CG dinucleotide, arranged either contiguously or separated by intervening nucleotide(s). The CpG motif(s) can be in the interior of the oligonucleotide sequence. Numerous nucleotide sequences stimulate TLR9 with variations in the number and location of CG dinucleotide(s), as well as the precise base sequences flanking the CG dimers. Typically, CG ODNs are classified based on their sequence, secondary structures, and effect on human peripheral blood mononuclear cells (PBMCs). The five classes are Class A (Type D), Class B (Type K), Class C, Class P, and Class S (Vollmer, J & Krieg, AM, Advanced drug delivery reviews 61(3): 195–204 (2009), incorporated herein by reference). CG ODNs can stimulate the production of Type I interferons (e.g., IFNα) and induce the maturation of dendritic cells (DCs). Some classes of ODNs are also strong activators of natural killer (NK) cells through indirect cytokine signaling. Some classes are strong stimulators of human B cell and monocyte maturation (Weiner, GL, PNAS USA 94(20): 10833-7 (1997); Dalpke, AH, Immunology 106(1): 102-12 (2002); Hartmann, G, J of Immun. 164(3):1617-2 (2000), each of which is incorporated herein by reference). Other PRR Toll-like receptors include TLR3, and TLR7 which may recognize double-stranded RNA, single-stranded and short double-stranded RNAs, respectively, and retinoic acid-inducible gene I (RIG-I)-like receptors, namely RIG-I and melanoma differentiation-associated gene 5 (MDA5), which are best known as RNA-sensing receptors in the cytosol. RIG-I (retinoic-acid-inducible protein 1, also known as Ddx58) and MDA-5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) are cytoplasmic RNA helicases that belong to the RIG-I-like receptors (RLRs) family and are critical for host antiviral responses. RIG-I and MDA-5 sense double-stranded RNA (dsRNA), a replication intermediate for RNA viruses, and signal through the mitochondrial antiviral signaling protein MAVS (also known as IPS-1, VISA or Cardif), leading to production of type-I interferons (IFN-α and IFN-β). RIG-I detects viral RNA that exhibit an uncapped 5’-di/triphosphate end and a short blunt-ended double stranded potion, two essential features facilitating discrimination from self-RNAs. The features of MDA-5 physiological ligands have not been fully characterized yet. However, it is admitted that RIG-I and MDA-5 exhibit a different dependency for the length of dsRNAs: RIG-I selectively binds short dsRNA while MDA-5 selectively binds long dsRNA. Consistent with this, RIG-I and MDA-5 bind Poly(I:C), a synthetic dsRNA analog, with different length predilection. Under some circumstances, RIG-I can also sense dsDNA indirectly. Viral dsDNA can be transcribed by the RNA polymerase III into dsRNA with a 5’-triphosphate moiety. Poly(dA:dT), a synthetic analog of B-form DNA, thus constitutes another RIG-I ligand. Exemplary RIG-I ligands include, but are not limited to, 5'ppp- dsRNA, a specific agonist of RIG-I; 3p-hpRNA, a specific agonist of RIG-I; Poly(I:C)/LyoVec complexes that are recognized by RIG-I and/or MDA-5 depending of the size of poly(I:C); Poly(dA:dT)/LyoVec complexes that are indirectly recognized by RIG-I. In some embodiments, the oligonucleotide contains a functional ligand for TLR3, TLR7, TLR8, TLR9, or RIG-I-like receptors, or combinations thereof. Examples of immunostimulatory oligonucleotides, and methods of making them are known in the art and commercially available, see for example, Bodera, P. Recent Pat Inflamm Allergy Drug Discov.5(1):87-93 (2011), incorporated herein by reference. c. Composition of the Cargo The disclosed nucleic acid cargo can be or include DNA or RNA nucleotides which typically include a heterocyclic base (nucleic acid base), a sugar moiety attached to the heterocyclic base, and a phosphate moiety which esterifies a hydroxyl function of the sugar moiety. The principal naturally-occurring nucleotides include uracil, thymine, cytosine, adenine and guanine as the heterocyclic bases, and ribose or deoxyribose sugar linked by phosphodiester bonds. In some embodiments, the cargo includes or is composed of nucleotide analogs that have been chemically modified to improve stability, half-life, or specificity or affinity for a target receptor, relative to a DNA or RNA counterpart. The chemical modifications include chemical modification of nucleobases, sugar moieties, nucleotide linkages, or combinations thereof. As used herein ‘modified nucleotide” or “chemically modified nucleotide” defines a nucleotide that has a chemical modification of one or more of the heterocyclic base, sugar moiety or phosphate moiety constituents. In some embodiments, the charge of the modified nucleotide is reduced compared to DNA or RNA of the same nucleobase sequence. For example, the oligonucleotide can have low negative charge, no charge, or positive charge. Typically, nucleoside analogs support bases capable of hydrogen bonding by Watson-Crick base pairing to standard polynucleotide bases, where the analog backbone presents the bases in a manner to permit such hydrogen bonding in a sequence-specific fashion between the oligonucleotide analog molecule and bases in a standard polynucleotide (e.g., single-stranded RNA or single-stranded DNA). In some embodiments, the analogs have a substantially uncharged, phosphorus containing backbone. i. Heterocyclic Bases The principal naturally-occurring nucleotides include uracil, thymine, cytosine, adenine and guanine as the heterocyclic bases. The cargo can include chemical modifications to their nucleobase constituents. Chemical modifications of heterocyclic bases or heterocyclic base analogs may be effective to increase the binding affinity or stability in binding a target sequence. Chemically-modified heterocyclic bases include, but are not limited to, inosine, 5-(1-propynyl) uracil (pU), 5-(1-propynyl) cytosine (pC), 5-methylcytosine, 8-oxo-adenine, pseudocytosine, pseudoisocytosine, 5 and 2-amino-5-(2'-deoxy-.beta.-D-ribofuranosyl)pyridine (2-aminopyridine), and various pyrrolo- and pyrazolopyrimidine derivatives. ii. Sugar Modifications Cargo can also contain nucleotides with modified sugar moieties or sugar moiety analogs. Sugar moiety modifications include, but are not limited to, 2'-O-aminoetoxy, 2'-O-amonioethyl (2'-OAE), 2'-O-methoxy, 2'- O-methyl, 2-guanidoethyl (2'-OGE), 2'-O,4'-C-methylene (LNA), 2'-O- (methoxyethyl) (2'-OME) and 2'-O-(N-(methyl)acetamido) (2'-OMA).2'-O- aminoethyl sugar moiety substitutions are especially preferred because they are protonated at neutral pH and thus suppress the charge repulsion between the TFO and the target duplex. This modification stabilizes the C3'-endo conformation of the ribose or dexyribose and also forms a bridge with the i-1 phosphate in the purine strand of the duplex. In some embodiments, the nucleic acid is a morpholino oligonucleotide. Morpholino oligonucleotides are typically composed of two more morpholino monomers containing purine or pyrimidine base-pairing moieties effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, which are linked together by phosphorus-containing linkages, one to three atoms long, joining the morpholino nitrogen of one monomer to the 5' exocyclic carbon of an adjacent monomer. The purine or pyrimidine base-pairing moiety is typically adenine, cytosine, guanine, uracil or thymine. The synthesis, structures, and binding characteristics of morpholino oligomers are detailed in U.S. Patent Nos.5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166,315, 5,521,063, and 5,506,337. Important properties of the morpholino-based subunits typically include: the ability to be linked in a oligomeric form by stable, uncharged backbone linkages; the ability to support a nucleotide base (e.g. adenine, cytosine, guanine, thymidine, uracil or inosine) such that the polymer formed can hybridize with a complementary-base target nucleic acid, including target RNA, with high T_m, even with oligomers as short as 10-14 bases; the ability of the oligomer to be actively transported into mammalian cells; and the ability of an oligomer:RNA heteroduplex to resist RNAse degradation. In some embodiments, oligonucleotides employ morpholino-based subunits bearing base-pairing moieties, joined by uncharged linkages, as described above. Morpholino oligonucleotides can be, for example, phosphorodiamidate morpholino oligomers. iii. Internucleotide Linkages Oligonucleotides are connected by an internucleotide bond that refers to a chemical linkage between two nucleoside moieties. Modifications to the phosphate backbone of DNA or RNA oligonucleotides may increase the binding affinity or stability oligonucleotides, or reduce the susceptibility of oligonucleotides nuclease digestion. Cationic modifications, including, but not limited to, diethyl-ethylenediamide (DEED) or dimethyl- aminopropylamine (DMAP) may be especially useful due to decrease electrostatic repulsion between the oligonucleotide and a target. Modifications of the phosphate backbone may also include the substitution of a sulfur atom for one of the non-bridging oxygens in the phosphodiester linkage. This substitution creates a phosphorothioate internucleoside linkage in place of the phosphodiester linkage. Oligonucleotides containing phosphorothioate internucleoside linkages have been shown to be more stable in vivo. Examples of modified nucleotides with reduced charge include modified internucleotide linkages such as phosphate analogs having achiral and uncharged intersubunit linkages (e.g., Sterchak, E. P. et al., Organic. Chem., 52:4202, (1987)), and uncharged morpholino-based polymers having achiral intersubunit linkages (see, e.g., U.S. Pat. No.5,034,506), as discussed above. Some internucleotide linkage analogs include morpholidate, acetal, and polyamide-linked heterocycles. In another embodiment, the cargo are composed of locked nucleic acids. Locked nucleic acids (LNA) are modified RNA nucleotides (see, for example, Braasch, et al., Chem. Biol., 8(1):1-7 (2001)). LNAs form hybrids with DNA which are more stable than DNA/DNA hybrids, a property similar to that of peptide nucleic acid (PNA)/DNA hybrids. Therefore, LNA can be used just as PNA molecules would be. LNA binding efficiency can be increased in some embodiments by adding positive charges to it. Commercial nucleic acid synthesizers and standard phosphoramidite chemistry are used to make LNAs. In some embodiments, the cargo are composed of peptide nucleic acids. Peptide nucleic acids (PNAs) are synthetic DNA mimics in which the phosphate backbone of the oligonucleotide is replaced in its entirety by repeating N-(2-aminoethyl)-glycine units and phosphodiester bonds are typically replaced by peptide bonds. The various heterocyclic bases are linked to the backbone by methylene carbonyl bonds. PNAs maintain spacing of heterocyclic bases that is similar to conventional DNA oligonucleotides, but are achiral and neutrally charged molecules. Peptide nucleic acids are composed of peptide nucleic acid monomers. Other backbone modifications include peptide and amino acid variations and modifications. Thus, the backbone constituents of oligonucleotides such as PNA may be peptide linkages, or alternatively, they may be non-peptide peptide linkages. Examples include acetyl caps, amino spacers such as 8-amino-3,6-dioxaoctanoic acid (referred to herein as O- linkers), amino acids such as lysine are particularly useful if positive charges are desired in the PNA, and the like. Methods for the chemical assembly of PNAs are well known. See, for example, U.S. Patent Nos.5,539,082, 5,527,675, 5,623,049, 5,714,331, 5,736,336, 5,773,571 and 5,786,571. Cargo optionally includes one or more terminal residues or modifications at either or both termini to increase stability, and/or affinity of the oligonucleotide for its target. Commonly used positively charged moieties include the amino acids lysine and arginine, although other positively charged moieties may also be useful. Cargo may further be modified to be end capped to prevent degradation using a propylamine group. Procedures for 3' or 5' capping oligonucleotides are well known in the art. In some embodiments, the nucleic acid can be single stranded or double stranded. iv. Fine Tuning Binding The sequence of cargo can be modified to account for these properties and fine tune the strength of binding between the cargo and the 4H2 binding protein. 4H2 antibodies bind to guanosine, so increasing the number of guanines and/or selecting the location of guanines in the polynucleotide sequence may be used to increasing binding of the antibodies, create binding sites for the antibodies, increase the number of antibodies that bind to a single polynucleotide, and/or target the antibodies to bind to certain locations along the polynucleotide. Additionally or alternatively, decreasing the number of guanines in the polynucleotide and/or selecting the location of absence of guanines in the polynucleotide sequence may be used to increase binding of the antibodies, reduce or remove binding sites for the antibodies, decrease the number of antibodies that bind to a single polynucleotide, and/or target the antibodies to bind an alternative locations along the polynucleotide. For example, any of the disclosed cargos may include or consist of guanine (G) (e.g., mono-, di- or polyG) alone or in combination of 2, 3, 4, or more of adenine (A), thymine (T), cytosine (C), uracil (U), or inosine (I). In some embodiments, a synthetic, non-coding sequence is added to the cargo to, e.g., increase or decrease binding to a 4H2 binding protein. Such sequences and can be, but need not necessarily be, at the 5’ or 3’ end of the nucleic acid cargo. The cargo can be single stranded or double stranded DNA or RNA. Additionally or alternatively, these binding properties can be accounted for in rational design of the nucleic acid sequence of the cargo using codon optimization of preferential increased binding (e.g., preference for guanine), or decrease binding (e.g., preference for adenine (A), thymine (T), cytosine (C), uracil (U), or inosine (I)). 2. Vaccine Formulations Vaccines require strong immune responses. The 4H2 antibodies described herein can be administered as a component of a vaccine to enhance the immune response associated therewith. In some embodiments, the vaccines disclosed herein include a 4H2 antibody, an antigen(s), and optionally an adjuvant(s) of other additional agent. a. Antigens Antigens can be peptides, proteins, polysaccharides, saccharides, lipids, nucleic acids, or combinations thereof. The antigen can be derived from a transformed cell such as a cancer or leukemic cell and can be a whole cell or immunogenic component thereof. Suitable antigens are known in the art and are available from commercial government and scientific sources. The antigens can be purified or partially purified polypeptides derived from tumors or can be recombinant polypeptides produced by expressing DNA encoding the polypeptide antigen in a heterologous expression system. The antigens can be a DNA or RNA (e.g., mRNA) encoding all or part of an antigenic protein. The DNA may be in the form of vector DNA such as a viral vector or plasmid DNA. Antigens may be provided as single antigens or may be provided in combination. Antigens may also be provided as complex mixtures of polypeptides or nucleic acids. The antigen can be, for example, a tumor antigen or derived from an infectious agent or disease against which vaccination is desired, such as polio, tetanus, flu (influenza), hepatitis B, hepatitis A, hepatitis C, rubella, Hib, measles, whooping cough (pertussis), pneumococcal disease, HIV, SAR-CoV-2, or any of the other infections and diseases discussed in more detail below. i. Viral Antigens A viral antigen can be isolated from any virus including, but not limited to, a virus from any of the following viral families: Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Badnavirus, Barnaviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Capillovirus, Carlavirus, Caulimovirus, Circoviridae, Closterovirus, Comoviridae, Coronaviridae (e.g., Coronavirus, such as severe acute respiratory syndrome (SARS) virus), Corticoviridae, Cystoviridae, Deltavirus, Dianthovirus, Enamovirus, Filoviridae (e.g., Marburg virus and Ebola virus (e.g., Zaire, Reston, Ivory Coast, or Sudan strain)), Flaviviridae, (e.g., Hepatitis C virus, Dengue virus 1, Dengue virus 2, Dengue virus 3, and Dengue virus 4), Hepadnaviridae, Herpesviridae (e.g., Human herpesvirus 1, 3, 4, 5, and 6, and Cytomegalovirus), Hypoviridae, Iridoviridae, Leviviridae, Lipothrixviridae, Microviridae, Orthomyxoviridae (e.g., Influenzavirus A and B and C), Papovaviridae, Paramyxoviridae (e.g., measles, mumps, and human respiratory syncytial virus), Parvoviridae, Picornaviridae (e.g., poliovirus, rhinovirus, hepatovirus, and aphthovirus), Poxviridae (e.g., vaccinia and smallpox virus), Reoviridae (e.g., rotavirus), Retroviridae (e.g., lentivirus, such as human immunodeficiency virus (HIV) 1 and HIV 2), Rhabdoviridae (for example, rabies virus, measles virus, respiratory syncytial virus, etc.), Togaviridae (for example, rubella virus, dengue virus, etc.), and Totiviridae. Suitable viral antigens also include all or part of Dengue protein M, Dengue protein E, Dengue D1NS1, Dengue D1NS2, and Dengue D1NS3. Viral antigens may be derived from a particular strain, or a combination of strains, such as a SAR-CoV-2, papilloma virus, a herpes virus, i.e. herpes simplex 1 and 2; a hepatitis virus, for example, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the delta hepatitis D virus (HDV), hepatitis E virus (HEV) and hepatitis G virus (HGV), the tick-borne encephalitis viruses; parainfluenza, varicella-zoster, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus, adenovirus, coxsackieviruses, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever,and lymphocytic choriomeningitis. ii. Bacterial Antigens Bacterial antigens can originate from any bacteria including, but not limited to, Actinomyces, Anabaena, Bacillus, Bacteroides, Bdellovibrio, Bordetella, Borrelia, Campylobacter, Caulobacter, Chlamydia, Chlorobium, Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus, Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus, Hemophilus influenza type B (HIB), Hyphomicrobium, Legionella, Leptspirosis, Listeria, Meningococcus A, B and C, Methanobacterium, Micrococcus, Myobacterium, Mycoplasma, Myxococcus, Neisseria, Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas, Phodospirillum, Rickettsia, Salmonella, Shigella, Spirillum, Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus, Thermoplasma, Thiobacillus, and Treponema, Vibrio, and Yersinia. iii. Parasitic Antigens Antigens of parasites can be obtained from parasites such as, but not limited to, antigens derived from Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis and Schistosoma mansoni. These include Sporozoan antigens, Plasmodian antigens, such as all or part of a Circumsporozoite protein, a Sporozoite surface protein, a liver stage antigen, an apical membrane associated protein, or a Merozoite surface protein. iv. Tumor Antigens The antigen can be a tumor antigen, including a tumor-associated or tumor-specific antigen, such as, but not limited to, alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR- fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-1, 2, and 3, neo-PAP, myosin class I, OS-9, pml- RARα fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomeras, Bage-1, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, Mage- A1,2,3,4,6,10,12, Mage-C2, NA-88, NY-Eso-1/Lage-2, SP17, SSX-2, and TRP2-Int2, MelanA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP- 180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm- 23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β- Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43- 9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7- Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, and TPS. Tumor antigens, such as BCG, may also be used as an immunostimulant to adjuvant. b. Adjuvants Optionally, the vaccines described herein may include adjuvants. The adjuvant can be, but is not limited to, one or more of the following: oil emulsions (e.g., Freund's adjuvant); saponin formulations; virosomes and viral-like particles; bacterial and microbial derivatives; immunostimulatory oligonucleotides; ADP-ribosylating toxins and detoxified derivatives; alum; BCG; mineral-containing compositions (e.g., mineral salts, such as aluminium salts and calcium salts, hydroxides, phosphates, sulfates, etc.); bioadhesives and/or mucoadhesives; microparticles; liposomes; polyoxyethylene ether and polyoxyethylene ester formulations; polyphosphazene; muramyl peptides; imidazoquinolone compounds; and surface active substances (e.g. lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol). Adjuvants may also include immunomodulators such as cytokines, interleukins (e.g., IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (e.g., interferon-.gamma.), macrophage colony stimulating factor, and tumor necrosis factor. In addition to PD-1 antagonists, other co-stimulatory molecules, including other polypeptides of the B7 family, may be administered. Such proteinaceous adjuvants may be provided as the full- length polypeptide or an active fragment thereof, or in the form of RNA or DNA, such as plasmid DNA. 3. Immune Checkpoint Modulators The 4H2 antibodies can be administered in combination with an immune checkpoint modulator. Immune checkpoints can be stimulatory or inhibitory, and tumors can use these checkpoints to protect themselves from immune system attacks. Currently approved checkpoint therapies block inhibitory checkpoint receptors, but investigations into therapies that activate stimulatory checkpoints are also underway. Thus, the immune checkpoint modulator can be one that blocks an inhibitory checkpoint, or activates a stimulatory checkpoint. Typically, the immune checkpoint modulator is one that induces or otherwise activates or increases an immune response against target cells for example cancer cells or infected cells. Accordingly, in some embodiments, the immune checkpoint modulator can be a chimeric antigen receptor (CAR) directed cell such as a CAR-T cell. In another embodiment, the immune checkpoint modulator can be an oncolytic virus. In preferred embodiments, the immune checkpoint modulator blocks an inhibitory checkpoint. Blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors. Thus, in some embodiments the immune checkpoint modulator is administered to the subject in an effective amount to block an inhibitory checkpoint. Exemplary compounds are those that block or otherwise inhibit, for example, PD-1, PD-L1, or CTLA4. a. PD-1 antagonists In some embodiments, the active agents are PD-1 antagonists. Activation of T cells normally depends on an antigen-specific signal following contact of the T cell receptor (TCR) with an antigenic peptide presented via the major histocompatibility complex (MHC) while the extent of this reaction is controlled by positive and negative antigen-independent signals emanating from a variety of co-stimulatory molecules. The latter are commonly members of the CD28/B7 family. Conversely, Programmed Death-1 (PD-1) is a member of the CD28 family of receptors that delivers a negative immune response when induced on T cells. Contact between PD-1 and one of its ligands (B7-H1 or B7-DC) induces an inhibitory response that decreases T cell multiplication and/or the strength and/or duration of a T cell response. Suitable PD-1 antagonists are described in U.S. Patent Nos. 8,114,845, 8,609,089, and 8,709,416, and include compounds or agents that either bind to and block a ligand of PD-1 to interfere with or inhibit the binding of the ligand to the PD-1 receptor, or bind directly to and block the PD-1 receptor without inducing inhibitory signal transduction through the PD-1 receptor. In some embodiments, the PD-1 receptor antagonist binds directly to the PD-1 receptor without triggering inhibitory signal transduction and also binds to a ligand of the PD-1 receptor to reduce or inhibit the ligand from triggering signal transduction through the PD-1 receptor. By reducing the number and/or amount of ligands that bind to PD-1 receptor and trigger the transduction of an inhibitory signal, fewer cells are attenuated by the negative signal delivered by PD-1 signal transduction and a more robust immune response can be achieved. It is believed that PD-1 signaling is driven by binding to a PD-1 ligand (such as B7-H1 or B7-DC) in close proximity to a peptide antigen presented by major histocompatibility complex (MHC) (see, for example, Freeman, Proc. Natl. Acad. Sci. U. S. A, 105:10275-10276 (2008)). Therefore, proteins, antibodies or small molecules that prevent co-ligation of PD-1 and TCR on the T cell membrane are also useful PD-1 antagonists. In preferred embodiments, the PD-1 receptor antagonists are small molecule antagonists or antibodies that reduce or interfere with PD-1 receptor signal transduction by binding to ligands of PD-1 or to PD-1 itself, especially where co-ligation of PD-1 with TCR does not follow such binding, thereby not triggering inhibitory signal transduction through the PD- 1 receptor. Other PD-1 antagonists include antibodies that bind to PD-1 or ligands of PD-1 such as PD-L1 (also known as B7-H1) and PD-L2 (also known as B7-DC), and other antibodies. Suitable anti-PD-1 antibodies include, but are not limited to, those described in the following publications: PCT/IL03/00425 (Hardy et al., WO/2003/099196) PCT/JP2006/309606 (Korman et al., WO/2006/121168) PCT/US2008/008925 (Li et al., WO/2009/014708) PCT/JP03/08420 (Honjo et al., WO/2004/004771) PCT/JP04/00549 (Honjo et al., WO/2004/072286) PCT/IB2003/006304 (Collins et al., WO/2004/056875) PCT/US2007/088851 (Ahmed et al., WO/2008/083174) PCT/US2006/026046 (Korman et al., WO/2007/005874) PCT/US2008/084923 (Terrett et al., WO/2009/073533) Berger et al., Clin. Cancer Res., 14:30443051 (2008). A specific example of an anti-PD-1 antibody is MDX-1106 (see Kosak, US 20070166281 (pub.19 July 2007) at par.42), a human anti-PD-1 antibody, preferably administered at a dose of 3 mg/kg. Exemplary anti-B7-H1 antibodies include, but are not limited to, those described in the following publications: PCT/US06/022423 (WO/2006/133396, pub.14 December 2006) PCT/US07/088851 (WO/2008/083174, pub.10 July 2008) US 2006/0110383 (pub.25 May 2006) A specific example of an anti-B7-H1 antibody is MDX-1105 (WO/2007/005874, published 11 January 2007)), a human anti-B7-H1 antibody. For anti-B7-DC antibodies see 7,411,051, 7,052,694, 7,390,888, and U.S. Published Application No.2006/0099203. The antibody can be a bi-specific antibody that includes an antibody that binds to the PD-1 receptor bridged to an antibody that binds to a ligand of PD-1, such as B7-H1. In some embodiments, the PD-1 binding portion reduces or inhibits signal transduction through the PD-1 receptor. Other exemplary PD-1 receptor antagonists include, but are not limited to B7-DC polypeptides, including homologs and variants of these, as well as active fragments of any of the foregoing, and fusion proteins that incorporate any of these. In a preferred embodiment, the fusion protein includes the soluble portion of B7-DC coupled to the Fc portion of an antibody, such as human IgG, and does not incorporate all or part of the transmembrane portion of human B7-DC. The PD-1 antagonist can also be a fragment of a mammalian B7-H1, preferably from mouse or primate, preferably human, wherein the fragment binds to and blocks PD-1 but does not result in inhibitory signal transduction through PD-1. The fragments can also be part of a fusion protein, for example an Ig fusion protein. Other useful polypeptides PD-1 antagonists include those that bind to the ligands of the PD-1 receptor. These include the PD-1 receptor protein, or soluble fragments thereof, which can bind to the PD-1 ligands, such as B7- H1 or B7-DC, and prevent binding to the endogenous PD-1 receptor, thereby preventing inhibitory signal transduction. B7-H1 has also been shown to bind the protein B7.1 (Butte et al., Immunity, Vol.27, pp.111-122, (2007)). Such fragments also include the soluble ECD portion of the PD-1 protein that includes mutations, such as the A99L mutation, that increases binding to the natural ligands (Molnar et al., PNAS, 105:10483-10488 (2008)). B7-1 or soluble fragments thereof, which can bind to the B7-H1 ligand and prevent binding to the endogenous PD-1 receptor, thereby preventing inhibitory signal transduction, are also useful. PD-1 and B7-H1 anti-sense nucleic acids, both DNA and RNA, as well as siRNA molecules can also be PD-1 antagonists. Such anti-sense molecules prevent expression of PD-1 on T cells as well as production of T cell ligands, such as B7-H1, PD-L1 and/or PD-L2. For example, siRNA (for example, of about 21 nucleotides in length, which is specific for the gene encoding PD-1, or encoding a PD-1 ligand, and which oligonucleotides can be readily purchased commercially) complexed with carriers, such as polyethyleneimine (see Cubillos-Ruiz et al., J. Clin. Invest.119(8): 2231- 2244 (2009), are readily taken up by cells that express PD-1 as well as ligands of PD-1 and reduce expression of these receptors and ligands to achieve a decrease in inhibitory signal transduction in T cells, thereby activating T cells. Exemplary PD-1 inhibitors include, but are not limited to, • Pembrolizumab (formerly MK-3475 or lambrolizumab, Keytruda) was developed by Merck and first approved by the Food and Drug Administration in 2014 for the treatment of melanoma. • Nivolumab (Opdivo) was developed by Bristol-Myers Squibb and first approved by the FDA in 2014 for the treatment of melanoma. • pidilizumab, by CureTech • AMP-224, by GlaxoSmithKline and MedImmune • AMP-514, by GlaxoSmithKline and MedImmune • PDR001, by Novartis • cemiplimab, by Regeneron and Sanofi Exemplary PD-L1 inhibitors include, but are not limited to, • Atezolizumab (Tecentriq) is a fully humanised IgG1 (immunoglobulin 1 antibody developed by Roche Genentech. In 2016, the FDA approved atezolizumab for urothelial carcinoma and non-small cell lung cancer. • Avelumab (Bavencio) is a fully human IgG1 antibody developed by Merck Serono and Pfizer. Avelumab is FDA approved for the treatment of metastatic merkel-cell carcinoma. It failed phase III clinical trials for gastric cancer. • Durvalumab (Imfinzi) is a fully human IgG1 antibody developed by AstraZeneca. Durvalumab is FDA approved for the treatment of urothelial carcinoma and unresectable non-small cell lung cancer after chemoradiation. • BMS-936559, by Bristol-Myers Squibb • CK-301, by Checkpoint Therapeutics See, e.g., Iwai, et al., Journal of Biomedical Science, (2017) 24:26, DOI 10.1186/s12929-017-0329-9. b. CTLA4 antagonists Other molecules useful in mediating the effects of T cells in an immune response are also contemplated as active agents. For example, in some embodiments, the molecule is an agent binds to an immune response mediating molecule that is not PD-1. In a preferred embodiment, the molecule is an antagonist of CTLA4, for example an antagonistic anti- CTLA4 antibody. An example of an anti-CTLA4 antibody is described in PCT/US2006/043690 (Fischkoff et al., WO/2007/056539). Dosages for anti-PD-1, anti-B7-H1, and anti-CTLA4 antibody, are known in the art and can be in the range of 0.1 to 100 mg/kg, with shorter ranges of 1 to 50 mg/kg preferred and ranges of 10 to 20 mg/kg being more preferred. An appropriate dose for a human subject is between 5 and 15 mg/kg, with 10 mg/kg of antibody (for example, human anti-PD-1 antibody, like MDX-1106) most preferred. Specific examples of CTLA antagonists include Ipilimumab, also known as MDX-010 or MDX-101, a human anti-CTLA4 antibody, preferably administered at a dose of about 10 mg/kg, and Tremelimumab a human anti-CTLA4 antibody, preferably administered at a dose of about 15 mg/kg. See also Sammartino, et al., Clinical Kidney Journal, 3(2):135-137 (2010), published online December 2009. In other embodiments, the antagonist is a small molecule. A series of small organic compounds have been shown to bind to the B7-1 ligand to prevent binding to CTLA4 (see Erbe et al., J. Biol. Chem., 277:7363-7368 (2002). Such small organics could be administered alone or together with an anti-CTLA4 antibody to reduce inhibitory signal transduction of T cells. c. Chimeric Antigen Receptor directed cells The modulator can be a chimeric antigen receptor directed cell. The term “Chimeric Antigen Receptor” or alternatively a “CAR” refers to a set of polypeptides, typically two in the simplest embodiments, which when in an immune effector cell, provides the cell with specificity for a cancer cell, and with intracellular signal generation. In some embodiments, a CARincludes at least an antigen binding domain such as an extracellular binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to as "an intracellular signaling domain") including a functional signaling domain derived from a stimulatory molecule and/or costimulatory molecule as defined below. In one embodiment, the stimulatory molecule is a zeta chain (“zeta stimulatory domain”) associated with a T cell receptor complex. In one embodiment, the cytoplasmic signaling domain further includes one or more functional signaling domains derived from at least one costimulatory molecule (e.g., 4-1BB (i.e., CD137), CD27 and/or CD28). In some embodiments, the CAR includes a chimeric fusion protein including an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain including a functional signaling domain derived from a stimulatory molecule. In various embodiments, CARs are fusion proteins of single-chain variable fragments (scFv) fused to a CD3-zeta transmembrane domain. However, other intracellular signaling domains such as CD28, 41-BB and Ox40 may be used in various combinations to give the desired intracellular signal. In some embodiments, CARs disclosed herein include an extracellular binding domain. The term “antigen binding domain” is used in the context of the present disclosure to refer to the portion of the CAR that specifically recognizes and binds to the antigen of interest. The “antigen binding domain” may be derived from a binding protein disclosed herein such as an antibody or fragment thereof. In some embodiments, the “binding domain” is a single-chain variable fragment (scFv). In certain embodiments, the “binding domain” includes the complementarity determining regions of a binding protein disclosed herein. In this embodiment, the CAR directed cell can represent the combination of a 4H2 cell-penetrating antibody (assuming it penetrates a cancer cell) that induces cGAS/STING signaling, or a combination thereof and an immune checkpoint modulator that induces, increases, or enhances an immune response. For example, the binding domain can represent the cell-penetrating antibody and the modified T-cell can represent the immune cell modulator. In another example, a CAR- directed cell disclosed herein is administered with a cell-penetrating 4H2 antibody disclosed herein. The terms “zeta” or “CD3-zeta” are used herein to define the protein provided as GenBan Acc. No. BAG36664.1, or the equivalent residues from a non- human species and a “zeta stimulatory domain” or alternatively a “CD3-zeta stimulatory domain” is defined as the amino acid residues from the cytoplasmic domain of the zeta chain, or functional derivatives thereof, that are sufficient to functionally transmit an initial signal necessary for T cell activation. The term “immune effector cell,” is used herein to refer to a cell that is involved in an immune response (e.g. promotion of an immune effector response). Examples of immune effector cells include T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloic-derived phagocytes. In some embodiments, the immune effector cell(s) is allogenic. In some embodiments, the immune effector cell(s) is autologous. In some embodiments, the immune checkpoint modulator is a CAR directed T cell (CAR-T cell). Exemplary CAR-T cells include Axicabtagene ciloleucel (KTE-C19, Axi-cel), Tisagenlecleucel, Lisocabtagene Maraleucel (liso-cel; JCAR017). Immune effector cells such as T cells may be activated and expanded generally using methods previously described, such as for example, as described in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041. As a general example, a population of immune effector cells e.g., T regulatory cell depleted cells, may be expanded by contact with a surface having attached thereto an agent that stimulates a CD3 complex associated signal and a ligand that stimulates a costimulatory molecule on the surface of the T cells. d. Oncolytic virus The modulator can be an oncolytic virus. The term “oncolytic virus” is used in the context of the present disclosure to refer to viruses that are able to infect and reduce growth of cancer cells. For example, oncolytic viruses can inhibit cell proliferation. In some embodiments, oncolytic viruses can kill cancer cells. In some embodiments, the oncolytic virus preferentially infects and inhibits growth of cancer cells compared with corresponding normal cells. In another embodiment, the oncolytic virus preferentially replicates in and inhibits growth of cancer cells compared with corresponding normal cells. In some embodiments, the oncolytic virus is able to naturally infect and reduce growth of cancer cells. Examples of such viruses include Newcastle disease virus, vesicular stomatitis, myxoma, reovirus, sindbis, measles and coxsackievirus. Oncolytic viruses able to naturally infect and reduce growth of cancer cells generally target cancer cells by exploiting the cellular aberrations that occur in these cells. For example, oncolytic viruses may exploit surface attachment receptors, activated oncogenes such as Ras, Akt, p53 and/or interferon (IFN) pathway defects. In another embodiment, oncolytic viruses encompassed by the present disclosure are engineered to infect and reduce growth of cancer cells. Exemplary viruses suitable for such engineering include oncolytic DNA viruses, such as adenovirus, herpes simplex virus (HSV) and Vaccinia virus; and oncolytic RNA viruses such as Lentivirus, Reovirus, Coxsackievirus, Seneca Valley Virus, Poliovirus, Measles virus, Newcastle disease virus, Vesicular stomatitis virus (VSV) and parvovirus such as rodent protoparvoviruses H-1PV. In some embodiments, the oncolytic virus includes a backbone of an above referenced virus. In some embodiments, tumor specificity of an oncolytic virus can be engineered to mutate or delete gene(s) required for survival of the virus in normal cells but expendable in cancer cells. For example, the oncolytic virus can be engineered by mutating or deleting a gene that encodes thymidine kinase, an enzyme needed for nucleic acid metabolism. In this example, viruses are dependent on cellular thymidine kinase expression, which is high in proliferating cancer cells but repressed in normal cells. In another example, the oncolytic virus is engineered to include a capsid protein that binds a tumor specific cell surface molecule. In some embodiments, the capsid protein is a fibre, a penton or hexon protein. In another example, the oncolytic virus is engineered to include a tumor specific cell surface molecule for transductionally targeting a cancer cell. Exemplary tumor specific cell surface molecules can include an integrin, an EGF receptor family member, a proteoglycan, a disialoganglioside, B7-H3, CA-125, EpCAM, ICAM-1, DAF, A21, integrin-α2β1, vascular endothelial growth factor receptor 1 , vascular endothelial growth factor receptor 2, CEA, a tumour associated glycoprotein, CD19, CD20, CD22, CD30, CD33, CD40, CD44, CD52, CD74, CD152, CD155, MUC1, a tumour necrosis factor receptor, an insulin-like growth factor receptor, folate receptor a, transmembrane glycoprotein NMB, a C-C chemokine receptor, PSMA, RON-receptor, and cytotoxic T-lymphocyte antigen 4. The oncolytic virus can be replication-competent. In some embodiments, the oncolytic viruses selectively replicate in cancer cells when compared with corresponding normal cells. Conditional replication can be achieved by, for example, the insertion of a tumor-specific promoter driving the expression of a critical gene(s). Such promoters can be identified based on differences in gene expression between tumor and corresponding surrounding tissue. Exemplary native promoters include AFP, CCKAR, CEA, erbB2, Cerb2, COX2, CXCR4, E2F1, HE4, LP, MUC1, PSA, Survivin, TRP1, STAT3, hTERT and Tyr. Exemplary composite promoters include AFP/hAFP, SV40/AFP, CEA/CEA, PSA/PSA, SV40/Tyr and Tyr/Tyr. Various viruses may be engineered as outlined in the above referenced examples. The oncolytic virus can be, for example, a modified HSV, Lentivirus, Baculovirus, Retrovirus, Adenovirus (AdV), Adeno- associated virus (AAV) or a recombinant form such as recombinant adeno- associated virus (rAAV) or a derivative thereof such as a self-complementary AAV (scAAV) or non-integrating AV. The oncolytic virus can be a modified HSVThe oncolytic virus can be a modified lentivirus. Other exemplary viruses include vaccina virus, vesicular stomatitis virus (VSV), measles virus and maraba virus. In other examples, the oncolytic virus may be one of various AV or AAV serotypes. In some embodiments, the oncolytic virus is serotype 1. In another example, the oncolytic virus is serotype 2. In other examples, the oncolytic virus is serotype 3, 4, 7, 8, 9, 10, 11, 12 or 13. In another example, the oncolytic virus is serotype 5. In another example, the oncolytic virus is serotype 6. Exemplary oncolytic viruses include T-Vec (HSV-1; Amgen), JX- 594 (Vaccina; Sillajen), JX-594 (AdV; Cold Genesys), Reolysin (Reovirus; Oncolytics Biotech). Other examples of oncolytic viruses are disclosed in WO 2003/080083, WO 2005/086922, WO 2007/088229, WO 2008/110579, WO 2010/108931, WO 2010/128182, WO 2013/112942, WO 2013/116778, WO 2014/204814, WO 2015/077624 and WO 2015/166082, WO 2015/089280. e. Other Immune Checkpoint Modulators Other immune checkpoint targets include, but are not limited to, ICOS, OX40, GITR, 4-1BB, CD40, CD27-CD70, LAG3, TIM-3, TIGIT, VISTA, B7-H3, KIR, PARP, and others, and are being targeting for cancer treatment alone and in combination with anti-PD-1, anti-PD-L1, and anti- CTLA compounds. See, for example, Iwai, et al., Journal of Biomedical Science.24 (1): 26. doi:10.1186/s12929-017-0329-9; Donini, et al., J Thorac Dis.2018 May;10(Suppl 13):S1581-S1601. doi: 10.21037/jtd.2018.02.79. Thus, in some embodiments, a 4H2 antibody is administered in combination with a compound that targets ICOS, OX40, GITR, 4-1BB, CD40, CD27- CD70, LAG3, TIM-3, TIGIT, VISTA, B7-H3, KIR, or PARP, or a combination thereof, alone or in combination with a compound that target PD-1, PD-L1, and/or CTLA. In another embodiment, the immune checkpoint modulator is an antibody disclosed in WO 2016/013870. C. Pharmaceutical Compositions The compositions can be used therapeutically in combination with a pharmaceutically acceptable carrier. The compositions are preferably employed for therapeutic uses in combination with a suitable pharmaceutical carrier. Such compositions include an effective amount of the composition, and a pharmaceutically acceptable carrier or excipient. The compositions may be in a formulation for administration topically, locally or systemically in a suitable pharmaceutical carrier. Remington's Pharmaceutical Sciences, 15th Edition by E. W. Martin (Mark Publishing Company, 1975), discloses typical carriers and methods of preparation. The antibodies or complexes formed therefrom may also be encapsulated in suitable biocompatible particles formed of biodegradable or non-biodegradable polymers or proteins or liposomes for targeting to cells. Such systems are well known to those skilled in the art. In some embodiments, the antibodies or complexes formed therefrom are encapsulated in nanoparticles. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, optionally with an added preservative. The compositions may take such forms as sterile aqueous or nonaqueous solutions, suspensions and emulsions, which can be isotonic with the blood of the subject in certain embodiments. Examples of nonaqueous solvents are polypropylene glycol, polyethylene glycol, vegetable oil such as olive oil, sesame oil, coconut oil, arachis oil, peanut oil, mineral oil, injectable organic esters such as ethyl oleate, or fixed oils including synthetic mono or di-glycerides. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, 1,3- butandiol, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, and electrolyte replenishers (such as those based on Ringer's dextrose).The materials may be in solution, emulsions, or suspension (for example, incorporated into particles, liposomes, or cells). Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Trehalose, typically in the amount of 1-5%, may be added to the pharmaceutical compositions. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, and surface-active agents. Carrier formulation can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. Those of skill in the art can readily determine the various parameters for preparing and formulating the compositions without resort to undue experimentation. The compositions alone or in combination with other suitable components, can also be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and air. For administration by inhalation, the compounds are delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant. In some embodiments, the include pharmaceutically acceptable carriers with formulation ingredients such as salts, carriers, buffering agents, emulsifiers, diluents, excipients, chelating agents, preservatives, solubilizers, or stabilizers. The nucleic acids may be conjugated to lipophilic groups like cholesterol and lauric and lithocholic acid derivatives with C32 functionality to improve cellular uptake. For example, cholesterol has been demonstrated to enhance uptake and serum stability of siRNA in vitro (Lorenz, et al., Bioorg. Med. Chem. Lett., 14(19):4975-4977 (2004)) and in vivo (Soutschek, et al., Nature, 432(7014):173-178 (2004)). In addition, it has been shown that binding of steroid conjugated oligonucleotides to different lipoproteins in the bloodstream, such as LDL, protect integrity and facilitate biodistribution (Rump, et al., Biochem. Pharmacol., 59(11):1407-1416 (2000)). Other groups that can be attached or conjugated to the nucleic acids described above to increase cellular uptake, include acridine derivatives; cross-linkers such as psoralen derivatives, azidophenacyl, proflavin, and azidoproflavin; artificial endonucleases; metal complexes such as EDTA- Fe(II) and porphyrin-Fe(II); alkylating moieties; nucleases such as alkaline phosphatase; terminal transferases; abzymes; cholesteryl moieties; lipophilic carriers; peptide conjugates; long chain alcohols; phosphate esters; radioactive markers; non-radioactive markers; carbohydrates; and polylysine or other polyamines. U.S. Patent No.6,919,208 to Levy, et al., also describes methods for enhanced delivery. These pharmaceutical formulations may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Further carriers include sustained release preparations such as semi- permeable matrices of solid hydrophobic polymers containing the antibodies or complexes formed therefrom, which matrices are in the form of shaped particles, e.g., films, liposomes or microparticles. Implantation includes inserting implantable drug delivery systems, e.g., microspheres, hydrogels, polymeric reservoirs, cholesterol matrixes, polymeric systems, e.g., matrix erosion and/or diffusion systems and non-polymeric systems. Inhalation includes administering the composition with an aerosol in an inhaler, either alone or attached to a carrier that can be absorbed. For systemic administration, it may be preferred that the composition is encapsulated in liposomes. The compositions may be delivered in a manner which enables tissue-specific uptake of the agent and/or nucleotide delivery system, using invasive devices such as vascular or urinary catheters, and using interventional devices such as stents having drug delivery capability and configured as expansive devices or stent grafts. The formulations may be delivered using a bioerodible implant by way of diffusion or by degradation of the polymeric matrix. In certain embodiments, the administration of the formulation may be designed to result in sequential exposures to the composition, over a certain time period, for example, hours, days, weeks, months or years. This may be accomplished, for example, by repeated administrations of a formulation or by a sustained or controlled release delivery system in which the compositions are delivered over a prolonged period without repeated administrations. Other delivery systems suitable include time-release, delayed release, sustained release, or controlled release delivery systems. Such systems may avoid repeated administrations in many cases, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include, for example, polymer-based systems such as polylactic and/or polyglycolic acids, polyanhydrides, polycaprolactones, copolyoxalates, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and/or combinations of these. Microcapsules of the foregoing polymers containing nucleic acids are described in, for example, U.S. Patent No.5,075,109. Other examples include non-polymer systems that are lipid-based including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; liposome-based systems; phospholipid based-systems; silastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; or partially fused implants. The formulation may be as, for example, microspheres, hydrogels, polymeric reservoirs, cholesterol matrices, or polymeric systems. In some embodiments, the system may allow sustained or controlled release of the composition to occur, for example, through control of the diffusion or erosion/degradation rate of the formulations containing the antibodies or complexes formed therefrom. The compositions can be formulated for pulmonary or mucosal administration. The administration can include delivery of the composition to the lungs, nasal, oral (sublingual, buccal), vaginal, or rectal mucosa. The term aerosol as used herein refers to any preparation of a fine mist of particles, which can be in solution or a suspension, whether or not it is produced using a propellant. Aerosols can be produced using standard techniques, such as ultrasonication or high-pressure treatment. For administration via the upper respiratory tract, the formulation can be formulated into a solution, e.g., water or isotonic saline, buffered or un- buffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. The compositions can be delivered to the target cells using a particle delivery vehicle. Nanoparticles generally refers to particles in the range of between 500 nm to less than 0.5 nm, preferably having a diameter that is between 50 and 500 nm, more preferably having a diameter that is between 50 and 300 nm. Cellular internalization of polymeric particles is highly dependent upon their size, with nanoparticulate polymeric particles being internalized by cells with much higher efficiency than micoparticulate polymeric particles. For example, Desai, et al. have demonstrated that about 2.5 times more nanoparticles that are 100 nm in diameter are taken up by cultured Caco-2 cells as compared to microparticles having a diameter on 1 µM (Desai, et al., Pharm. Res., 14:1568-73 (1997)). Nanoparticles also have a greater ability to diffuse deeper into tissues in vivo. In some embodiments, the delivery vehicle is a dendrimer. Examples of preferred biodegradable polymers include synthetic polymers that degrade by hydrolysis such as poly(hydroxy acids), such as polymers and copolymers of lactic acid and glycolic acid, other degradable polyesters, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates), poly(lactide-co-caprolactone), and poly(amine-co- ester) polymers, such as those described in Zhou, et al., Nature Materials, 11:82-90 (2012) and WO 2013/082529, U.S. Published Application No. 2014/0342003, and WO 2016/081621. In some embodiments, particularly those for targeting T cells in vivo, for example, for in vivo production of CAR T cells, immune cell or T cell markers such as CD3, CD7, or CD8, or markers of a target tissue such as the liver, can be targeted. For example, anti-CD8 antibodies and anti-CD3 Fab fragments have both been used to target T cells in vivo (Pfeiffer, et al., EMBO Mol Med., 10(11) (2018). pii: e9158. doi: 10.15252/emmm.201809158., Smith, et al., Nat Nanotechnol., 12(8):813-820 (2017). doi: 10.1038/nnano.2017.57). Thus, in some embodiments, the particle or other delivery vehicle includes a targeting moiety specific for CD3, CD7, CD8, or another immune cell (e.g., T cell) marker, or a marker for a specific tissue such as the thymus, spleen, or liver. The binding moiety can be, for example, an antibody or antigen binding fragment thereof. Targeting moieties can be associated with, linked, conjugated, or otherwise attached directly or indirectly to a nanoparticle or other delivery vehicle thereof. Targeting molecules can be proteins, peptides, nucleic acid molecules, saccharides or polysaccharides that bind to a receptor or other molecule on the surface of a targeted cell. The degree of specificity and the avidity of binding to the graft can be modulated through the selection of the targeting molecule. Examples of moieties include, for example, targeting moieties which provide for the delivery of molecules to specific cells, e.g., antibodies to hematopoietic stem cells, CD34⁺ cells, T cells or any other preferred cell type, as well as receptor and ligands expressed on the preferred cell type. Preferably, the moieties target hematopoeitic stem cells. Examples of molecules targeting extracellular matrix (“ECM”) include glycosaminoglycan (“GAG”) and collagen. In one embodiment, the external surface of polymer particles may be modified to enhance the ability of the particles to interact with selected cells or tissue. The method described above wherein an adaptor element conjugated to a targeting molecule is inserted into the particle is preferred. However, in another embodiment, the outer surface of a polymer micro- or nanoparticle having a carboxy terminus may be linked to targeting molecules that have a free amine terminus. Other useful ligands attached to polymeric micro- and nanoparticles include pathogen-associated molecular patterns (PAMPs). PAMPs target Toll-like Receptors (TLRs) on the surface of the cells or tissue, or signal the cells or tissue internally, thereby potentially increasing uptake. PAMPs conjugated to the particle surface or co-encapsulated may include: unmethylated CpG DNA (bacterial), double-stranded RNA (viral), lipopolysacharride (bacterial), peptidoglycan (bacterial), lipoarabinomannin (bacterial), zymosan (yeast), mycoplasmal lipoproteins such as MALP-2 (bacterial), flagellin (bacterial) poly(inosinic-cytidylic) acid (bacterial), lipoteichoic acid (bacterial) or imidazoquinolines (synthetic). In another embodiment, the outer surface of the particle may be treated using a mannose amine, thereby mannosylating the outer surface of the particle. This treatment may cause the particle to bind to the target cell or tissue at a mannose receptor on the antigen presenting cell surface. Alternatively, surface conjugation with an immunoglobulin molecule containing an Fc portion (targeting Fc receptor), heat shock protein moiety (HSP receptor), phosphatidylserine (scavenger receptors), and lipopolysaccharide (LPS) are additional receptor targets on cells or tissue. Lectins that can be covalently attached to micro- and nanoparticles to render them target specific to the mucin and mucosal cell layer. The choice of targeting moiety will depend on the method of administration of the nanoparticle composition and the cells or tissues to be targeted. The targeting molecule may generally increase the binding affinity of the particles for cell or tissues or may target the nanoparticle to a particular tissue in an organ or a particular cell type in a tissue. In some embodiments, the targeting moiety targets the thymus, spleen, or cancer cells. The covalent attachment of any of the natural components of mucin in either pure or partially purified form to the particles would decrease the surface tension of the bead-gut interface and increase the solubility of the bead in the mucin layer. The attachment of polyamino acids containing extra pendant carboxylic acid side groups, e.g., polyaspartic acid and polyglutamic acid, increases bioadhesiveness. Using polyamino acids in the 15,000 to 50,000 kDa molecular weight range yields chains of 120 to 425 amino acid residues attached to the surface of the particles. The polyamino chains increase bioadhesion by means of chain entanglement in mucin strands as well as by increased carboxylic charge. III. Methods of Use A. Delivery of Nucleic Acids Methods for using 4H2 antibodies to enhance delivery of nucleic acid constructs are provided. Typically an effective amount of 4H2 antibody is first contacted with a nucleic acid cargo whose delivery into cells is desired. For example, the nucleic acid cargo and antibody can be mixed in solution for sufficient time for the nucleic acid cargo and antibody to form complexes. Next, the mixture is contacted with cells. In other embodiments, the cargo and antibody are added to a solution containing or otherwise bathing cells, and the complexes are formed in the presence of the cells. The complexes can be contacted with cells in vitro, ex vivo, or in vivo. Thus, in some embodiments, the solution of complexes is added to the cells in culture or injected into an animal to be treated. The treatment can be, for example, administration of a mixture of an antibody and nucleic acid cargo to a subject in need thereof by simple IV administration. The compositions and methods can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different nucleic acid constructs formed of RNA, DNA, PNA or other modified nucleic acids, or a combination thereof. The effective amount or therapeutically effective amount of the composition can be a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of a disease or disorder, or to otherwise provide a desired pharmacologic and/or physiologic effect, for example, reducing, inhibiting, or reversing one or more of the pathophysiological mechanisms underlying a disease or disorder. An effective amount may also be an amount effective to increase the rate, quantity, and/or quality of delivery of the nucleic acid cargo relative to administration of the cargo in the absence of the antibody. The formulation of the composition is made to suit the mode of administration. Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions containing the complexes. The precise dosage will vary according to a variety of factors such as subject- dependent variables (e.g., age, immune system health, clinical symptoms etc.). The composition can be administered or otherwise contacted with target cells once, twice, or three times daily; one, two, three, four, five, six, seven times a week, one, two, three, four, five, six, seven or eight times a month. For example, in some embodiments, the composition is administered every two or three days, or on average about 2 to about 4 times about week. Thus, in some embodiments, the composition is administered as part of dosage regimen including two or more separate treatments. Dosage regimens include maintenance regimens, where the dosage remains the same between two or more administrations, escalation regimens where the dosage increases between two or more administrations, de- escalation regimens, where the dosage decreases between two or more administrations, or a combination thereof. In some embodiments, the first dose can be a low dose. Dose escalation can be continued until a satisfactory biochemical or clinical response is reached. The clinical response will depend on the disease or disorder being treated, and/or the desired outcome. In some embodiments the dosage may increase until a therapeutic effect is identified, preferably without also inducing undesired toxicity or an acceptably high amount thereof. Next, the dosages can be maintained or steadily reduced to a maintenance dose. The methods can used to standardize, optimize, or customize the dose level, dose frequency, or duration of the therapy. Generally, prior to administration, particularly for in vivo administration, antibody and nucleic acid are mixed for a period of time, e.g., at room temperature. In some embodiments, time of complexation ranges from, for example, 1 minute to 30 minutes, or 10 minutes to 20, each inclusive, with a preferred complexation time of about 15 minutes. Antibody dose can range from 0.0001 mg to 1 mg, each inclusive, with a preferred dose of about 0.1 mg. Nucleic acid dose can range from 0.001 µg to 100 µg, inclusive, with a preferred dose of 10 µg. In the experiments below, 4H2/mRNA were utilized in ratio of 1:1 w/w and 3:1 w/w, though other ratios are also contemplated. In some embodiments, antibody:nucleic acid is utilized in a ratio of e.g., 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, or 1:5 w/w. In some embodiments, RNA and/or DNA cargo is mixed with carrier DNA. Carrier DNA can be, for example, plasmid DNA or low molecular weight, from e.g., salmon sperm. In some embodiments, carrier DNA is non-coding DNA. Carrier DNA can be single stranded or double stranded or a combination thereof. In some embodiments, carrier DNA is composed of nucleic acids having 1-10, 1-100, 1-1,000, or 1-10,000 nucleotides in length, or any subrange or integer thereof, or combination thereof. Typically carrier DNA is not conjugated or otherwise covalently attached to the antibody. Typically carrier DNA is co-incubated with cargo nucleic acid and antibody, and co-delivered as a complex therewith. 1. In vitro and Ex vivo Methods For in vitro and ex vivo methods, cells are typically contacted with the composition while in culture. For ex vivo methods, cells may be isolated from a subject and contacted ex vivo with the composition to produce cells containing the cargo nucleic acid(s). In a preferred embodiment, the cells are isolated from the subject to be treated or from a syngeneic host. Target cells can be removed from a subject prior to contacting with composition. The antibody and cargo can be contacted with the cells together or separately, or as a pre-formed complex. 2. In vivo Methods In some embodiments, in vivo delivery of nucleic acid cargo to cells is used for gene editing and/or treatment of a disease or disorder in a subject. The composition, typically including antibody-nucleic acid cargo complex, can be administered directly to a subject for in vivo therapy. In general, methods of administering compounds, including antibodies, oligonucleotides and related molecules, are well known in the art. In particular, the routes of administration already in use for nucleic acid therapeutics, along with formulations in current use, provide preferred routes of administration and formulation for the donor oligonucleotides described above. Preferably the composition is injected or infused into the animal. The compositions can be administered by a number of routes including, but not limited to, intravenous, intraperitoneal, intraamniotic, intramuscular, subcutaneous, or topical (sublingual, rectal, intranasal, pulmonary, rectal mucosa, and vaginal), and oral (sublingual, buccal). In some embodiments, the composition is formulated for pulmonary delivery, such as intranasal administration or oral inhalation. Administration of the formulations may be accomplished by any acceptable method that allows the complexes to reach their targets. The administration may be localized (i.e., to a particular region, physiological system, tissue, organ, or cell type) or systemic, depending on the condition being treated. Compositions and methods for in vivo delivery are also discussed in WO 2017/143042. The methods can also include administering an effective amount of the antibody-nucleic acid complex composition to an embryo or fetus, or the pregnant mother thereof, in vivo. In some methods, compositions are delivered in utero by injecting and/or infusing the compositions into a vein or artery, such as the vitelline vein or the umbilical vein, or into the amniotic sac of an embryo or fetus. See, e.g., Ricciardi, et al., Nat Commun.2018 Jun 26;9(1):2481. doi: 10.1038/s41467-018-04894-2, and WO 2018/187493. 3. Applications Nucleic acid cargo, e.g., mRNA, functional nucleic acid, DNA expression constructs, vectors, etc., encoding a polypeptide of interest or functional nucleic acid, can be delivered into cells using a 4H2 antibody, for expression of, or inhibition of, a polypeptide in the cells. The compositions and methods can be used over a range of different applications. Non-limiting examples include CRISPR and gRNA expression vectors +/- editing DNAs, delivery of large DNAs (plasmids and expression vectors), gene replacement and gene therapy, delivery of DNAs and/or RNAs to, for example, generate CAR-T cells in vivo or ex vivo and to simplify CAR-T cell production in vivo or ex vivo, delivery of siRNAs, delivery of mRNAs, etc. Exemplary applications related to gene therapy/gene editing and immunomodulation, particularly chimeric antigen receptor T cell production, are discussed below. a. Gene Therapy and Editing In some embodiments, the compositions are used for gene editing. For example, the methods can be especially useful to treat genetic deficiencies, disorders and diseases caused by mutations in single genes, for example, to correct genetic deficiencies, disorders and diseases caused by point mutations. If the target gene contains a mutation that is the cause of a genetic disorder, then the methods can be used for mutagenic repair that may restore the DNA sequence of the target gene to normal. The target sequence can be within the coding DNA sequence of the gene or within an intron. The target sequence can also be within DNA sequences that regulate expression of the target gene, including promoter or enhancer sequences. In the methods herein, cells that have been contacted with the complexes may be administered to a subject. The subject may have a disease or disorder such as hemophilia, muscular dystrophy, globinopathies, cystic fibrosis, xeroderma pigmentosum, or lysosomal storage diseases, or inherited or acquired diseases of the retina, eye, brain, or spine, or coronary artery or other vascular disease. In such embodiments, gene modification, gene replacement, gene addition, or a combination thereof, may occur in an effective amount to reduce one or more symptoms of the disease or disorder in the subject. In some embodiments, the disclosed compositions are used in retinal gene therapy. Inherited retinal diseases (IRDs) are typically caused by single-gene mutations, and include, but are not limited to, Type 2 Leber Congenital Amaurosis (LCA), Choroideremia (CHM), Stargardt disease, Retinitis pigmentosa (e.g., mutations in RHO, USH2A, and RPGR), and X- Linked Retinoschisis (XLRS). Different routes of administration, including intravitreal, subretinal and suprachoroidal, can be used and provide different biodistribution. See also Gupta, et al., “Gene Therapy for Inherited Retinal Disease,” Review of Ophthalmology, May 10, 2022. In some embodiments, the disclosed compositions and methods are used to induce or enhance repair of damaged endothelial cells e.g., at the time of revascularization. Thus, the disclosed compositions and methods can be used an adjunct to cardiovascular surgeries and other interventions. For example, revascularization is a procedure that can restore blood flow in blocked arteries or veins. The disclosed compositions and methods may be utilized in conjunction with such interventions to, for example, to reduce the expression or bioactivity of proinflammatory cytokines such as IL-6, Il-8 and TNF-a, increase endothelial cell growth and proliferation, and/or reduce neointimal hyperplasia (e.g., growth, proliferation, migration, etc. of smooth muscle cells). In some embodiments, the disclosed compositions and methods include local delivery to, or adjacent to, a site in need of treatment. Such local sites include, but are not limited to, the brain, ears, and skin, where such delivery can be used to treat diseases associated therewith. In some embodiments, the cargo includes a nucleic acid encoding a nuclease, a donor oligonucleotide or nucleic acid encoding a donor oligonucleotide, or a combination thereof. 1. Gene Editing Nuclease Nucleic acid cargos include those that encode an element or elements that induce a single or a double strand break in the target cell’s genome, and optionally, but preferable in combination with other elements such as donor oligonucleotides and/or, particularly in the case of CRISPR/Cas, other elements of the system such as gRNA. The compositions can be used, for example, to reduce or otherwise modify expression of a target gene. (1). Strand Break Inducing Elements CRISPR/Cas In some embodiments, the nucleic acid cargo includes one or more elements of a CRISPR/Cas-mediated genome editing composition, a nucleic acid encoding one or more elements of a CRISPR/Cas-mediated genome editing composition, or a combination thereof. As used herein, CRISPR/Cas-mediated genome editing composition refers to the elements of a CRISPR system needed to carry out CRISPR/Cas-mediated genome editing in a mammalian subject. As discussed in more detail below, CRISPR/Cas-mediated genome editing compositions typically include one or more nucleic acids encoding a crRNA, a tracrRNA (or chimeric thereof also referred to a guide RNA or single guide RNA) and a Cas enzyme, such as Cas9. The CRISPR/Cas-mediated genome editing composition can optionally include a donor polynucleotide that can be recombined into the target cell’s genome at or adjacent to the target site (e.g., the site of single or double stand break induced by the Cas9). The CRISPR/Cas system has been adapted for use as gene editing (silencing, enhancing or changing specific genes) for use in eukaryotes (see, for example, Cong, Science, 15:339(6121):819–823 (2013) and Jinek, et al., Science, 337(6096):816-21 (2012)). By transfecting a cell with the required elements including a cas gene and specifically designed CRISPRs, the organism's genome can be cut and modified at any desired location. Methods of preparing compositions for use in genome editing using the CRISPR/Cas systems are described in detail in WO 2013/176772 and WO 2014/018423, which are specifically incorporated by reference herein in their entireties. The methods of delivery disclosed herein are suitable for use with numerous variations on the CRISPR/Cas system. In general, “CRISPR system” refers collectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated (“Cas”) genes, including sequences encoding a Cas gene, a tracr (trans-activating CRISPR) sequence (e.g., tracrRNA or an active partial tracrRNA), a tracr-mate sequence (encompassing a “direct repeat” and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a “spacer” in the context of an endogenous CRISPR system), or other sequences and transcripts from a CRISPR locus. One or more tracr mate sequences operably linked to a guide sequence (e.g., direct repeat-spacer- direct repeat) can also be referred to as pre-crRNA (pre-CRISPR RNA) before processing or crRNA after processing by a nuclease. As discussed in more detail below, in some embodiments, a tracrRNA and crRNA are linked and form a chimeric crRNA-tracrRNA hybrid where a mature crRNA is fused to a partial tracrRNA via a synthetic stem loop to mimic the natural crRNA:tracrRNA duplex as described in Cong, Science, 15:339(6121):819–823 (2013) and Jinek, et al., Science, 337(6096):816-21 (2012)). A single fused crRNA-tracrRNA construct is also referred to herein as a guide RNA or gRNA (or single-guide RNA (sgRNA)). Within an sgRNA, the crRNA portion can be identified as the ‘target sequence’ and the tracrRNA is often referred to as the ‘scaffold’. In some embodiments, one or more elements of a CRISPR system is derived from a type I, type II, or type III CRISPR system. In some embodiments, one or more elements of a CRISPR system is derived from a particular organism including an endogenous CRISPR system, such as Streptococcus pyogenes. In general, a CRISPR system is characterized by elements that promote the formation of a CRISPR complex at the site of a target sequence (also referred to as a protospacer in the context of an endogenous CRISPR system). In the context of formation of a CRISPR complex, “target sequence” refers to a sequence to which a guide sequence is designed to have complementarity, where hybridization between a target sequence and a guide sequence promotes the formation of a CRISPR complex. A target sequence can be any polynucleotide, such as DNA or RNA polynucleotides. In some embodiments, a target sequence is located in the nucleus or cytoplasm of a cell. In the target nucleic acid, each protospacer is associated with a protospacer adjacent motif (PAM) whose recognition is specific to individual CRISPR systems. In the Streptococcus pyogenes CRISPR/Cas system, the PAM is the nucleotide sequence NGG. In the Streptococcus thermophiles CRISPR/Cas system, the PAM is the nucleotide sequence is NNAGAAW. The tracrRNA duplex directs Cas to the DNA target consisting of the protospacer and the requisite PAM via heteroduplex formation between the spacer region of the crRNA and the protospacer DNA. Typically, in the context of an endogenous CRISPR system, formation of a CRISPR complex (including a guide sequence hybridized to a target sequence and complexed with one or more Cas proteins) results in cleavage of one or both strands in or near (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the target sequence. All or a portion of the tracr sequence may also form part of a CRISPR complex, such as by hybridization to all or a portion of a tracr mate sequence that is operably linked to the guide sequence. There are many resources available for helping practitioners determine suitable target sites once a desired DNA target sequence is identified. For example, numerous public resources, including a bioinformatically generated list of about 190,000 potential sgRNAs, targeting more than 40% of human exons, are available to aid practitioners in selecting target sites and designing the associate sgRNA to affect a nick or double strand break at the site. See also, crispr.u-psud.fr/, a tool designed to help scientists find CRISPR targeting sites in a wide range of species and generate the appropriate crRNA sequence. In some embodiments, one or more vectors driving expression of one or more elements of a CRISPR system are introduced into a target cell such that expression of the elements of the CRISPR system direct formation of a CRISPR complex at one or more target sites. For example, a Cas enzyme, a guide sequence linked to a tracr-mate sequence, and a tracr sequence could each be operably linked to separate regulatory elements on separate vectors. Alternatively, two or more of the elements expressed from the same or different regulatory elements may be combined in a single vector, with one or more additional vectors providing any components of the CRISPR system not included in the first vector. CRISPR system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5' with respect to (“upstream” of) or 3' with respect to (“downstream” of) a second element. The coding sequence of one element can be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In some embodiments, a single promoter drives expression of a transcript encoding a CRISPR enzyme and one or more of the guide sequence, tracr mate sequence (optionally operably linked to the guide sequence), and a tracr sequence embedded within one or more intron sequences (e.g., each in a different intron, two or more in at least one intron, or all in a single intron). In some embodiments, the CRISPR enzyme, guide sequence, tracr mate sequence, and tracr sequence are operably linked to and expressed from the same promoter. In some embodiments, a vector includes one or more insertion sites, such as a restriction endonuclease recognition sequence (also referred to as a “cloning site”). In some embodiments, one or more insertion sites (e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more insertion sites) are located upstream and/or downstream of one or more sequence elements of one or more vectors. In some embodiments, a vector includes an insertion site upstream of a tracr mate sequence, and optionally downstream of a regulatory element operably linked to the tracr mate sequence, such that following insertion of a guide sequence into the insertion site and upon expression the guide sequence directs sequence-specific binding of a CRISPR complex to a target sequence in a eukaryotic cell. In some embodiments, a vector includes two or more insertion sites, each insertion site being located between two tracr mate sequences so as to allow insertion of a guide sequence at each site. In such an arrangement, the two or more guide sequences can include two or more copies of a single guide sequence, two or more different guide sequences, or combinations of these. When multiple different guide sequences are used, a single expression construct may be used to target CRISPR activity to multiple different, corresponding target sequences within a cell. For example, a single vector can include about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 guide sequences. In some embodiments, about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, such guide-sequence-containing vectors may be provided, and optionally delivered to a cell. In some embodiments, a vector includes a regulatory element operably linked to an enzyme-coding sequence encoding a CRISPR enzyme, such as a Cas protein. Non-limiting examples of Cas proteins include Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csxl2), CaslO, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, homologues thereof, or modified versions thereof. In some embodiments, the unmodified CRISPR enzyme has DNA cleavage activity, such as Cas9. In some embodiments, the CRISPR enzyme directs cleavage of one or both strands at the location of a target sequence, such as within the target sequence and/or within the complement of the target sequence. In some embodiments, the CRISPR enzyme directs cleavage of one or both strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. In some embodiments, a vector encodes a CRISPR enzyme that is mutated with respect to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence. For example, an aspartate-to-alanine substitution (D10A) in the RuvC I catalytic domain of Cas9 from S. pyogenes converts Cas9 from a nuclease that cleaves both strands to a nickase (cleaves a single strand). Other examples of mutations that render Cas9 a nickase include, without limitation, H840A, N854A, and N863A. As a further example, two or more catalytic domains of Cas9 (RuvC I, RuvC II, and RuvC III) can be mutated to produce a mutated Cas9 substantially lacking all DNA cleavage activity. In some embodiments, a D10A mutation is combined with one or more of H840A, N854A, or N863A mutations to produce a Cas9 enzyme substantially lacking all DNA cleavage activity. In some embodiments, a CRISPR enzyme is considered to substantially lack all DNA cleavage activity when the DNA cleavage activity of the mutated enzyme is less than about 25%, 10%, 5%>, 1%>, 0.1 %>, 0.01%, or lower with respect to its non-mutated form. In some embodiments, an enzyme coding sequence encoding a CRISPR enzyme is codon optimized for expression in particular cells, such as eukaryotic cells. The eukaryotic cells can be those of or derived from a particular organism, such as a mammal, including but not limited to human, mouse, rat, rabbit, dog, or non-human primate. In general, codon optimization refers to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing at least one codon (e.g., about or more than about 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more codons) of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit particular bias for certain codons of a particular amino acid. Codon bias (differences in codon usage between organisms) often correlates with the efficiency of translation of messenger RNA (mRNA), which is in turn believed to be dependent on, among other things, the properties of the codons being translated and the availability of particular transfer RNA (tRNA) molecules. The predominance of selected tRNAs in a cell is generally a reflection of the codons used most frequently in peptide synthesis. Accordingly, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are readily available, for example, at the “Codon Usage Database”, and these tables can be adapted in a number of ways. See Nakamura, Y., et al., Nucl. Acids Res., 28:292 (2000). Computer algorithms for codon optimizing a particular sequence for expression in a particular host cell, for example Gene Forge (Aptagen; Jacobus, PA), are also available. In some embodiments, one or more codons (e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more, or all codons) in a sequence encoding a CRISPR enzyme correspond to the most frequently used codon for a particular amino acid. In some embodiments, a vector encodes a CRISPR enzyme including one or more nuclear localization sequences (NLSs). When more than one NLS is present, each may be selected independently of the others, such that a single NLS may be present in more than one copy and/or in combination with one or more other NLSs present in one or more copies. In some embodiments, an NLS is considered near the N- or C-terminus when the nearest amino acid of the NLS is within about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 40, 50, or more amino acids along the polypeptide chain from the N-or C- terminus. In general, the one or more NLSs are of sufficient strength to drive accumulation of the CRISPR enzyme in a detectable amount in the nucleus of a eukaryotic cell. In general, strength of nuclear localization activity may derive from the number of NLSs in the CRISPR enzyme, the particular NLS(s) used, or a combination of these factors. Detection of accumulation in the nucleus may be performed by any suitable technique. For example, a detectable marker may be fused to the CRISPR enzyme, such that location within a cell may be visualized, such as in combination with a means for detecting the location of the nucleus (e.g., a stain specific for the nucleus such as DAPI). Cell nuclei may also be isolated from cells, the contents of which may then be analyzed by any suitable process for detecting protein, such as immunohistochemistry, Western blot, or enzyme activity assay. Accumulation in the nucleus may also be determined indirectly, such as by an assay for the effect of CRISPR complex formation (e.g., assay for DNA cleavage or mutation at the target sequence, or assay for altered gene expression activity affected by CRISPR complex formation and/or CRISPR enzyme activity), as compared to a control no exposed to the CRISPR enzyme or complex, or exposed to a CRISPR enzyme lacking the one or more NLSs. In some embodiments, one or more of the elements of CRISPR system are under the control of an inducible promoter, which can include inducible Cas, such as Cas9. Cong, Science, 15:339(6121):819–823 (2013) reported heterologous expression of Cas9, tracrRNA, pre-crRNA (or Cas9 and sgRNA) can achieve targeted cleavage of mammalian chromosomes. Therefore, CRISPR system utilized in the methods disclosed herein, and thus the cargo nucleic acid, be a vector system which can include one or more vectors encoding elements of the CRISPR system which can include a first regulatory element operably linked to a CRISPR/Cas system chimeric RNA (chiRNA) polynucleotide sequence, wherein the polynucleotide sequence includes (a) a guide sequence capable of hybridizing to a target sequence in a eukaryotic cell, (b) a tracr mate sequence, and (c) a tracr sequence; and a second regulatory element operably linked to an enzyme-coding sequence encoding a CRISPR enzyme which can optionally include at least one or more nuclear localization sequences. Elements (a), (b) and (c) can be arranged in a 5' to 3 orientation, wherein Cas9 and CRISPR RNA are located on the same or different vectors of the system, wherein when transcribed, the tracr mate sequence hybridizes to the tracr sequence and the guide sequence directs sequence-specific binding of a CRISPR complex to the target sequence, and wherein the CRISPR complex can include the CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the tracr mate sequence that is hybridized to the tracr sequence, wherein the enzyme coding sequence encoding the CRISPR enzyme further encodes a heterologous functional domain. In some embodiments, one or more of the vectors also encodes a suitable Cas enzyme, for example, Cas9. The different genetic elements can be under the control of the same or different promoters. While the specifics can be varied in different engineered CRISPR systems, the overall methodology is similar. A practitioner interested in using CRISPR technology to target a DNA sequence (identified using one of the many available online tools) can insert a short DNA fragment containing the target sequence into a guide RNA expression plasmid. The sgRNA expression plasmid contains the target sequence (about 20 nucleotides), a form of the tracrRNA sequence (the scaffold) as well as a suitable promoter and necessary elements for proper processing in eukaryotic cells. Such vectors are commercially available (see, for example, Addgene). Many of the systems rely on custom, complementary oligos that are annealed to form a double stranded DNA and then cloned into the sgRNA expression plasmid. Co-expression of the sgRNA and the appropriate Cas enzyme from the same or separate plasmids in transfected cells results in a single or double strand break (depending of the activity of the Cas enzyme) at the desired target site. (2) Zinc Finger Nucleases In some embodiments, the element that induces a single or a double strand break in the target cell’s genome is a nucleic acid construct or constructs encoding a zinc finger nucleases (ZFNs). Thus, the nucleic acid cargo can encode a ZFN. ZFNs are typically fusion proteins that include a DNA-binding domain derived from a zinc-finger protein linked to a cleavage domain. The most common cleavage domain is the Type IIS enzyme Fokl. Fok1 catalyzes double-stranded cleavage of DNA, at 9 nucleotides from its recognition site on one strand and 13 nucleotides from its recognition site on the other. See, for example, U.S. Pat. Nos.5,356,802; 5,436, 150 and 5,487,994; as well as Li et al. Proc., Natl. Acad. Sci. USA 89 (1992):4275- 4279; Li et al. Proc. Natl. Acad. Sci. USA, 90:2764-2768 (1993); Kim et al. Proc. Natl. Acad. Sci. USA.91:883-887 (1994a); Kim et al. J. Biol. Chem. 269:31 ,978-31,982 (1994b). One or more of these enzymes (or enzymatically functional fragments thereof) can be used as a source of cleavage domains. The DNA-binding domain, which can, in principle, be designed to target any genomic location of interest, can be a tandem array of Cys2His2 zinc fingers, each of which generally recognizes three to four nucleotides in the target DNA sequence. The Cys2His2 domain has a general structure: Phe (sometimes Tyr)-Cys-(2 to 4 amino acids)-Cys-(3 amino acids)- Phe(sometimes Tyr)-(5 amino acids)-Leu-(2 amino acids)-His-(3 amino acids)-His. By linking together multiple fingers (the number varies: three to six fingers have been used per monomer in published studies), ZFN pairs can be designed to bind to genomic sequences 18-36 nucleotides long. Engineering methods include, but are not limited to, rational design and various types of empirical selection methods. Rational design includes, for example, using databases including triplet (or quadruplet) nucleotide sequences and individual zinc finger amino acid sequences, in which each triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of zinc fingers which bind the particular triplet or quadruplet sequence. See, for example, U.S. Pat. Nos.6, 140,081; 6,453,242; 6,534,261; 6,610,512; 6,746,838; 6,866,997; 7,067,617; U.S. Published Application Nos.2002/0165356; 2004/0197892; 2007/0154989; 2007/0213269; and International Patent Application Publication Nos. WO 98/53059 and WO 2003/016496. (3). Transcription Activator-Like Effector Nucleases In some embodiments, the element that induces a single or a double strand break in the target cell’s genome is a nucleic acid construct or constructs encoding a transcription activator-like effector nuclease (TALEN). Thus, the nucleic acid cargo can encode a TALEN. TALENs have an overall architecture similar to that of ZFNs, with the main difference that the DNA-binding domain comes from TAL effector proteins, transcription factors from plant pathogenic bacteria. The DNA- binding domain of a TALEN is a tandem array of amino acid repeats, each about 34 residues long. The repeats are very similar to each other; typically they differ principally at two positions (amino acids 12 and 13, called the repeat variable diresidue, or RVD). Each RVD specifies preferential binding to one of the four possible nucleotides, meaning that each TALEN repeat binds to a single base pair, though the NN RVD is known to bind adenines in addition to guanine. TAL effector DNA binding is mechanistically less well understood than that of zinc-finger proteins, but their seemingly simpler code could prove very beneficial for engineered-nuclease design. TALENs also cleave as dimers, have relatively long target sequences (the shortest reported so far binds 13 nucleotides per monomer) and appear to have less stringent requirements than ZFNs for the length of the spacer between binding sites. Monomeric and dimeric TALENs can include more than 10, more than 14, more than 20, or more than 24 repeats. Methods of engineering TAL to bind to specific nucleic acids are described in Cermak, et al, Nucl. Acids Res.1-11 (2011). US Published Application No.2011/0145940, which discloses TAL effectors and methods of using them to modify DNA. Miller et al. Nature Biotechnol 29: 143 (2011) reported making TALENs for site-specific nuclease architecture by linking TAL truncation variants to the catalytic domain of Fokl nuclease. The resulting TALENs were shown to induce gene modification in immortalized human cells. General design principles for TALE binding domains can be found in, for example, WO 2011/072246. ii. Donor Polynucleotides The nuclease activity of the genome editing systems described herein cleave target DNA to produce single or double strand breaks in the target DNA. Double strand breaks can be repaired by the cell in at least two ways: non-homologous end joining, and homology- directed repair. In non- homologous end joining (NHEJ), the double-strand breaks are repaired by direct ligation of the break ends to one another. As such, no new nucleic acid material is inserted into the site, although some nucleic acid material may be lost, resulting in a deletion. In homology-directed repair (HDR), a donor polynucleotide with homology to the cleaved target DNA sequence is used as a template for repair of the cleaved target DNA sequence, resulting in the transfer of genetic information from a donor polynucleotide to the target DNA. As such, new nucleic acid material can be inserted/copied into the site. Therefore, in some embodiments, the nucleic acid cargo is or includes a donor polynucleotide. The modifications of the target DNA due to NHEJ and/or homology-directed repair can be used to induce gene correction, gene replacement, gene tagging, transgene insertion, nucleotide deletion, gene disruption, gene mutation, etc. Accordingly, cleavage of DNA by the genome editing composition can be used to delete nucleic acid material from a target DNA sequence by cleaving the target DNA sequence and allowing the cell to repair the sequence in the absence of an exogenously provided donor polynucleotide. Alternatively, if the genome editing composition includes a donor polynucleotide sequence that includes at least a segment with homology to the target DNA sequence, the methods can be used to add, i.e., insert or replace, nucleic acid material to a target DNA sequence (e.g., to “knock in” a nucleic acid that encodes for a protein, an siRNA, an miRNA, etc.), to add a tag (e.g., 6xHis, a fluorescent protein (e.g., a green fluorescent protein; a yellow fluorescent protein, etc.), hemagglutinin (HA), FLAG, etc.), to add a regulatory sequence to a gene (e.g., promoter, polyadenylation signal, internal ribosome entry sequence (IRES), 2A peptide, start codon, stop codon, splice signal, localization signal, etc.), to modify a nucleic acid sequence (e.g., introduce a mutation), and the like. As such, the compositions can be used to modify DNA in a site- specific, i.e., “targeted”, way, for example gene knock-out, gene knock-in, gene editing, gene tagging, etc. as used in, for example, gene therapy. In applications in which it is desirable to insert a polynucleotide sequence into a target DNA sequence, a polynucleotide including a donor sequence to be inserted is also provided to the cell. By a “donor sequence” or “donor polynucleotide” or “donor oligonucleotide” it is meant a nucleic acid sequence to be inserted at the cleavage site. The donor polynucleotide typically contains sufficient homology to a genomic sequence at the cleavage site, e.g., 70%, 80%, 85%, 90%, 95%, or 100% homology with the nucleotide sequences flanking the cleavage site, e.g., within about 50 bases or less of the cleavage site, e.g., within about 30 bases, within about 15 bases, within about 10 bases, within about 5 bases, or immediately flanking the cleavage site, to support homology-directed repair between it and the genomic sequence to which it bears homology. The donor sequence is typically not identical to the genomic sequence that it replaces. Rather, the donor sequence may contain at least one or more single base changes, insertions, deletions, inversions or rearrangements with respect to the genomic sequence, so long as sufficient homology is present to support homology-directed repair. In some embodiments, the donor sequence includes a non-homologous sequence flanked by two regions of homology, such that homology-directed repair between the target DNA region and the two flanking sequences results in insertion of the non-homologous sequence at the target region. b. Immunomodulation i. CAR T Cells The disclosed compositions and methods are particularly useful in the context of preparing lymphocytes expressing immune receptors, particularly chimeric immune receptors (CIR) such as chimeric antigen receptors (CAR). Artificial immune receptors (also known and referred to herein, as chimeric T cell receptors, chimeric immunoreceptors, chimeric antigen receptors (CARs), and chimeric immune receptors (CIR)) are engineered receptors, which graft a selected specificity onto a cell. Cells modified according to the discussed methods can be utilized, as discussed in more detail below, in a variety of immune therapies for treatment of cancers, infections, inflammation, and autoimmune diseases. In particularly preferred embodiments, mRNA or DNA encoding a chimeric antigen receptor cargo is delivered to immune cells, such as lymphocytes. The cargo can be delivered to immune cells in vivo, ex vivo, or in vitro. In preferred embodiments, the cargo is mRNA, which may allow for one or more of reduced cost, ease of manufacturing, reduced side effects (e.g., cytokine storm, neurotoxicity, graft vs. host diseases, etc.). In particular embodiments, immune cells (e.g., T cells) are harvested from a subject in need of CAR T cell therapy, the compositions and methods disclosed herein are used to deliver mRNA encoding one or more CAR T cell constructs into the harvested cells, and the cells are returned to the subject. In some embodiments, the process, from initially harvesting the cells to returning them to the subject, takes 1 week or less, for example, 1, 2, 3, 4, 5, 6, or 7 days. In particular embodiments, the process, from initially harvesting the cells to returning them to subject is carried in out in 1 or 2 days, or in less than 1 days, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours. Strategies for the design and development of chimeric antigen receptors are reviewed in Dotti, et al., Immunol Rev.2014 January; 257(1): . doi:10.1111/imr.12131 (35 pages), which is a specifically incorporated by reference herein in its entirety, as well as Dotti, Molecular Therapy, 22(5):899-890 (2014), Karlsson, et al., Cancer Gene Therapy, 20:386-93 (2013), Charo, et al., Cancer Res., 65(5):2001-8 (2005), Jensen, et al., Immunol Rev., 257(1): 127–144 (2014), Eaton, et al., Gene Therapy, 9:527- 35 (2002), Barrett, et al., Annu Rev Med., 65: 333–347 (2014), Cartellieri, et al., Journal of Biomedicine and Biotechnology, Volume 2010, Article ID 956304, 13 pages doi:10.1155/2010/956304; and U.S. Published Application Nos.2015/0017120, 2015/0283178, 2015/0290244, 2014/0050709, and 2013/0071414. CARs combine the antigen-binding property of monoclonal antibodies with the lytic capacity and self-renewal of T cells and have several advantages over conventional T cells (Ramos and Dotti, Expert Opin Biol Ther., 11:855–873 (2011), Curran, et al., J Gene Med., 14:405–415 (2012), Maher, ISRN Oncol.2012:278093 (2012)). CAR-T cells recognize and kill cancer cells independently of the major histocompatibility complex (MHC). Thus target cell recognition is unaffected by some of the mechanisms by which tumors evade MHC-restricted T-cell recognition, for example downregulation of human leukocyte antigen (HLA) class I molecules and defective antigen processing. Chimeric immune receptors were initially developed in the 1980s and originally included the variable (antigen binding) regions of a monoclonal antibody and the constant regions of the T-cell receptor (TCR) α and β chains (Kuwana, et al., Biochem Biophys Res Commun., 149:960–968 (1987)). In 1993 this design was modified to include an ectodomain, from a single chain variable fragment (scFv) from the antigen binding regions of both heavy and light chains of a monoclonal antibody, a transmembrane domain, and an endodomain with a signaling domain derived from CD3-ζ. Later CARs have generally followed a similar structural design, with a co- stimulatory signaling endodomain. Accordingly, the CAR constructs utilized in the methods herein can include an antigen binding domain or ectodomain, a hinge domain, a transmembrane domain, an endodomain, and combinations thereof. In some embodiments the ectodomain is an scFv. The affinity of the scFv predicts CAR function (Hudecek, et al., Clin Cancer Res., 19(12):3153- 64 (2013), Chmielewski, et al., J Immunol., 173:7647–7653 (2004)). Antigen binding and subsequent activation can also be modified by adding a flexible linker sequence in the CAR, which allows for expression of two distinct scFvs that can recognize two different antigens (Grada, et al., Mol Ther Nucleic Acids, 2:e105 (2013)) (referred to as tandem CARs (TanCARs)). Tandem CARS may be more effective in killing cancers expressing low levels of each antigen individually and may also reduce the risk of tumor immune escape due by single antigen loss variants. Other ectodomains include IL13Rα2 (Kahlon, et al., Cancer Res., 64:9160–9166 (2004), Brown, et al., Clin Cancer Res., 18(8):2199-209 (2012), Kong, et al., Clin Cancer Res., 18:5949–5960 (2012), NKG2D-ligand and CD70 receptor, peptide ligands (e.g., T1E peptide ligand), and so-called “universal ectodomains” (e.g., avidin ectodomain designed to recognize targets that have been contacted with biotinylated monoclonal antibodies, or FITC- specific scFv designed to recognize targets that have been contacted with FITC-labeled monoclonal antibodies (Zhang, et al., Blood, 106:1544–1551 (2005), Barber, et al., Exp Hematol., 36:1318–1328 (2008), Shaffer , et al., Blood, 117:4304–4314 (2011), Davies, et al., Mol Med., 18:565–576 (2012), Urbanska, et al., Cancer Res., 72:1844–1852 (2012), Tamada, et al., Clin Cancer Res.,18:6436–6445 (2012)). In some embodiments, the CAR includes a hinge region. While the ectodomain is important for CAR specificity, the sequence connecting the ectodomain to the transmembrane domain (the hinge region) can also influence CAR-T-cell function by producing differences in the length and flexibility of the CAR. Hinges can include, for example, a CH2CH3 hinge, or a fragment thereof, derived from an immunoglobulin such as IgG1. For example, Hudecek et al. (Hudecek, et al., Clin Cancer Res., 19(12):3153-64 (2013)) compared the influence of a CH2-CH3 hinge [229 amino acids (AA)], CH3 hinge (119 AA), and short hinge (12AA) on the effector function of T cells expressing 3rd generation ROR1-specific CARs and found that T cells expressing ‘short hinge’ CARs had superior antitumor activity, while other investigators found that a CH2-CH3 hinge impaired epitope recognition of a 1st generation CD30-specific CAR (Hombach, et al., Gene Ther., 7:1067–1075 (2000)). Between the hinge (or ectodomain if no hinge domain) and the signaling endodomains typically lies a transmembrane domain, most typically derived from CD3-ζ, CD4, CD8, or CD28 molecules. Like hinges, the transmembrane domain can also influence CAR-T-cell effector function. Upon antigen recognition, CAR endodomains transmit activation and costimulatory signals to T cells. T-cell activation relies on the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domain to the cytoplasmic CD3-ζ domain of the TCR complex (Irving, et al., Cell, 64:891–901 (1991)). Although the majority of CAR endomains contain an activation domain derived from CD3-ζ, others can include ITAM-containing domains such as the Fc receptor for IgE-γ domain (Haynes, et al., J Immunol., 166:182–187 (2001)). The target specificity of the cell expressing a CAR is determined by the antigen recognized by the antibody/ectodomain. The disclosed compositions and methods can be used to create constructs, and cells expressing the constructs, that target any antigen. In the context of immunotherapy, particularly cancer immunotherapy, numerous antigens, and suitable ectodomains for targeting them, are well known. Unlike the native TCR, the majority of scFv-based CARs recognize target antigens expressed on the cell surface rather than internal antigens that are processed and presented by the cells’ MHC, however, CARs have the advantage over the classical TCR that they can recognize structures other than protein epitopes, including carbohydrates and glycolipids Dotti, et al., Immunol Rev.2014 January ; 257(1): . doi:10.1111/imr.12131 (35 pages) thus increasing the pool of potential target antigens. Preferred targets include antigens that are only expressed on cancer cells or their surrounding stroma (Cheever, et al., Clin Cancer Res.,15:5323–5337 (2009)), such as the splice variant of EGFR (EGFRvIII), which is specific to glioma cells (Sampson, et al., Semin Immunol., 20(5):267-75 (2008)). However, human antigens meet this requirement, and the majority of target antigens are expressed either at low levels on normal cells (e.g. GD2, CAIX, HER2) and/or in a lineage restricted fashion (e.g. CD19, CD20). Preferred targets, and CARs that target them are known in the art (see, e.g., Dotti, et al., Immunol Rev.2014 January ; 257(1): . doi:10.1111/imr.12131 (35 pages). For example, CAR targets for hematological malignancies include, but are not limited to, CD 19 (e.g., B- cell) (Savoldo, et al., J Clin Invest., 121:1822-1826 (2011), Cooper, et al., Blood, 105:1622-1631 (2005); Jensen, et al., Biol Blood Marrow Transplant (2010), Kochenderfer, et al., Blood, 119:2709-2720 (2012), Brentjens, et al., Molecular Therapy, 17:S157 (2009), Brentjens, et al., Nat Med., 9:279-286 (2003), Brentjens, et al., Blood, 118:4817-4828 (2011), Porter, et al., N Engl J Med., 365:725-733 (2011), Kalos, et al., Sci Transl Med., 3:95ra73 (2011), Brentjens, et al., Sci Transl Med., 5:177ra38 (2013), Grupp, et al., N Engl J Med (2013)); CD20 (e.g., B-cell) (Jensen, et al., Biol Blood Marrow Transplant (2010), Till, et al., Blood, 112:2261-2271 (2008), Wang, et al., Hum Gene Ther., 18:712-725 (2007), Wang, et al., Mol Ther., 9:577-586 (2004), Jensen, et al., Biol Blood Marrow Transplant, 4:75-83 (1998)); CD22 (e.g., B-cell) (Haso, et al., Blood, 121:1165-1174 (2013)); CD30 (e.g., B-cell) (Di Stasi, et al., Blood, 113:6392-6402 (2009), Savoldo, et al., Blood, 110:2620-2630 (2007), Hombach, et al., Cancer Res., 58:1116-1119 (1998)); CD33 (e.g., Myeloid) (Finney, et al., J Immunol., 161:2791-2797 (1998)); CD70 (e.g., B-cell/T-cell) (Shaffer, et al., Blood, 117:4304-4314 (2011)); CD123 (e.g., Myeloid) (Tettamanti, et al., Br J Haematol., 161:389-401 (2013)); Kappa (e.g., B-cell) (Vera, et al., Blood, 108:3890-3897 (2006)); Lewis Y (e.g., Myeloid) (Peinert, et al., Gene Ther., 17:678-686 (2010), Ritchie, et al., Mol Ther. (2013)); NKG2D ligands (e.g., Myeloid) (Barber, et al., Exp Hematol., 36:1318-1328 (2008), Lehner, et al., PLoS One., 7:e31210 (2012), Song, et al., Hum Gene Ther., 24:295-305 (2013), Spear, et al., J Immunol.188:6389-6398 (2012)); ROR1 (e.g., B-cell) (Hudecek, et al., Clin Cancer Res. (2013)). CAR targets for solid tumors include, but are not limited to, B7H3 (e.g., sarcoma, glioma) (Cheung, et al., Hybrid Hybridomics, 22:209–218 (2003)); CAIX (e.g., kidney) (Lamers, et al., J Clin Oncol., 24:e20–e22. (2006)), Weijtens, et al., Int J Cancer, 77:181–187 (1998)); CD44 v6/v7 (e.g., cervical) (Hekele, et al., Int J Cancer, 68:232-238 (1996)), Dall, et al., Cancer Immunol Immunother, 54:51-60 (2005); CD171 (e.g., neuroblastoma) (Park, et al., Mol Ther., 15:825-833 (2007)); CEA (e.g., colon) (Nolan, et al., Clin Cancer Res., 5:3928-3941 (1999)); EGFRvIII (e.g., glioma) (Bullain, et al., J Neurooncol. (2009), Morgan, et al., Hum Gene Ther., 23:1043-1053 (2012)); EGP2 (e.g., carcinomas) (Meier, et al., Magn Reson Med., 65:756-763 (2011), Ren-Heidenreich, et al., Cancer Immunol Immunother., 51:417-423 (2002)); EGP40 (e.g., colon) (Daly, et al., Cancer Gene Ther., 7:284-291 (2000); EphA2 (e.g., glioma, lung) (Chow, et al., Mol Ther., 21:629-637 (2013)); ErbB2(HER2) (e.g., breast, lung, prostate, glioma) (Zhao, et al., J Immunol., 183:5563-5574 (2009), Morgan, et al., Mol Ther., 18:843-851 (2010), Pinthus, et al., 114:1774-1781 (2004), Teng, et al., Hum Gene Ther., 15:699-708 (2004), Stancovski, et al., J Immunol., 151:6577-6582 (1993), Ahmed, et al., Mol Ther., 17:1779-1787 (2009), Ahmed, et al., Clin Cancer Res., 16:474-485 (2010), Moritz, et al., Proc Natl Acad Sci U.S.A., 91:4318-4322 (1994)); ErbB receptor family (e.g., breast, lung, prostate, glioma) (Davies, et al., Mol Med., 18:565-576 (2012)); ErbB3/4 (e.g., breast, ovarian) (Muniappan, et al., Cancer Gene Ther., 7:128-134 (2000), Altenschmidt, et al., Clin Cancer Res., 2:1001-1008 (1996)); HLA-A1/MAGE1 (e.g., melanoma) (Willemsen, et al., Gene Ther., 8:1601-1608 (2001), Willemsen, et al., J Immunol., 174:7853-7858 (2005)); HLA-A2/NY-ESO-1 (e.g., sarcoma, melanoma) (Schuberth, et al., Gene Ther., 20:386-395 (2013)); FR-ɑ (e.g., ovarian) (Hwu, et al., J Exp Med., 178:361-366 (1993), Kershaw, et al., Nat Biotechnol., 20:1221-1227 (2002), Kershaw, et al., Clin Cancer Res., 12:6106-6115 (2006), Hwu, et al., Cancer Res., 55:3369-3373 (1995)); FAP (e.g., cancer associated fibroblasts) (Kakarla, et al., Mol Ther. (2013)); FAR (e.g., rhabdomyosarcoma) (Gattenlohner, et al., Cancer Res., 66:24-28 (2006)); GD2 (e.g., neuroblastoma, sarcoma, melanoma) (Pule, et al., Nat Med., 14:1264-1270 (2008), Louis, et al., Blood, 118:6050-6056 (2011), Rossig, et al., Int J Cancer., 94:228-236 (2001)); GD3 (e.g., melanoma, lung cancer) (Yun, et al., Neoplasia., 2:449-459 (2000)); HMW-MAA (e.g., melanoma) (Burns, et al., Cancer Res., 70:3027-3033 (2010)); IL11Rɑ (e.g., osteosarcoma) (Huang, et al., Cancer Res., 72:271-281 (2012)); IL13Rɑ2 (e.g., glioma) (Kahlon, et al., Cancer Res., 64:9160-9166 (2004), Brown, et al., Clin Cancer Res. (2012), Kong, et al., Clin Cancer Res., 18:5949-5960 (2012), Yaghoubi, et al., Nat Clin Pract Oncol., 6:53-58 (2009)); Lewis Y (e.g., breast/ovarian/pancreatic) (Peinert, et al., Gene Ther., 17:678-686 (2010), Westwood, et al., Proc Natl Acad Sci U.S.A., 102:19051-19056 (2005), Mezzanzanica, et al., Cancer Gene Ther., 5:401-407 (1998)); Mesothelin (e.g., mesothelioma, breast, pancreas) (Lanitis, et al., Mol Ther., 20:633-643 (2012), Moon, et al., Clin Cancer Res., 17:4719-4730 (2011)); Mue1 (e.g., ovarian, breast, prostate) (Wilkie, et al., J Immunol., 180:4901-4909 (2008)); NCAM (e.g., neuroblastoma, colorectal) (Gilham, et al., J Immunother., 25:139-151 (2002)); NKG2D ligands (e.g., ovarian, sacoma) (Barber, et al., Exp Hematol., 36:1318-1328 (2008), Lehner, et al., PLoS One, 7:e31210 (2012), Song, et al., Gene Ther., 24:295-305 (2013), Spear, et al., J Immunol., 188:6389-6398 (2012)); PSCA (e.g., prostate, pancreatic) (Morgenroth, et al., Prostate, 67:1121-1131 (2007), Katari, et al., HPB, 13:643-650 (2011)); PSMA (e.g., prostate) (Maher, et al., Nat Biotechnol., 20:70-75 (2002), Gong, et al., Neoplasia., 1:123-127 (1999)); TAG72 (e.g., colon) (Hombach, et al., Gastroenterology, 113:1163-1170 (1997), McGuinness, et al., Hum Gene Ther., 10:165-173 (1999)); VEGFR-2 (e.g., tumor vasculature) (J Clin Invest., 120:3953-3968 (2010), Niederman, et al., Proc Natl Acad Sci U.S.A., 99:7009-7014 (2002)). ii. Metabolic Stability In some embodiments, cells’ (e.g., CAR cells’) metabolic stability is improved by equipping them with the capacity to make the very growth factors that are limiting in vivo. In some embodiments, nucleic acid cargo encoding an anti-apoptotic factor such as BCL-XL is transiently delivered to cells. B-cell lymphoma-extra large (Bcl-XL, or BCL2-like 1 isoform 1) is a transmembrane protein in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as a pro-survival protein in the intrinsic apoptotic pathway by preventing the release of mitochondrial contents such as cytochrome c, which would lead to caspase activation. Both amino acid and nucleic acid sequences encoding BCL-XL are known in the art and include, for example, UniProtKB - Q07817 (B2CL1_HUMAN), Isoform Bcl-X(L) (identifier: Q07817-1) (amino acid sequence); ENA|U72398|U72398.1 Human Bcl-x beta (bcl-x) gene, complete cds (genomic nucleic acid sequences); ENA|Z23115|Z23115.1 H.sapiens bcl-XL mRNA (mRNA/cDNA nucleic acid sequences). In some embodiments, the nucleic cargo encodes a proliferation inducing factor such as IL-2. Both amino acid and nucleic acid sequences encoding IL-2 are known in the art and include, for example, UniProtKB - P60568 (IL2_HUMAN) (amino acid sequence); ENA|X00695|X00695.1 Human interleukin-2 (IL-2) gene and 5'-flanking region (genic nucleic acid sequence); and ENA|V00564|V00564.1 Human mRNA encoding interleukin- 2 (IL-2) (mRNA/cDNA nucleic acid sequence). However, the production of secreted IL-2 may have the unwanted side effect of also stimulating the proliferation of the lymphoma and Treg cells, and impairing the formation of memory T cells (Zhang, et al., Nature Medicine, 11:1238-1243 (2005)). In addition, the use of IL-2 in patients treated with Tumor Infiltrating Lymphocytes (TILs) led to increased toxicity (Heemskerk, et al., Human Gene Therapy, 19:496-510 (2008)). To avoid this potentiality, in addition or alternative to IL-2, the nucleic acid cargo can encode a chimeric γc cytokine receptor (CγCR) such as one composed of Interleukin-7 (IL-7) tethered to IL-7Rα/CD127 that confers exogenous cytokine independent, cell intrinsic, STAT5 cytokine signals (Hunter, et al., Molecular Immunology, 56:1-11 (2013)). The design is modular in that the IL-2Rβ/CD122 cytoplasmic chain can be exchanged for that of IL- 7Rα/CD127, to enhance Shc activity. The constructs mimic wild type IL-2 signaling in human CD8+ T cells (Hunter, et al., Molecular Immunology, 56:1-11 (2013)) and should, therefore, work similarly to the IL-2 mRNA, without the unwanted to side effects. Additionally and alternatively other antiapoptotic molecules and cytokines can be used to preserve cell viability in the native state. Exemplary factors include, but are not limited to: Myeloid Cell Leukemia 1 (MCL-1) (e.g., UniProtKB - Q07820 (MCL1_HUMAN) (amino acid sequence); ENA|AF147742|AF147742.1 Homo sapiens myeloid cell differentiation protein (MCL1) gene, promoter and complete cds (genomic nucleic acid sequence); ENA|AF118124|AF118124.1 Homo sapiens myeloid cell leukemia sequence 1 (MCL1) mRNA, complete cds. (mRNA/cDNA nucleic acid sequence)) which is an antiapoptotic factor; IL-7 (e.g., UniProtKB - P13232 (IL7_HUMAN) (amino acid sequence); ENA|EF064721|EF064721.1 Homo sapiens interleukin 7 (IL7) gene, complete cds. (genomic nucleic acid sequence); ENA|J04156|J04156.1 Human interleukin 7 (IL-7) mRNA, complete cds. (mRNA/cDNA nucleic acid sequence) which is important for T cell survival and development, and IL-15 (e.g., UniProtKB - P40933 (IL15_HUMAN) (amino acid sequence); ENA|X91233|X91233.1 H.sapiens IL15 gene (genomic nucleic acid sequence); ENA|U14407|U14407.1 Human interleukin 15 (IL15) mRNA, complete cds. (mRNA/cDNA nucleic acid sequence)) which promotes T and NK cell survival (Opferman, et al., Nature, 426: 671-676 (2003); Meazza, et al., Journal of Biomedicine & Biotechnology, 861920, doi:10.1155/2011/861920 (2011); Michaud, et al., Journal of Immunotherapy, 33:382-390 (2010)). These cytokine mRNAs can be used either independently or in combination with BCL-XL, IL-2, and/or CγCR mRNA. Accordingly, in some embodiments, an mRNA encoding MCL-1, IL-7, IL-15, or a combination thereof is delivered to cells. iii. Inhibitory CAR (iCAR) In some embodiments, T cell therapies are delivered to the CAR cells that have demonstrated long-term efficacy and curative potential for the treatment of some cancers, however, their use is limited by damage to non- cancerous tissues reminiscent of graft-versus-host disease after donor lymphocyte infusion. Any of the disclosed compositions and methods can be used in combination with a non-specific immunosuppression (e.g., high-dose corticosteroid therapy, which exert cytostatic or cytotoxic effects on T cells, to restrain immune responses), irreversible T cell elimination (e.g., so-called suicide gene engineering strategies), or a combination thereof. However, in some preferred embodiments, off-target effects are reduced by introducing into the CAR cell a construct encoding an inhibitory chimeric antigen receptor (iCAR). T cells with specificity for both tumor and off-target tissues can be restricted to tumor only by using an antigen-specific iCAR introduced into the T cells to protect the off-target tissue (Fedorov, et al., Science Translational Medicine, 5:215ra172 (2013)). The iCAR can include a surface antigen recognition domain combined with a powerful acute inhibitory signaling domain to limit T cell responsiveness despite concurrent engagement of an activating receptor (e.g., a CAR). In preferred embodiments, the iCAR includes a single-chain variable fragment (scFv) specific for an inhibitory antigen fused to the signaling domains of an immunoinhibitory receptor (e.g., CTLA-4, PD-1, LAG-3, 2B4 (CD244), BTLA (CD272), KIR, TIM-3, TGF beta receptor dominant negative analog etc.) via a transmembrane region that inhibits T cell function specifically upon antigen recognition. Once the CAR cell encounters a cell (e.g., a cancer cell) that does not express the inhibitory antigen, iCAR-transduced T cells can mount a CAR-induced response against the CAR’s target antigen. A DNA iCAR using an scFv specific for PSMA with the inhibitory signaling domains of either CTLA-4 or PD-1 is discussed in (Fedorov, et al., Science Translational Medicine, 5:215ra172 (2013)). Design considerations include that observation that PD-1 was a stronger inhibitor than CTLA-4, CTLA-4 exhibited cytoplasmic localization unless a Y165G mutant was used, and that the iCAR expression level is important. iCAR can be designed against cell type specific surface molecules. In some embodiments the iCAR is designed to prevent T cells, NK cells, or other immune cell reactivity against certain tissues or cell types. iv. Reducing Endogenous Inhibitory Signaling In some embodiments the cells are contacted with a nucleic acid cargo that reprograms the cells to prevent expression of one or more antigens. For example, in some embodiments the nucleic acid cargo is or encodes an interfering RNA that prevents expression of an mRNA encoding antigens such as CTLA-4 or PD-1. This method can be used to prepare universal donor cells. RNAs used to alter the expression of allogenic antigens may be used alone or in combination with RNAs that result in de- differentiation of the target cell. Although the section above provides compositions and methods that utilized inhibitory signaling domains e.g., from CTLA-4 or PD-1 in an artificial iCAR to restrict on-target/off-tumor cytotoxicity, additionally or alternatively overall CAR cell on-tumor effector efficiency can be increased by reducing the expression of endogenous inhibitory signaling in the CAR cells so that the CAR cells become resistant to the inhibitory signals of the hostile tumor microenvironment. CTLA-4 and PD-1 inhibit T cells at different stages in activation and function. CTLA-4 regulates T cell responses to self-antigens, as knockout mice spontaneously develop organ damage due to highly active, tissue- infiltrating T cells without specific antigen exposure (Tivol, et al., Immunity, 3:541-547 (1995); Waterhouse, et al., Science, 270:985-988 (1995)). Interestingly, conditional knockout of CTLA-4 in Treg cells recapitulates the global knockout indicating that it normally functions within Tregs (Wing, et al., Science, 322:271-275 (2008)). In contrast, PD-L1 knockout mice are autoimmune prone, but do not spontaneously develop massive inflammatory cell infiltration of normal organs, indicating that it’s major physiological function is to mediate negative feedback control of ongoing tissue inflammation in an inducible manner (Dong, et al., Immunity, 20:327-336 (2004)). Indeed, according to the “adaptive resistance” hypothesis most tumors up-regulate PD-L1 in response to IFNγ; a key cytokine released by effector T cells including CART cells (Greenwald, et al., Annu Rev Immunol, 23:515-548 (2005); Carreno, et al., Annu Rev Immunol, 20:29-53 (2002); Chen, et al., The Journal of Clinical Investigation, 125:3384-3391 (2015); Keir, et al., Annu Rev Immunol, 26:677-704 (2008); Pentcheva-Hoang, et al., Immunological Reviews, 229:67-87 (2009)). PD-L1 then delivers an inhibitory signal to T cells decreasing their proliferation, and cytokine and perforin production (Butte, et al., Immunity, 27:111-122 (2007); Chen, et al., Immunology, 4:336-347 (2004); Park, et al., Blood, 116:1291-1298 (2010); Wherry, et al., Nat Immunol, 12:492-499 (2011); Zou, et al., Immunology, 8:467-477 (2008)). In addition, reverse signaling from the T cell through B7-H1 on cancer cells induces an anti-apoptotic effect that counteracts Fas-L signaling (Azuma, et al., Blood, 111:3635-3643 (2008)). Azuma, et al., Blood, 111:3635-3643 (2008) In light of the up-regulation of B7-H1 by cancer cells and the association of its expression with cancer progression and poor clinical outcome (Flies, et al., Journal of Immunotherapy, 30:251-260 (2007); Nishimura, et al., Immunity, 11:141-151 (1999); Wang, et al., Curr Top Microbiol Immunol, 344:245-267 (2011)), antibodies antagonizing the PD-1 and CTLA-4 pathways have shown dramatic efficacy in solid tumors, particularly melanoma, with the combination of the two showing even more activity. The anti-CTLA-4 antibody, ipilimumab, improves overall survival in metastatic melanoma with increased T cell infiltration into tumors and increased intratumoral CD8+:Treg ratios, predominantly through inhibition of Treg cells (Hamid, et al., J Transl Med, 9:204 (2011); Ribas, et al., Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 15:6267-6276 (2009); Twyman-Saint, et al., Nature, 520:373-377 (2015)). The anti-PD-1 antibody, nivolumab, shows an overall response rate of 30-40% in metastatic melanoma (Robert, et al., The New England Journal of Medicine, 372:320-330 (2015); Topalian, et al., J Clin Oncol, 32:1020-1030 (2014)), with similar findings in early phase clinical trials for other solid tumors including metastatic renal cancer, non-small cell lung cancer and relapsed Hodgkin’s Lymphoma (Ansell, et al., The New England Journal of Medicine, 372:311-319 (2015); Brahmer, et al., J Clin Oncol, 28:3167-3175 (2010); Topalian, et al., The New England Journal of Medicine, 366:2443-2454 (2012)). As resistance to anti-CTLA-4 antibodies in mouse melanoma models is due to up-regulation of PD-L181, the combination of both ipilimumab and nivolumab demonstrates further efficacy in both mouse models and human patients (Larkin, et al., The New England Journal of Medicine, 373:23-34 (2015); Spranger, et al., J Immunother Cancer, 2, 3, doi:10.1186/2051-1426-2-3 (2014); Yu, et al., Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 16:6019-6028 (2010)). Given the importance of the checkpoint inhibition pathway, it is believed that PD-1/CTLA-4 inhibition will release the brake, while the chimeric antigen receptor will push on the gas pedal. Importantly, transient delivery can be utilized to only transiently release the brake so that these cells will not lead to future autoimmune disease. (1). CRISPRi To avoid permanent genome modification and inactivation of inhibitory signals such as PD-1 and CTLA-4, the dCAS9 CRISPRi system (Larson, et al., Nat Protoc, 8:2180-2196 (2013)) can be utilized. Nucleic acids encoding the enzymatically-inactive dCAS9-KRAB-repression domain, fusion protein, and sgRNAs to the inhibitory signaling protein (e.g. CTLA-4, PD-1, LAG-3, 2B4 (CD244), BTLA (CD272), KIR, TIM-3, TGF beta receptor dominant negative analog, etc.) can be co-delivered into the CAR cell. One or multiple sgRNA can be utilized. sgRNA can be designed to target the proximal promoter region and the coding region (nontemplate strand). An alternative approach utilizes the single-component Cpf1 CRISPR system, which is a smaller RNA to electroporate and express (Zetsche, et al., Cell, doi:10.1016/j.cell.2015.09.038 (2015)). Any of the foregoing RNA components can also be encoded by DNA expression construct such as a vector, for example a plasmid. Thus, either RNA, DNA, or a combination thereof can serve as the nucleic acid cargo. Although broad inhibition of CTLA-4 with ipilimumab results in autoimmune sequelae, it is believed these side–effects will be decreased by restricting loss to CAR cells and transient nature of the mRNA delivery. Inhibitory function will be regained in time. (2). Inhibitory RNAs Nucleic acid cargo that can be delivered to cells can be or encode a functional nucleic acid or polypeptide designed to target and reduce or inhibit expression or translation of an inhibitory signaling molecule mRNA; or to reduce or inhibit expression, reduce activity, or increase degradation of inhibitory signaling molecule protein. Suitable technologies include, but are not limited to, antisense molecules, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, etc. In some embodiments, the mRNA encode antagonist polypeptide that reduce inhibitory signaling. In some embodiments, cargo that is or encodes functional RNAs suitable to reducing or silencing expression of CTLA-4, PD-1, LAG-3, 2B4 (CD244), BTLA (CD272), KIR, TIM-3, TGF beta receptor dominant negative analog, etc. alone or in combination can be delivered to cells. In some embodiments, the cargo is an RNA or DNA that encodes a polypeptide that reduces bioavailability or serves as an antagonist or other negative regulator or inhibitor of CTLA-4, PD-1, LAG-3, 2B4 (CD244), BTLA (CD272), KIR, TIM-3, TGF beta receptor dominant negative analog, or another protein in an immune inhibitory pathway. The protein can be a paracrine, endocrine, or autocrine. It can regulate the cell intracellularly. It can be secreted and regulate the expressing cell and/or other (e.g., neighboring) cells. It can be a transmembrane protein that regulates the expressing cell and/or other cells. The protein can be fusion protein, for example an Ig fusion protein. v. Pro-apoptotic Factors Compositions and methods for activating and reactivating apoptotic pathways are also provided. In some embodiments, the nucleic acid is or encodes a factor or agent that activates, reactivates, or otherwise enhances or increases the intrinsic apoptosis pathway. Preferably the factor activates, reactivates, or otherwise enhances the intrinsic apoptosis pathway in cancer (e.g., tumor) cells, and is more preferably specific or targeted to the cancer cells. In some embodiments, cells, following delivery of an anti-apoptotic factor or pro-proliferation factor, such as those discussed above or otherwise known in the art, are more resistant or less sensitive to induced apoptosis than untreated cells. A pro-apoptotic factor can induce or increase apoptosis in, for example, untreated cells relative to the treated T cells, and is preferably selective for cancer cells. The regimen results in a two-pronged attack, one cellular and one molecular, against the cancer cells. The intrinsic apoptosis pathway can be activated, reactivated, or otherwise enhanced by targeting BCL-2 family members. BCL-2 family members are classified into three subgroups based on function and Bcl-2 Homology (BH) domains: multi-domain anti-apoptotic (e.g. BCL-2 or BCL- XL), multi-domain pro-apoptotic (e.g. BAX and BAK), and BH3-only pro- apoptotic (e.g. BIM) proteins. Members of the BH3-only subgroup, such as BIM, function as death sentinels that are situated throughout the cell, poised to transmit a variety of physiological and pathologic signals of cellular injury to the core apoptotic machinery located at the mitochondrion (Danial, et al., Cell, 116:205-219 (2004)). In some embodiments, the pro-apoptotic factor is a pro-apoptotic BH3-mimetic. Various pro-apoptotic BH3-mimetics can simulate the native pro-apoptotic activities of BIM and afford the ability to manipulate multiple points of the apoptotic pathway. For example, BIM SAHB (Stabilized Alpha Helix of BCL-2 domains), ABT-737, and ABT-199 are pro-apoptotic BH3- mimetics designed by structural studies of the interaction between the pro- apoptotic BH3-only helical domain and the hydrophobic groove formed by the confluence of the BH1, BH2 and BH3 domains of anti-apoptotic proteins (Oltersdorf, et al., Nature, 435:677-681 (2005)). 4. Target Cells In some embodiments, one or more particular cell types or tissue is the target of the disclosed complexes. The target cells can be in vitro, ex vivo or in a subject (i.e., in vivo). The application discussed herein can be carried out in vitro, ex vivo, or in vivo. For ex vivo application, the cells can be collected or isolated and treated in culture. Ex vivo treated cells can be administered to a subject in need thereof in therapeutically effective amount. For in vivo applications, cargo can be delivered to target cells passively, e.g., based on circulation of the composition, local delivery, etc., or can be actively targeted, e.g., with the additional a cell, tissue, organ specific targeting moiety. Thus, in some embodiments, cargo is delivered to the target cells to the exclusion of other cells. In some embodiments, cargo is delivered to target cells and non-target cells. Target cells can be selected by the practitioner based on the desired treatment and therapy, and the intended effect of the nucleic acid cargo. For example, when the nucleic acid cargo is intended to induce cell death, the target cells may be cancer cells; when the nucleic acid cargo is intended to induce a genomic alteration, the target cells may be stem cells; when the nucleic acid cargo encodes a chimeric antigen receptor, the target cells may be immune cells. 4H2 penetrates into cells in a dipyridamole-sensitive manner that is enhanced by addition of GUO, indicating nucleoside transporter-dependent transport that is promoted by local nucleic acid. In some embodiments, the target cells express nucleoside transporter on their plasma membrane. Expression of nucleoside transporters is relatively ubiquitous but varies in abundance among tissues and cell types. For example, ENT2 expression has been confirmed in the brain, heart, placenta, thymus, pancreas, prostate and kidney (Griffiths, et al., Biochem J, 1997.328 (Pt 3): p.739-43, Crawford, et al., J Biol Chem, 1998.273(9): p. 5288-93). Relative to other transporters, ENT2 has one of the highest mRNA expressions in skeletal muscle (Baldwin, et al., Pflugers Arch, 2004.447(5): p.735-43, Govindarajan, et al., Am J Physiol Regul Integr Comp Physiol, 2007.293(5): p. R1809-22). Thus, in some embodiments the target cells are brain, heart, placenta, thymus, pancreas, prostate, kidney, or skeletal muscle. Additional, non-limiting, exemplary target cells are discussed below. i. Progenitor and Stem Cells The cells can be hematopoietic progenitor or stem cells. In some embodiments, particularly those related to gene editing and gene therapy the target cells are CD34⁺ hematopoietic stem cells. Hematopoietic stem cells (HSCs), such as CD34+ cells are multipotent stem cells that give rise to all the blood cell types including erythrocytes. Stem cells can be isolated and enriched by one of skill in the art. Methods for such isolation and enrichment of CD34⁺ and other cells are known in the art and disclosed for example in U.S. Patent Nos.4,965,204; 4,714,680; 5,061,620; 5,643,741; 5,677,136; 5,716,827; 5,750,397 and 5,759,793. As used herein in the context of compositions enriched in hematopoietic progenitor and stem cells, “enriched” indicates a proportion of a desirable element (e.g. hematopoietic progenitor and stem cells) which is higher than that found in the natural source of the cells. A composition of cells may be enriched over a natural source of the cells by at least one order of magnitude, preferably two or three orders, and more preferably 10, 100, 200 or 1000 orders of magnitude. In humans, CD34⁺ cells can be recovered from cord blood, bone marrow or from blood after cytokine mobilization effected by injecting the donor with hematopoietic growth factors such as granulocyte colony stimulating factor (G-CSF), granulocyte-monocyte colony stimulating factor (GM-CSF), stem cell factor (SCF) subcutaneously or intravenously in amounts sufficient to cause movement of hematopoietic stem cells from the bone marrow space into the peripheral circulation. Initially, bone marrow cells may be obtained from any suitable source of bone marrow, e.g. tibiae, femora, spine, and other bone cavities. For isolation of bone marrow, an appropriate solution may be used to flush the bone, which solution will be a balanced salt solution, conveniently supplemented with fetal calf serum or other naturally occurring factors, in conjunction with an acceptable buffer at low concentration, generally from about 5 to 25 mM. Convenient buffers include Hepes, phosphate buffers, lactate buffers, etc. Cells can be selected by positive and negative selection techniques. Cells can be selected using commercially available antibodies which bind to hematopoietic progenitor or stem cell surface antigens, e.g. CD34, using methods known to those of skill in the art. For example, the antibodies may be conjugated to magnetic beads and immunogenic procedures utilized to recover the desired cell type. Other techniques involve the use of fluorescence activated cell sorting (FACS). The CD34 antigen, which is found on progenitor cells within the hematopoietic system of non-leukemic individuals, is expressed on a population of cells recognized by the monoclonal antibody My-10 (i.e., express the CD34 antigen) and can be used to isolate stem cell for bone marrow transplantation. My-10 deposited with the American Type Culture Collection (Rockville, Md.) as HB-8483 is commercially available as anti-HPCA 1. Additionally, negative selection of differentiated and “dedicated” cells from human bone marrow can be utilized, to select against substantially any desired cell marker. For example, progenitor or stem cells, most preferably CD34⁺ cells, can be characterized as being any of CD3-, CD7-, CD8-, CD10-, CD14-, CD15-, CD19-, CD20-, CD33-, Class II HLA⁺ and Thy-1⁺. Once progenitor or stem cells have been isolated, they may be propagated by growing in any suitable medium. For example, progenitor or stem cells can be grown in conditioned medium from stromal cells, such as those that can be obtained from bone marrow or liver associated with the secretion of factors, or in medium including cell surface factors supporting the proliferation of stem cells. Stromal cells may be freed of hematopoietic cells employing appropriate monoclonal antibodies for removal of the undesired cells. The isolated cells are contacted ex vivo with antibody and nucleic acid cargo complexes. Cells to which cargo has been delivered can be referred to as modified cells. A solution of the complexes may simply be added to the cells in culture. It may be desirable to synchronize the cells in S-phase. Methods for synchronizing cultured cells, for example, by double thymidine block, are known in the art (Zielke, et al., Methods Cell Biol., 8:107-121 (1974)). The modified cells can be maintained or expanded in culture prior to administration to a subject. Culture conditions are generally known in the art depending on the cell type. Conditions for the maintenance of CD34⁺ in particular have been well studied, and several suitable methods are available. A common approach to ex vivo multi-potential hematopoietic cell expansion is to culture purified progenitor or stem cells in the presence of early-acting cytokines such as interleukin-3. It has also been shown that inclusion, in a nutritive medium for maintaining hematopoietic progenitor cells ex vivo, of a combination of thrombopoietin (TPO), stem cell factor (SCF), and flt3 ligand (Flt-3L; i.e., the ligand of the flt3 gene product) was useful for expanding primitive (i.e., relatively non-differentiated) human hematopoietic progenitor cells in vitro, and that those cells were capable of engraftment in SCID-hu mice (Luens et al., 1998, Blood 91:1206-1215). In other known methods, cells can be maintained ex vivo in a nutritive medium (e.g., for minutes, hours, or 3, 6, 9, 13, or more days) including murine prolactin-like protein E (mPLP-E) or murine prolactin-like protein F (mPIP-F; collectively mPLP- E/IF) (U.S. Patent No.6,261,841). It will be appreciated that other suitable cell culture and expansion methods can be used as well. Cells can also be grown in serum-free medium, as described in U.S. Patent No.5,945,337. In another embodiment, the modified hematopoietic stem cells are differentiated ex vivo into CD4⁺ cells culture using specific combinations of interleukins and growth factors prior to administration to a subject using methods well known in the art. The cells may be expanded ex vivo in large numbers, preferably at least a 5-fold, more preferably at least a 10-fold and even more preferably at least a 20-fold expansion of cells compared to the original population of isolated hematopoietic stem cells. In another embodiment cells, can be dedifferentiated somatic cells. Somatic cells can be reprogrammed to become pluripotent stem-like cells that can be induced to become hematopoietic progenitor cells. The hematopoietic progenitor cells can then be treated with the compositions as described above with respect to CD34⁺ cells. Representative somatic cells that can be reprogrammed include, but are not limited to fibroblasts, adipocytes, and muscles cells. Hematopoietic progenitor cells from induced stem-like cells have been successfully developed in the mouse (Hanna, J. et al. Science, 318:1920-1923 (2007)). To produce hematopoietic progenitor cells from induced stem-like cells, somatic cells are harvested from a host. In a preferred embodiment, the somatic cells are autologous fibroblasts. The cells are cultured and transduced with vectors encoding Oct4, Sox2, Klf4, and c-Myc transcription factors. The transduced cells are cultured and screened for embryonic stem cell (ES) morphology and ES cell markers including, but not limited to AP, SSEA1, and Nanog. The transduced ES cells are cultured and induced to produce induced stem-like cells. Cells are then screened for CD41 and c-kit markers (early hematopoietic progenitor markers) as well as markers for myeloid and erythroid differentiation. The modified hematopoietic stem cells or modified cells including, e.g., induced hematopoietic progenitor cells, are then introduced into a subject. Delivery of the cells may be affected using various methods and includes most preferably intravenous administration by infusion as well as direct depot injection into periosteal, bone marrow and/or subcutaneous sites. The subject receiving the modified cells may be treated for bone marrow conditioning to enhance engraftment of the cells. The recipient may be treated to enhance engraftment, using a radiation or chemotherapeutic treatment prior to the administration of the cells. Upon administration, the cells will generally require a period of time to engraft. Achieving significant engraftment of hematopoietic stem or progenitor cells typically takes weeks to months. A high percentage of engraftment of modified hematopoietic stem cells may not be necessary to achieve significant prophylactic or therapeutic effect. It is believed that the engrafted cells will expand over time following engraftment to increase the percentage of modified cells. It is believed that in some cases, engraftment of only a small number or small percentage of modified hematopoietic stem cells will be required to provide a prophylactic or therapeutic effect. In preferred embodiments, the cells to be administered to a subject will be autologous, e.g. derived from the subject, or syngenic. ii. Embryos In some embodiments, the compositions and methods can be used to deliver cargo to embryonic cells in vitro. The methods typically include contacting an embryo in vitro with an effective amount of antibody-cargo DNA to improve cargo transduction into the embryo. The embryo can be a single cell zygote, however, treatment of male and female gametes prior to and during fertilization, and embryos having 2, 4, 8, or 16 cells and including not only zygotes, but also morulas and blastocytes, are also provided. In some embodiments, the embryo is contacted with the compositions on culture days 0-6 during or following in vitro fertilization. The contacting can be adding the compositions to liquid media bathing the embryo. For example, the compositions can be pipetted directly into the embryo culture media, whereupon they are taken up by the embryo. iii. Immune cells In some embodiments, the target cells are one or more types of immune cells. For example, different type of cells can be utilized or otherwise targeted for immunodulation and CAR-based therapies. The preferred targeted/engineered T cells may vary depending on the tumor and goals of the adoptive therapy. Effector T cells are typically preferred because they secreted high levels of effector cytokines and were proficient killers of tumor targets in vitro (Barrett, et al., Annu Rev Med., 65: 333–347 (2014). Two complimentary lymphocyte populations with robust CAR mediated cytotoxicity are CD3-CD56+ NK cells and CD3+CD8+ T cells. Use of CD8+ T cells with CD4+ helper T cells leads to the increased presence of suppressive T-reg cells and dampened CD8+ T cell cytotoxicity. Since reprogrammed CD8+ T cells are pre-activated so that they act directly on tumor cells without the need for activation in the lymph node, CD4+ T cell support is not essential. Additionally, there is evidence that infusion of naive T cells (Rosenberg, et al. Adv. Cancer Res., 25:323–388 (1977)), central memory T cells (T_CM cells) (Berger, et al. J. Clin. Invest., 118:294–305 (2008)), Th17 cells (Paulos, et al., Sci. Transl. Med., 2:55–78 (2010)), and T stem memory cells (Gattinoni, et al., Nat. Med., 17:1290–1297 (2012)) may all have certain advantages in certain applications due, for example, to their high replicative capacity. Tumor Infiltrating Lymphocytes (TILs) also have certain advantages due to their antigen specificity and may be used in the delivery strategies disclosed herein. Although sometime referred to as CAR cells, CAR immune, cells, and CART cells (or CAR T cells), it will be appreciated that the CAR and other delivery strategies disclosed herein can also be carried out in other cell types, particularly different types of immune cells, including those discussed herein (e.g., lymphocytes, Natural Killer Cells, dendritic cells, B cells, antigen presenting cells, macrophage, etc.) and described elsewhere (see, e.g., Barrett, et al., Annu Rev Med., 65: 333–347 (2014)). iv. Cancer Cells and Tumors In some embodiments, the target cells are cancer cells. In such embodiments, methods of treatment are provided that may be useful in the context of cancer, including tumor therapy. Cargos that may be delivered to cancer cells include, but are not limited to, constructs for the expression of one or more pro-apoptotic factors, immunogenic factors, or tumor suppressors; gene editing compositions, inhibitory nucleic acids that target oncogenes; as well as other strategies discussed herein and elsewhere. In some embodiments, the cargo is mRNA that encodes a pro-apoptotic factor, or immunogenic factor that increases and immune response against the cells. In other embodiments, the cargo is siRNA the reduces expression of an oncogene or other cancer-causing transcript. In a mature animal, a balance usually is maintained between cell renewal and cell death in most organs and tissues. The various types of mature cells in the body have a given life span; as these cells die, new cells are generated by the proliferation and differentiation of various types of stem cells. Under normal circumstances, the production of new cells is so regulated that the numbers of any particular type of cell remain constant. Occasionally, though, cells arise that are no longer responsive to normal growth-control mechanisms. These cells give rise to clones of cells that can expand to a considerable size, producing a tumor or neoplasm. A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is benign. A tumor that continues to grow and becomes progressively invasive is malignant. The term cancer refers specifically to a malignant tumor. In addition to uncontrolled growth, malignant tumors exhibit metastasis. In this process, small clusters of cancerous cells dislodge from a tumor, invade the blood or lymphatic vessels, and are carried to other tissues, where they continue to proliferate. In this way a primary tumor at one site can give rise to a secondary tumor at another site. The compositions and methods described herein may be useful for treating subjects having benign or malignant tumors by delaying or inhibiting the growth of a tumor in a subject, reducing the growth or size of the tumor, inhibiting or reducing metastasis of the tumor, and/or inhibiting or reducing symptoms associated with tumor development or growth. Malignant tumors which may be treated are classified herein according to the embryonic origin of the tissue from which the tumor is derived. Carcinomas are tumors arising from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. The disclosed compositions are particularly effective in treating carcinomas. Sarcomas, which arise less frequently, are derived from mesodermal connective tissues such as bone, fat, and cartilage. The leukemias and lymphomas are malignant tumors of hematopoietic cells of the bone marrow. Leukemias proliferate as single cells, whereas lymphomas tend to grow as tumor masses. Malignant tumors may show up at numerous organs or tissues of the body to establish a cancer. The types of cancer that can be treated with the provided compositions and methods include, but are not limited to, cancers such as vascular cancer such as multiple myeloma, adenocarcinomas and sarcomas, of bone, bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, and uterine. In some embodiments, the disclosed compositions are used to treat multiple cancer types concurrently. The compositions can also be used to treat metastases or tumors at multiple locations. B. Methods of Modulating Immune Responses Methods of increasing immune responses are provided. The immune responses can be increased against, for example, cancer and infections. Thus, methods of treating cancer and infections in a subject, and methods of vaccinating subjects both health and sick, are also provided. The immune response is also involved in wound healing, and thus methods of promoting wound healing are also provided. Immune regulation is also involved in some autoimmune diseases such as multiple sclerosis, and thus methods of promoting immune regulation in multiple sclerosis are also provided. Thus, in some embodiments, the subject has a wound or multiple sclerosis. The methods typically include administering a subject in need thereof an effective amount of 4H2 antibody to increase activation of cGAS and/or another PRR such as TLR7. In some embodiments, the compositions and methods increase activation of cGAS and/or another PRR such as TLR7 e.g., by direct binding and activation by 4H2, or indirect binding through simultaneous interactions between the cGAS and/or other PPR, 4H2, and cytoplasmic nucleic acid and/or GTP. Activated cGAS catalyzes the formation of cGAMP from precursor molecules ATP and GTP, and cGAMP generated by cGAS promotes nuclear translocation by NF-kB. Thus, in some embodiments, the disclosed composition increases cGAMP production and or promotes nuclear translocation by NF-kB. Typically the methods enhance an immune response through induction or enhanced signaling through the cGAS/STING pathway. In some embodiments, the compositions and methods include stimulating T cell proliferation, tumor vascular collapse and contributes to tumor cell death and apoptosis, enhanced release of tumor-associated antigens, improve antigen-specific IgG response through a mechanism dependent on a T helper 1 (TH1), TH2 and/or TH17 cell response, reduced viral or bacterial load, reduced susceptibility to a virus or bacteria, or any combination thereof. See, also Motwani and Fitzgerald, Nature Reviews Genetics volume 20, pages657–674 (2019), which is specifically incorporated by reference herein in its entirety, and describes additional outcomes of enhancing cGAS/STING signaling. In some embodiments, the compositions and methods include increasing recruitment of tumor- infiltrating lymphocytes (TILs) to tumors. Results below also show that 4H2 interacts with TLR7, and it is believed to do so in a nucleic acid-dependent manner. The TLR family plays an important role in pathogen recognition and activation of innate immunity. TLRs recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. TLR7 is an intracellular pattern recognition receptor that recognizes single-stranded RNA in endosomes, which is a common feature of viral genomes which are internalized by macrophages and dendritic cells. For example, TLR7 recognizes single-stranded RNA of viruses such as HIV and HCV. TLR7 can recognize GU-rich single-stranded RNA. This adds another dimension to the use of 4H2 as a stimulator of immunity because results indicated that 4H2 activates at least cGAS and TLR7, and perhaps other immune response inducing receptors. Other immune receptors that may be activated by 4H2 include, but are not limited to, other PPRs such as RIG-I-like receptors and other toll-like receptors including but not limited to TLR3, TLR8, TLR9, etc. Other receptors include, but are not limited to, those whose ligands are mentioned as cargo and/or adjuvants. In certain embodiments, the methods include administering to a subject in need thereof an effective amount of 4H2 antibody in combination with one or more additional agents such as a nucleic acid cargo, an immunostimulatory nucleic acid, vaccine component(s), an immune checkpoint modulator, or a combination thereof. In some embodiments, 4H2 antibody and additional agent can be used in combination to provide enhance cGAS/STING and/or another immune receptor such as a PPR (e.g., TLR7) signaling to greater degree than the use of either agent alone. For example, in some embodiments, e.g., the treatment of cancer the enhance activity is greater antitumor activity. The 4H2 antibody, and/or immune checkpoint modulator can be administered locally or systemically to the subject, or coated or incorporated onto, or into a device. The disclosed monotherapies and combination therapies and treatment regimens typically include treatment of a disease or symptom thereof, or a method for achieving a desired physiological change, including administering to an animal, such as a mammal, especially a human being, an effective amount of 4H2 antibody to treat a disease such as cancer or infection or symptom thereof, or to produce the physiological change. When administered in combination with an additional agent, the 4H2 antibody and additional agent can be administered together, such as part of the same composition, or administered separately and independently at the same time or at different times (i.e., administration of the 4H2 antibody and immune checkpoint modulator is separated by a finite period of time from each other). Therefore, the term “combination” or “combined” is used to refer to either concomitant, simultaneous, or sequential administration of two agents. The combinations can be administered either concomitantly (e.g., as an admixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject; one agent is given orally while the other agent is given by infusion or injection, etc.,), or sequentially (e.g., one agent is given first followed by the second). In some embodiments, the result achieved by the combination is partially or completely additive of the results achieved by the individual components alone. In some embodiments, the result achieved by the combination is more than additive of the results achieved by the individual components alone. In some embodiments, the effective amount of one or both agents used in combination is lower than the effective amount of each agent when administered separately. In some embodiments, the amount of one or both agents when used in the combination therapy is sub-therapeutic when used alone. The effect of the combination therapy, or individual agents thereof can depend on the disease or condition to be treated or progression thereof. For example, in some embodiments, the combination expands the subjects (e.g., the types of cancer or infection) that can be treated relative the each of the agents alone. Accordingly, in some embodiments, the effect of the combination on a cancer or infection can compared to the effect of the individual agents alone on the cancer or infection. A treatment regimen of monotherapies and combination therapies can include one or multiple administrations of a 4H2 antibody. A treatment regimen of the combination therapy can include one or multiple administrations of an additional agent. In some embodiments 4H2 antibody and additional agent are administered sequentially, for example, in two or more different pharmaceutical compositions. In certain embodiments, the 4H2 antibody is administered prior to the first administration of the additional agent. In other embodiments, the additional agent is administered prior to the first administration of the 4H2 antibody. For example, the 4H2 antibody and additional agent can be administered to a subject on the same day. Alternatively, the 4H2 antibody and additional agent can be administered to the subject on different days. The 4H2 antibody can be administered at least 1, 2, 3, 5, 10, 15, 20, 24 or 30 hours or days prior to or after administering of the additional agent. Alternatively, the immune checkpoint modulator can be administered at least 1, 2, 3, 5, 10, 15, 20, 24 or 30 hours or days prior to or after administering of the 4H2 antibody. In certain embodiments, additive or more than additive effects of the 4H2 antibody and additional agent is evident after one day, two days, three days, four days, five days, six days, one week, or more than one week following administration. Dosage regimens or cycles of the agents can be completely or partially overlapping, or can be sequential. For example, in some embodiments, all such administration(s) of the 4H2 antibody occur before or after administration of the additional agent. Alternatively, administration of one or more doses of the 4H2 antibody can be temporally staggered with the administration of additional agent to form a uniform or non-uniform course of treatment whereby one or more doses of 4H2 antibody are administered, followed by one or more doses of the additional agent, followed by one or more doses of the 4H2 antibody; or one or more doses of additional agent are administered, followed by one or more doses of 4H2 antibody, followed by one or more doses of additional agent; etc., all according to whatever schedule is selected or desired by the researcher or clinician administering the therapy. An effective amount of each of the agents can be administered as a single unit dosage (e.g., as dosage unit), or sub-therapeutic doses that are administered over a finite time interval. Such unit doses may be administered on a daily basis for a finite time period, such as up to 3 days, or up to 5 days, or up to 7 days, or up to 10 days, or up to 15 days or up to 20 days or up to 25 days, are all specifically contemplated. 1. Treatment of Cancer The therapies disclosed herein can be used to treat, reduce, and/or prevent cancer in a subject. Therefore, the compositions can be administered in an effective amount to treat, reduce, and/or prevent cancer in a subject. The effective amount or therapeutically effective amount to treat cancer or a tumor thereof is typically a dosage sufficient to reduce or prevent a least one symptom of the cancer, or to otherwise provide a desired pharmacologic and/or physiologic effect. The symptom may be physical, such as tumor burden, or biological such as reducing proliferation or increasing death of cancer cells. In some embodiments, the amount is effective to kill tumor cells or reduce or inhibit proliferation or metastasis of the tumor cells. In some embodiments, the amount is effective to reduce tumor burden. In some embodiments, the amount is effective to reduce or prevent at least one comorbidity of the cancer. In a mature animal, a balance usually is maintained between cell renewal and cell death in most organs and tissues. The various types of mature cells in the body have a given life span; as these cells die, new cells are generated by the proliferation and differentiation of various types of stem cells. Under normal circumstances, the production of new cells is so regulated that the numbers of any particular type of cell remain constant. Occasionally, though, cells arise that are no longer responsive to normal growth-control mechanisms. These cells give rise to clones of cells that can expand to a considerable size, producing a tumor or neoplasm. A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is benign. A tumor that continues to grow and becomes progressively invasive is malignant. The term cancer typically refers to a malignant tumor. In addition to uncontrolled growth, malignant tumors exhibit metastasis. In this process, small clusters of cancerous cells dislodge from a tumor, invade the blood or lymphatic vessels, and are carried to other tissues, where they continue to proliferate. In this way a primary tumor at one site can give rise to a secondary tumor at another site. The compositions and methods described herein are useful for treating subjects having benign or malignant tumors by delaying or inhibiting the growth of a tumor in a subject, reducing the growth or size of the tumor, inhibiting or reducing metastasis of the tumor, and/or inhibiting or reducing symptoms associated with tumor development or growth. Malignant tumors which may be treated can be classified according to the embryonic origin of the tissue from which the tumor is derived. Carcinomas are tumors arising from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. The disclosed compositions are particularly effective in treating carcinomas. Sarcomas, which arise less frequently, are derived from mesodermal connective tissues such as bone, fat, and cartilage. The leukemias and lymphomas are malignant tumors of hematopoietic cells of the bone marrow. Leukemias proliferate as single cells, whereas lymphomas tend to grow as tumor masses. Malignant tumors may show up at numerous organs or tissues of the body to establish a cancer. The disclosed antigen binding molecules can be used to treat cells undergoing unregulated growth, invasion, or metastasis. Cancer cells characterized by mutation of one or more Ras genes or mutation of genes encoding other components of Ras/MAPK signaling pathways are particularly good targets for the disclosed compositions. Cancerous cells can develop as a result of somatic, gain-of-function mutations in Ras genes, resulting in activating mutations in small GTPase Ras enzymes. Oncogenic mutations of the H-Ras, N-Ras, or K-Ras genes are most frequently associated with malignancies in humans. In certain embodiments, the cells express a mutant form of the small GTPase Ras family, such as K-Ras. In certain embodiments the cells do not express the wild type Ras genes. Oncogenic mutations have also been identified in other upstream or downstream components of the Ras intracellular signaling pathways, including cytosolic kinases and membrane RTKs (Ras/MAPK pathways). Oncogenic mutations in the K-Ras gene can result in constitutive activation of the out-coming Ras proteins. Exemplary mutations include mutations in codons 12, 13, and/or 61 that result in any changes in the amino acids occurring at positions 12, 13, or 61 of the K-ras protein. This includes for example but is not limited to K-ras amino acid 12 (changing glycine to aspartic acid, cysteine, serine, threonine, arginine, or valine) and amino acid 13 and 61 (changing glutamine to lysine, arginine, leucine, or aspartic acid). Another way of describing these K-Ras mutations that are exemplary in this context is G12A, G12C, G12D, G12S, G12I, G12R, G12V, G13C, G13D, G13S, Q61L, Q61R. Again, any change in amino acid content at positions 12, 13, 61 are considered exemplary mutations. A representative but non-limiting list of cancers that the compositions can be used to treat include cancers of the blood and lymphatic system (including leukemias, Hodgkin’s lymphomas, non-Hodgkin’s lymphomas, solitary plasmacytoma, multiple myeloma), cancers of the genitourinary system (including prostate cancer, bladder cancer, renal cancer, urethral cancer, penile cancer, testicular cancer,), cancers of the nervous system (including meningiomas, gliomas, glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas) cancers of the head and neck (including squamous cell carcinomas of the oral cavity, nasal cavity, nasopharyngeal cavity, oropharyngeal cavity, larynx, and paranasal sinuses), lung cancers (including small cell and non-small cell lung cancer), gynecologic cancers (including cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer ovarian and fallopian tube cancer), gastrointestinal cancers (including gastric, small bowel, colorectal, liver, hepatobiliary, and pancreatic cancers), skin cancers (including melanoma, squamous cell carcinomas, and basal cell carcinomas), breast cancer (including ductal and lobular cancer and triple negative breast cancers), and pediatric cancers (including neuroblastoma, Ewing’s sarcoma, Wilms tumor, medulloblastoma). Accordingly, in some embodiments, the present disclosure relates to a method of treating breast, ovarian, colon, prostate, lung, brain, skin, liver, stomach, pancreatic or blood based cancer. In some embodiments, the present disclosure relates to treating glioblastoma. Any of the disclosed methods can be used in used in further combination with radiotherapy, chemotherapy (e.g., antineoplastic drug), or a combination thereof, to treat any cancer, including carcinomas, gliomas, sarcomas, or lymphomas. Examples of antineoplastic drugs that can be combined with the disclosed antigen binding molecules include, but are not limited to, alkylating agents (such as temozolomide, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, dacarbazine, lomustine, carmustine, procarbazine, chlorambucil and ifosfamide), antimetabolites (such as fluorouracil, gemcitabine, methotrexate, cytosine arabinoside, fludarabine, and floxuridine), some antimitotics, and vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine), anthracyclines (including doxorubicin, daunorubicin, valrubicin, idarubicin, and epirubicin, as well as actinomycins such as actinomycin D), cytotoxic antibiotics (including mitomycin, plicamycin, and bleomycin), and topoisomerase inhibitors (including camptothecins such as irinotecan and topotecan and derivatives of epipodophyllotoxins such as amsacrine, etoposide, etoposide phosphate, and teniposide). Strategies that combine STING immunotherapy with other immunomodulatory agents are being explored. The antitumor efficacy of cGAMP administered by i.t. injection into B16.F10 tumors was enhanced when combined with anti-programmed death-1 (PD-1) and anti-cytotoxic T- lymphocyte associated-4 (CTLA-4) antibodies (Demaria, et al., Proc Natl Acad Sci U S A (2015) 112(50):15408–13.10.1073/pnas.1512832112). In other studies, CDNs together with anti-PD-1 incited much stronger antitumor effects than monotherapy in a mouse model of squamous cell carcinoma model as well as of melanoma (Gadkaree, et al., Head Neck (2017) 39(6):1086–94.10.1002/hed.24704; Wang, et al., Proc Natl Acad Sci U S A (2017) 114(7):1637–42.10.1073/pnas.1621363114). Luo et al. showed encouraging results by combining a STING-activating nanovaccine and an anti-PD1 antibody, which lead to generation of long-term antitumor memory in TC-1 tumor model (Luo, et al., Nat Nanotechnol (2017) 12(7):648– 54.10.1038/nnano.2017.52). Thus, a particularly preferred method of treating cancer includes administering a subject a combination of 4H2 antibody and a checkpoint modulator. 2. Infections and Virally Transformed Cells In some embodiments, the compositions can be used to treat or prevent infection of cells with, for example, a bacteria or virus such as an oncovirus. Thus, the compositions can be administered for the treatment of local or systemic infections. Representative infections that can be treated, include but are not limited to infections cause by microoganisms including, but not limited to, Actinomyces, Anabaena, Bacillus, Bacteroides, Bdellovibrio, Bordetella, Borrelia, Campylobacter, Caulobacter, Chlamydia, Chlorobium, Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus, Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus, Hemophilus influenza type B (HIB), Histoplasma, Hyphomicrobium, Legionella, Leishmania, Leptspirosis, Listeria, Meningococcus A, B and C, Methanobacterium, Micrococcus, Myobacterium (e.g., Tuberculosis), Mycoplasma, Myxococcus, Neisseria, Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas, Phodospirillum, Rickettsia, Salmonella, Shigella, Spirillum, Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus, Thermoplasma, Thiobacillus, and Treponema, Vibrio, Yersinia, Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Plasmodium vivax, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis and Schistosoma mansoni. Exemplary viruses that can be affected by disclosed compositions include Human papillomaviruses (HPV), Hepatitis B (HBV), Hepatitis C (HCV), Human T-lymphotropic virus (HTLV), Kaposi’s sarcoma-associated herpesvirus (HHV-8), Merkel cell polyomavirus, Epstein–Barr virus (EBV), Human immunodeficiency virus (HIV), and Human cytomegalovirus (CMV), including, but not limited to, immunodeficiency (e.g., HIV), papilloma (e.g., HPV), herpes (e.g., HSV), encephalitis, influenza (e.g., human influenza virus A), common cold (e.g., human rhinovirus), coronavirus (e.g., SARS-CoV-2), Zika virus, Dengue virus, and vesicular stomatitis virus (VSV) viral infections. For example, the compositions can be administered topically to treat viral skin diseases such as herpes lesions or shingles, or genital warts. The composition can also be administered to treat systemic viral diseases, including, but not limited to, AIDS, influenza, the common cold, or encephalitis. Other viral diseases that may be affected by administration of the compositions include Colorado Tick Fever (caused by Coltivirus, RNA virus), West Nile Fever (encephalitis, caused by a flavivirus that primarily occurs in the Middle East and Africa), Yellow Fever, Rabies (caused by a number of different strains of neurotropic viruses of the family Rhabdoviridae), viral hepatitis, gastroenteritis (viral)-acute viral gastroenteritis caused by Norwalk and Norwalk-like viruses, rotaviruses, caliciviruses, and astroviruses, poliomyelitis, influenza (flu), caused by orthomyxoviruses that can undergo frequent antigenic variation, measles (rubella), paramyxoviridae, mumps, respiratory syndromes including viral pneumonia and acute respiratory syndromes including croup caused by a variety of viruses collectively referred to as acute respiratory viruses, and respiratory illness caused by the respiratory syncytial virus (RSV, the most dangerous cause of respiratory infection in young children). In some embodiments, the disclosed compositions are used to treat or prevent a viral infection or the spread or worsening of a viral infection. For example, in some embodiments, the compositions are used to treat or prevent a viral infection or the spread or worsening of a viral infection in a subject that has been exposed to or is at risk of being exposed to a virus, such as those discussed herein. 3. Vaccination The compositions can be administered prior to, concurrently with, or after the administration of a vaccine. In one embodiment the 4H2 antibody composition is administered at the same time as administration of a vaccine. The disclosed compositions may be administered in conjunction with prophylactic vaccines, or therapeutic vaccines, which can be used to initiate or enhance a subject’s immune response to a pre-existing antigen, such as a tumor antigen in a subject with cancer. The desired outcome of a prophylactic, therapeutic or de-sensitized immune response may vary according to the disease, according to principles well known in the art. Similarly, immune responses against cancer, allergens or infectious agents may completely treat a disease, may alleviate symptoms, or may be one facet in an overall therapeutic intervention against a disease. For example, the stimulation of an immune response against a cancer may be coupled with surgical, chemotherapeutic, radiologic, hormonal and other immunologic approaches in order to affect treatment. STING agonists can enhance antitumor responses when combined with tumor vaccines. For example, CDN ligands formulated with granulocyte-macrophage colony-stimulating factor-producing cellular cancer vaccines, termed STINGVAX, showed strong in vivo therapeutic efficacy in several established cancer models (Fu, et al., Sci Transl Med (2015) 7(283):283ra52.10.1126/scitranslmed.aaa4306), and STING agonists in combination with traditional chemotherapeutic agents or radiotherapy can trigger an antitumor response (Xia, et al., Cancer Res (2016) 76(22):6747– 59.10.1158/0008-5472.CAN-16-1404; Baird, et al., Cancer Res (2016) 76(1):50–61.10.1158/0008-5472.CAN-14-3619). Thus, a particularly preferred method of treating a subject in need thereof includes administering a subject a combination of 4H2 antibody and one or more components of a vaccine. The vaccine can against, for example, cancer or an infectious disease-causing agent. 4. Wound Healing In some embodiments, the compositions can be used to promote wound healing. Activation of STING by cGAMP increases cutaneous wound healing (Mizutani et al., J Dermatol Sci 202097(10: 21-29). Representative wounds in which healing can be promoted by the compositions include skin wounds sustained from trauma or surgery, ocular wounds sustained from trauma or surgery, and internal organ wounds sustained from trauma or surgery. For example, the compositions can be administered topically to treat skin or ocular wounds sustained from trauma or surgery, or by local injection to treat skin or ocular or internal organ wounds sustained from trauma or surgery. 5. Immune Regulation for Treatment of Multiple Sclerosis In some embodiments, the compositions can be used to promote immune regulation to treat autoimmune and/or diseases of immune dysregulation such as multiple sclerosis. Activation of STING by cGAMP suppresses disease in a model of multiple sclerosis (Johnson et al., J Immunol 2021206(9):2015-28). For example, the compositions can be administered systemically to treat multiple sclerosis. 6. Neurofibromatosis (NF) Neurofibromatosis (NF), a type of phakomatosis or syndrome with neurological and cutaneous manifestations, is a rare genetic disorder that typically causes benign tumors of the nerves and growths in other parts of the body, including the skin. Neurofibromatosis type 2 is a disorder characterized by the growth of noncancerous tumors in the nervous system cause by mutations in the NF2 gene (which encodes the protein Merlin). The most common tumors associated with neurofibromatosis type 2 are called vestibular schwannomas. These growths develop along the nerve that carries information from the inner ear to the brain (the auditory nerve). Tumors that form on the membrane that covers the brain and spinal cord (meninges) are also common in neurofibromatosis type 2. These tumors are called meningiomas. Tumors can also occur on other nerves or tissues in the brain or spinal cord in people with this condition. In some embodiments, the methods include delivery of nucleic acids encoding NF2 (e.g., mRNA). The results below show that 4H2 can mediate gene delivery to NF2 mRNA and effect NF2 tumors in vivo. Thus, in some embodiments, the subject has neurofibromatosis, e.g., Neurofibromatosis type 2. In some embodiments, the compositions are used to treat subjects with schwannomas and/or meningiomas. The invention can be further understood by the following numbered paragraphs: 1. A composition including or consisting of (a) an intact 4H2 monoclonal antibody or a cell- penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) a nucleic acid cargo including a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. 2. The composition of paragraph 1, wherein (a) includes: (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv). 3. The composition of paragraphs 1 or 2, wherein (a) includes the same or different epitope specificity as monoclonal antibody 4H2. 4. The composition of any one of paragraphs 1-3, wherein (a) is a recombinant antibody having the paratope of monoclonal antibody 4H2. 5. A composition including (a) a binding protein including (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv), and (b) a nucleic acid cargo including a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. 6. The composition of any one of paragraphs 1-5, wherein (a) is bispecific. 7. The composition of paragraph 6, wherein (a) targets a cell type of interest. 8. The composition of any one of paragraphs 1-7, wherein (a) and (b) are non-covalently linked or associated. 9. The composition of any one of paragraphs 1-8, wherein (a) and (b) are in a complex. 10. The composition of any one of paragraphs 1-9 wherein (b) includes DNA, RNA, PNA or other modified nucleic acids, or nucleic acid analogs, or a combination thereof. 11. The composition of any one of paragraphs 1-10, wherein (b) includes mRNA. 12. The composition of any one of paragraphs 1-11, wherein (b) includes a vector. 13. The composition of paragraph 12, wherein the vector includes a nucleic acid sequence encoding a polypeptide of interest operably linked to expression control sequence. 14. The composition of paragraph 13, wherein the vector is a plasmid. 15. The composition of any one of paragraphs 1-14, wherein (b) includes a nucleic acid encoding a Cas endonuclease, a gRNA, or a combination thereof. 16. The composition of any one of paragraphs 1-15, wherein (b) includes a nucleic acid encoding a chimeric antigen receptor polypeptide. 17. The composition of any one of paragraphs 1-16, wherein (b) includes a functional nucleic acid. 18. The composition of any one of paragraphs 1-17, wherein (b) includes a nucleic acid encoding a functional nucleic acid. 19. The composition of paragraphs 17 or 18, wherein the functional nucleic acid is antisense molecules, siRNA, miRNA, aptamers, ribozymes, RNAi, or external guide sequences. 20. The composition of any one of paragraphs 1-19, wherein (b) includes a plurality of a single nucleic acid molecules. 21. The composition of any one of paragraphs 1-19, wherein (b) includes a plurality of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different nucleic acid molecules. 22. The composition of any one of paragraphs 1-21, wherein (b) includes or consists of nucleic acid molecules between about 1 and 25,000 nucleobases in length. 23. The composition of any one of paragraphs 1-22, wherein (b) includes or consists of single stranded nucleic acids, double stranded nucleic acids, or a combination thereof. 24. The composition of any one of paragraphs 1-23, further including carrier DNA. 25. The composition of paragraph 24, wherein the carrier DNA is non-coding DNA. 26. The composition of paragraphs 24 or 25, wherein (b) is composed of RNA. 27. A pharmaceutical composition including the composition of any one of paragraphs 1-26 and a pharmaceutically acceptable excipient. 28. The composition of paragraph 27 further including polymeric nanoparticles encapsulating a complex of (a) and (b). 29. The composition of paragraph 28, wherein a targeting moiety, a cell penetrating peptide, or a combination thereof is associated with, linked, conjugated, or otherwise attached directly or indirectly to the nanoparticle. 30. A method of delivering a nucleic acid cargo to a cell including contacting the cell with an effective amount of the composition of any one of paragraphs 1-29. 31. The method of paragraph 30, wherein the contacting occurs ex vivo. 32. The method of paragraph 31, wherein the cells are hematopoietic stem cells, or T cells. 33. The method of any one of paragraphs 30-32, further including administering the cells to a subject in need thereof. 34. The method of paragraph 33, wherein the cells are administered to the subject in an effective amount to treat one or more symptoms of a disease or disorder. 35. The method of paragraph 30 wherein the contacting occurs in vivo following administration to a subject in need thereof. 36. The method of any one of paragraphs 33-35, wherein the subject has a disease or disorder. 37. The method of paragraph 36, wherein the disease or disorder is a genetic disorder, cancer, or an infection or infectious disease. 38. The method of paragraphs 36 or 37, wherein (b) is delivered into cells of the subject in an effective amount to reduce one or more symptoms of the disease or disorder in the subject. 39. A method of making the composition of any one of paragraphs 1-29 including incubating and/or mixing of (a) and (b) for an effective amount of time and at a suitable temperature to form complexes of (a) and (b), prior to contact with cells. 40. A method of making the composition of any one of paragraphs 1-29, including incubating and/or mixing of (a) and (b) for between about 1 min and about 30 min, about 10 min and about 20 min, or about 15 min, optionally at room temperature or 37 degrees Celsius. 41. The composition or method of any one of the foregoing paragraphs wherein the ratio of (a):(b) is between 1:3 and 5:1, optionally wherein the ratio is 1:1 or 3:1. 42. A method of increasing activation of an immune receptor in cells of a subject in need thereof including administering an effective amount of (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof, optionally wherein the immune receptor is cGAS or another Pattern Recognition Receptor (PRR) optionally a toll-like receptor optionally TLR7. 43. The method of paragraph 42, wherein the subject has cancer or an infection. 44. The method of paragraphs 42 or 43, wherein the subject does not have cancer. 45. The method of any one of paragraphs 42-44, wherein the subject has a wound that needs healing. 46. The method of any one of paragraphs 42-44, wherein the subject has an immune dysregulation, optionally wherein the immune dysregulation is multiple sclerosis. 47. The method of any one of paragraphs 42-46, further including administering the subject (b) an additional agent. 48. The method of paragraph 47, wherein (b) is selected from a nucleic acid cargo, immunostimulatory nucleic acids, one or more vaccine component, an immune checkpoint modulator that induces, increases, or enhances an immune response, and combinations thereof. 49. A method of treating cancer or an infection including administering to a subject in need thereof an effective amount of the combination of (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) an immune checkpoint modulator that induces, increases, or enhances an immune response. 50. The method of any one of paragraphs 48-49, wherein the immune checkpoint modulator induces an immune response against the cancer or infection. 51. The method of any one of paragraphs 48-50, wherein the immune checkpoint modulator reduces an immune inhibitory pathway. 52. The method of paragraph 51, wherein the immune inhibitory pathway is the PD-1 pathway. 53. The method of any one of paragraphs 48-52, wherein the immune checkpoint modulator is selected from the group consisting of PD-1 antagonists, PD-1 ligand antagonists, and CTLA4 antagonists. 54. The method of any one of paragraphs 48-50, wherein the immune checkpoint modulator increases an immune activating pathway. 55. The method of any one of paragraphs 48-54, wherein the immune checkpoint modulator is an antibody. 56. The method of any one of paragraphs 48-54, wherein the immune checkpoint modulator is a CAR-T cell. 57. The method of any one of paragraphs 48-54, wherein the immune checkpoint modulator is an oncolytic virus. 58. A method of treating cancer or an infection including administering to a subject in need thereof an effective amount of the combination of (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) an immunostimulatory nucleic acid. 59. The method of paragraphs 48 or 58, wherein the immunostimulatory nucleic acid is a STING agonist. 60. A method of vaccinating a subject including administrating the subject (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) one or more vaccine components. 61. The method of paragraphs 48 or 60, wherein the one or more vaccine components include an antigen, a nucleic acid encoding an antigen, an adjuvant, a nucleic acid encoding an adjuvant, or a combination thereof. 62. The method of paragraph 61, wherein the antigen is derived from a bacteria or virus. 63. The method of any one of paragraphs 48-62, wherein administration of the combination (a) and (b) to the results in a more than additive reduction in one or more symptoms of cancer or infection compared to the reduction achieved by administering (a) or (b) in the absence of the other. 64. The method of any one of paragraphs 48-63, wherein (a) is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of (b) to the subject. 65. The method of any one of paragraphs 48-63 wherein (b) is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of (a) to the subject. 66. The method any one of paragraphs 42-65 further including administering to the subject one or more additional active agents selected from the group consisting of a chemotherapeutic agent, an anti-infective agent, and combinations thereof. 67. The method of any one of paragraphs 42-66 further including surgery or radiation therapy. 68. The method of any one of paragraphs 42-67 including a nucleic acid cargo. 69. The method of paragraph 68, wherein the (a) and the nucleic acid cargo are in a complex. 70. The method of paragraphs 68 or 69, wherein (b) is the nucleic acid cargo, optionally wherein the nucleic acid cargo is composed of includes DNA, RNA, PNA, PMO, or other modified nucleic acids, or nucleic acid analogs, or a combination thereof. 71. The method of paragraphs 68 or 69, wherein (b) is not the nucleic acid cargo. 72. The method of any one of paragraphs 42-71, wherein (a) includes: (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv). 73. The method of any one of paragraphs 42-72, wherein (a) includes the same or different epitope specificity as monoclonal antibody 4H2. 74. The method of any one of paragraphs 42-73, wherein (a) is a recombinant antibody having the paratope of monoclonal antibody 4H2. 75. The method of any one of paragraphs 42-74, wherein (a) include: (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv) 76. The method of any one of paragraphs 42-75, wherein (a) is bispecific. 77. The method of paragraph 76, wherein (a) targets a cell type of interest. 78. A pharmaceutical composition including (a) and (b) of any one of paragraphs 48-77 and a pharmaceutically acceptable excipient. 79. The pharmaceutical composition of paragraph 78 including a nucleic acid cargo. 80. The pharmaceutical composition of paragraph 79, wherein (b) is the nucleic acid cargo. 81. The pharmaceutical composition of paragraph 79, wherein (b) is not the nucleic acid cargo. 82. The pharmaceutical composition of any one of paragraphs 79- 81, wherein (a) and nucleic acid cargo are in a complex. 83. The pharmaceutical composition of paragraph 82 further including polymeric nanoparticles encapsulating (a), (b), the nucleic acid cargo, or a combination thereof. 84. The pharmaceutical composition of any one of paragraphs 78- 83, wherein a targeting moiety, a cell penetrating peptide, or a combination thereof is associated with, linked, fused, conjugated, or otherwise attached directly or indirectly to (a), (b), the nucleic acid cargo, the nanoparticle, or a combination thereof. 85. A composition including (a) a bispecific binding protein including (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (ai) or (aii); (iv) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv), and a binding domain that binds to an immune cell marker. 86. The composition of paragraph 85, wherein the immune cell marker is CD5. 87. The composition of paragraph 86, wherein the binding domain that binds to CD5 includes (vi) the CDRs of SEQ ID NO:24 in combination with the CDRs of SEQ ID NO:23; (vii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:25-27, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:28-30, respectively; (viii) a humanized form of (iv) or (iiv); (ix) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:24 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:23; or (x) a humanized form of (ix). 88. The composition of any one of paragraphs 85-87 including (b) a nucleic acid cargo including a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. 89. A method of increasing an immune response in a subject in need thereof including administering the subject an effective amount of the composition of any one of paragraphs 85-88. 90. The method of claim 89, wherein the subject has cancer or an infection. 91. A binding protein optionally an antibody including (i) the CDRs of SEQ ID NO:24 in combination with the CDRs of SEQ ID NO:23; (ii) first, second, and third heavy chain CDRs including the amino acid sequences of SEQ ID NOS:25-27, respectively in combination with first, second and third light chain CDRs including the amino acid sequences of SEQ ID NOS:28-30, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:24 in combination with a light chain including an amino acid sequence including at least 85% sequence identity to SEQ ID NO:23; or (v) a humanized form of (iv). Examples Autoantibodies reactive against host DNA contribute to the inflammation and type I interferon signature associated with systemic lupus erythematosus (SLE) (Nehar-Belaid, et la., Nat Immunol 2(9): 1094-1106 (2020), Li, et al., Clin Exp Immunol 159(3): 281-291 (2010)). Some anti- DNA autoantibodies penetrate live cells, avoid lysosomal degradation, and traffic into the nucleus or the cytoplasm (Hansen, et al., J Biol Chem.282: 20790-20793 (2007), Noble, et al., Nat Rev Rheumatol 12(7): 429-34 (2016)). The cGAS cytoplasmic nucleic acid sensor causes activation of the STING/interferon pathway in a central mechanism of innate immunity (Wan, et al., Front Immunol.13: 826880 (2022)), and it is presently unknown if there is an interplay between cytoplasmic-localizing anti-DNA autoantibodies and cGAS activity. Anti-DNA autoantibodies exhibit a diverse repertoire of nucleic acid binding specificities, with some recognizing multiple conformations and sequences of DNA (Shoenfeld, et al., N Engl J Med.308(8): 414-420 (1983)) and others exhibiting fine specificity for individual nucleosides (Weisbar, et al., Clin Immunol and Immunopathol.27: 403-11 (1983), Yee & Weisbart, Clin Immunol and Immunopathol.36: 161-67 (1985)). Guanosine (GUO) is the most immunogenic nucleoside, and anti-GUO autoantibody titers correlate better with SLE disease than other anti-DNA autoantibodies (Stollar & Borel, J Immunol 117: 1308-1313 (1976), Colburn, et al., Lupus 10: 410-7 (2001), Weisbar, et al., Clin Immunol and Immunopathol.27: 403- 11 (1983)). Remarkably, anti-GUO autoantibodies in SLE patient serum bind the same epitope on GUO as G-proteins (Colburn, et al., Journal of Rheumatology 30(5): 993-97 (2003), Pai, et al., Nature 341: 209-14 (1989)), and cell-penetrating anti-GUO autoantibodies are thought to perturb G- protein mediated cell signaling (Colburn & Green, Clin Chim Acta 370: 9-16 (2006)). Multiple cell-penetrating anti-DNA autoantibodies have been isolated from murine models of SLE. While most of these antibodies penetrate live cell nuclei, the anti-GUO autoantibody 4H2 is distinguished by its cytoplasmic localization. The epitope on GUO to which 4H2 binds maps to the site to which G-proteins bind, matching reports on anti-GUO autoantibody binding in human SLE patient serum (Colburn, et al., Journal of Rheumatology 30(5): 993-97 (2003)). Additionally, 4H2 penetrates and reduces cAMP concentrations in cultured cells, consistent with interference with G-protein signaling (Colburn & Green, Clin Chim Acta 370: 9-16 (2006)). The results presented below show that 4H2 cytoplasmic penetration is linked to nucleoside transport, and that 4H2 binds and mediates delivery of nucleic acids, and binds and enhances the activity of cGAS to cause cGAS- dependent toxicity to tumor cells. Example 1: 4H2 localizes to the cytoplasm of cancer cells and avoids endosomes and lysosomes. Materials and Methods Hybridomas and cell lines. The 4H2 hybridoma was obtained under MTA with the University of California, Los Angeles. The hybridoma was maintained and antibody was purified from supernatants as previously described (Noble, et al., Sci Rep 4: 5958 (2014)). IgG control is murine monoclonal IgG2a. A humanized, deimmunized, and CDR-optimized di-scFv fragment of 3E10, referred to as Deoxymab-1 (“DX1”), was purified from CHO cell media as previously described (Rattray, et al., JCI Insight 6(14): e145875 (2021)), which is specifically incorporated by reference herein in its entirety. Cal12T cells were obtained from Horizon Discovery Ltd (Cambridge, UK). U87, A549, and H358 cells were obtained from the ATCC. hCMEC/D3 cells were purchased MilliporeSigma (SCC066). NHA were purchased from Lonza. Murine GSCs syngeneic with C57/BL6 mice were obtained from MD Anderson Cancer Center. Cells were grown in culture 10% FBS supplemented RPMI 1640 and maintained at 37^oC/5% CO₂. Cell penetration and co-localization immunofluorescence assays. Live Cal12T cells were grown on glass coverslips and treated with control media or media containing 0.5 mg/mL 4H2 for one hour. Cells were then washed and fixed, and intracellular location of 4H2 was detected by immunostaining with an Alexa Fluor 488-conjugated goat anti-mouse IgG antibody (Cell Signaling, Danvers, MA) as previously described (Chang, et al., Acta neuropathol Commun 9: 112 (2021)). For co-localization studies, the fixed cells were also probed overnight with separate rabbit primary antibodies to detect endosomes (C45B10 anti-EEA1 antibody, Cell Signaling), lysosomes (D2D11 anti-LAMP1 antibody, Cell Signaling), endoplasmic reticulum (C81H6 anti-PDI antibody, Cell Signaling), Golgi apparatus (D2B6N anti-RCAS1 antibody, Cell Signaling), mitochondria (3E11 anti-COX IV, Cell Signaling), after which they were washed with PBS and incubated with an Alexa Fluor 555-conjugated goat anti-rabbit IgG antibody (Cell Signaling) at room temperature for one hour. After a final series of washes, cells were treated with Prolong Gold Antifade Reagent with DAPI (Cell Signaling) and imaged using an EVOS fl digital fluorescence microscope (Advanced Microscopy Group, Bothell, WA) under light, DAPI, GFP, or RFP filters. Fluorescence images were merged using ImageJ (NIH, Bethesda, MD). For DP studies, cells were pre-treated with control media or media containing 100 mM DP (MilliporeSigma, D9766) for thirty minutes, followed by addition of 1 mg/mL 4H2 for one hour, and then evaluated for cellular penetration as described above.4H2 fluorescence intensity from a minimum of 30 cells was quantified using ImageJ. FITC-labeling of 4H2 and live cell imaging. Purified 4H2 was labeled with FITC using the Pierce FITC Antibody Labeling Kit (Thermo Fisher Scientific, Waltham, MA). For the live cell penetration assays Cal12T and A549 cells were treated with FITC-labeled 4H2 at 0.5 mg/mL overnight, and then treated with 500 nM MitoTracker Red FM (Thermo Fisher Scientific) for 45 minutes followed by 1 µg/mL Hoechst 33342 (Thermo Fisher Scientific) for 15 minutes. Cells were then washed with PBS and imaged using the EVOS fl digital fluorescence microscope. Western blotting. Cells were treated with media containing specified amounts of IgG control or 4H2 overnight, after which cell lysates were prepared, subjected to 4-15% SDS-PAGE, and nitrocellulose transfer. Membranes blocked with 5% milk in TBST were incubated with relevant primary antibodies overnight at 4^oC, washed and incubated with HRP-conjugated anti-rabbit or mouse IgG secondary antibodies (Cell Signaling) for one hour at room temperature. After additional washing, bands were detected by Lumiglo (Cell Signaling Technologies). Primary antibodies used include rabbit anti-p-ERK1/2 (T202/Y204) (Cell Signaling), rabbit anti-pan-ERK1/2 (Cell Signaling), or mouse anti-β-actin (Ambion, Austin, TX), NF-kB p65 rabbit antibody (Cell Signaling, #8242). Statistical analysis. Graphs were generated using GraphPad Prism version 9.4.1. P values were determined by Student’s t-test or log-rank test for in vivo studies. Error bars represent SEM. Results Previous work with 4H2 reported on its penetration into lymphocytes and thyroid epithelial cells (13). Experiments were designed to test penetration by 4H2 into cancer cells from solid tumors.4H2 purified from hybridoma supernatant migrated as expected on SDS-PAGE and penetrated cultured non-small cell lung cancer Cal12T cells and exhibited distinct cytoplasmic localization. Analysis of cell lysates twenty-four hours after treatment with 4H2 by western blot probed with anti-actin primary and anti- mouse IgG secondary antibodies revealed 4H2 heavy chain (HC) and light chain (LC) at their expected MW (Fig.1A). This demonstrated retention of intact antibody chains twenty-four hours after penetrating cells. Any contribution of fixation artifact was ruled out by live cell imaging of non- small cell lung cancer cells (A549 and Cal12T) treated with FITC-labeled 4H2 and counterstained with MitoTracker Red FM and Hoechst 33342 (ThermoFisher Scientific, Waltham, MA). Overlay of FITC, Hoechst, and MitoTracker images showed an absence of 4H2 FITC signal in the nuclei and confirmed overlap with MitoTracker consistent with previous reports (Colburn & Green, Clin Chim Acta 370: 9-16 (2006)). Antibody endocytosis and degradation in lysosomes is common, but 4H2 remained intact 24 hours after penetrating cells (Fig.1A). Fluorescence co-localization studies probed the intracellular location of 4H2. Cal12T cells treated with 4H2 were immunostained with Alexa Fluor 488-conjugated anti- mouse IgG antibody to detect 4H2 and rabbit primary antibodies to detect markers of early endosomes (EEA1), lysosomes (LAMP1), Golgi (RASC1), endoplasmic reticulum (PDI), and mitochondria (COX IV), followed by Alexa Fluor 555-conjugated anti-rabbit IgG antibody and DAPI nuclear counterstain (Cell Signaling Technology, Danvers, MA).4H2 did not co- localize with any of the organelles tested, including endosomes or lysosomes. Example 2: 4H2 reduces ERK1/2 activation. 4H2 was previously reported to reduce cAMP content in rat epithelial cells, indicative of interference with G-protein mediated signaling (Colburn & Green, Clin Chim Acta 370: 9-16 (2006)). Measurement of ERK1/2 phosphorylation that is downstream of Ras provides an alternate method for evaluating G-protein activity. Lysates of Cal12T cells treated with control media or 1 mg/mL IgG control or 4H2 were probed for total and phosphorylated ERK1/2 content by western blot.4H2 did not impact total ERK1/2 content but reduced its phosphorylation, while IgG control had no effect on total or pERK1/2 (Fig.1B). These results are consistent with interference with G-protein signaling by 4H2. Example 3: 4H2 penetrates live cells through a nucleoside transporter- dependent mechanism. The lack of early degradation and the avoidance of endosomes/lysosomes by 4H2 observed here indicates a non-endocytic mechanism of cellular penetration. Previous work has shown that 3E10, a nuclear-penetrating anti-DNA autoantibody isolated from the same lupus model that yielded 4H2, uses an equilibrative nucleoside transporter (ENT) to traverse membranes and to cross the blood-brain barrier (BBB) (Hansen, et al., J Biol Chem.282: 20790-20793 (2007), Rattray, et al., JCI Insight 6(14): e145875 (2021)). Preliminary data reported in a meeting abstract showed a similar role for nucleoside transporters in 4H2 uptake into Jurkat cells (Andersen, et al., J Investig Med.57(1): 168 (2009)). Experiments were designed to probe the dependence of 4H2 transport on nucleoside transport by treating Cal12T cells with the transport inhibitor dipyridamole (DP) and examine its effect on subsequent efficiency of cellular penetration by 4H2. 4H2 penetration was reduced to 0.29±0.03 (P<0.0001) in the presence of DP relative to its absence (images quantified by ImageJ in Fig.1C). This indicates 4H2, like 3E10, uses a nucleoside transporter-dependent mechanism of transport into cells. Example 4: 4H2 binds RNA in cells 3E10 and 4H2 are anti-DNA antibodies isolated from the same lupus model, and both use nucleoside transport to penetrate cells. However, they exhibit disparate patterns of intracellular localization (3E10: nuclear, 4H2: cytoplasmic). It was initially believed that 4H2 is simply unable to traverse the nuclear envelope, and that 4H2 would bind nuclear DNA if it was able to access to it. If correct, comparisons between 4H2 and 3E10 might then facilitate further elucidation of the mechanism by which 3E10 crosses the nuclear membrane. EO771 cells, pre-fixed with chilled ethanol to expose both cytoplasmic and nuclear antigens, were probed with IgG control, 3E10 in IgG1 Deoxymab format also referred to herein as “Deoxymab-3” and “DX3” (Shirali, et al., DNA-targeting and cell-penetrating antibody-drug conjugate. bioRxiv. doi: doi.org/10.1101/2023.04.12.536500)), or 4H2. IgG control showed minimal binding to the cells, and DX3 showed specific nuclear binding. However, 4H2 signal was still primarily in the cytoplasm despite its access to the exposed nuclear contents yielded by pre-fixation in ethanol. An important difference between images of live and pre-fixed EO771 cells treated with 4H2 indicate an alternative explanation for 4H2 cytoplasmic rather than nuclear localization in live cells. No 4H2 signal was detectable in the nuclei of the live treated cells but discrete packets of 4H2 signal were observed in the nucleus of the fixed cells. These focal areas of 4H2 signal in the nucleus are consistent with 4H2 binding of nucleoli (Pederson, et al., Cold Spring Harb Perspect Biol.3, a000638 (2011)). Binding by 4H2 to cytoplasm and nucleoli raised the possibility that 4H2 preferentially binds RNA rather than DNA in cells. Consistent with this, the binding pattern of an anti-RNA IgG to pre-fixed EO771 cells closely matched the observed 4H2 pattern. To confirm 4H2 binds RNA in cells, EO771 cells were pre-fixed in chilled ethanol and incubated with IgG control or the anti-RNA IgG antibody (to block RNA binding sites) followed by incubation with FITC-labeled 4H2. Anti-RNA IgG, but not IgG control, interfered with 4H2-FITC binding to the cytoplasm and nucleoli, which confirmed that 4H2 binds to RNA in cells. Based on these findings, it is believed that RNA binding by 4H2 contributes to its sequestration in the cytoplasm. Example 5: GUO enhances cellular penetration by 4H2. Extracellular DNA/nucleosides promotes cellular penetration by 3E10 (Weisbart, et al., Sci Rep 5:12022 (2015), Chen, et al., Oncotarget 7(37): 59965-59975 (2016)) and drives its localization into necrotic tumors where DNA is released. This trait combined with its ability to cross the BBB underly the rationale for ongoing efforts to develop enhanced 3E10 fragments (e.g., DX1) for use in brain tumor therapy (Rattray, et al., JCI Insight 6(14): e145875 (2021)). After recognizing that 4H2 uses a similar mechanism of cellular penetration as 3E10 experiments were designed to determine if the addition of nucleoside, specifically GUO based on the known binding epitope of 4H2, would enhance 4H2 cellular penetration. Human U87 glioma and murine glioma stem-like cells (GSCs) were treated with control PBS, IgG control, DX1, or 4H2 and probed for antibody penetration by immunofluorescence. DX1 localized to nuclei and 4H2 to cytoplasm of both U87 and GSCs. IgG control did not markedly penetrate any cells. Addition of adenosine (ADE) enhanced nuclear penetration by DX1 into the GSCs to 1.7±0.01 compared to its penetration in media lacking ADE (P<0.0001) (Fig.2A). In contrast, ADE did not improve 4H2 penetration, with observed penetration ratio of 0.97±0.16 relative to the absence of ADE (ns) (Fig.2B). However, addition of GUO increased 4H2 penetration to 3.2±0.3 (P<0.0001) relative to its transit in the absence of GUO (Fig.2C). These findings are consistent with a nucleoside transporter- dependent and GUO-responsive mechanism of cellular penetration by 4H2. Example 6: 4H2 crosses a transwell model of the BBB in a nucleoside transporter-dependent manner. Materials and Methods Transwell model of the BBB. The ability of 4H2 to cross a transwell model of the BBB was tested using a previously described protocol (Rattray, et al., JCI Insight 6(14): e145875 (2021)). Briefly, hCMEC/D3 brain endothelial cells and normal human astrocytes (NHA) were respectively adhered to apical and basolateral sides of cell culture inserts (MilliporeSigma 353095) coated with fibronectin (MilliporeSigma F1141) and poly-L-lysine (MilliporeSigma P4832). Formation of a functional barrier was confirmed as previously described (REF), and BBB models treated with control buffer or 50 mM DP for 30 minutes followed by 5 mM 4H2 ± 50 mM DP. Relative 4H2 crossing of the barrier at 15 and 30 minutes in the presence or absence of DP was evaluated by ImageJ quantification of anti-mouse IgG dot blots on basolateral chamber contents. Results Nucleoside transport facilitates BBB crossing and brain tumor localization by 3E10 (Rattray, et al., JCI Insight 6(14): e145875 (2021)). Given similarities in mechanism of cellular penetration experiments were designed to determine if 4H2 would also cross the BBB and penetrate brain tumors. Consistent with this, 4H2 successfully crossed a transwell model of the BBB to move from apical to basolateral chambers. Treatment of the BBB with the nucleoside transport inhibitor dipyridamole (DP) prior to application of 4H2 reduced antibody transport, indicating nucleoside transport- dependent crossing (Fig.2D). Example 7: 4H2 localizes into orthotopic GBM, increases recruitment of TILs, and prolongs survival in vivo. Materials and Methods Orthotopic GBM studies. Studies were conducted under a Yale University IACUC approved protocol. Orthotopic GBM tumors were established in female C57/BL6 mice age 5-6 weeks by stereotactic injection of 50,000 cells (GSCs or GL261 engineered to express luciferase) using a previously described method (Rattray, et al., JCI Insight 6(14): e145875 (2021)). Mice with tumor formation confirmed by IVIS were randomized to treatment with tail vein injection of IgG control (40 mg/kg tail vein) or 4H2 (40 mg/kg tail vein) once per week for three weeks in the GSC study, and IgG control (40 mg/kg tail vein), 4H2 (40 mg/kg tail vein), anti-PD1 (5 mg/kg IP), and combinations thereof as described in the results in the GL261 study. Mice were closely monitored throughout and after treatment and were humanely euthanized for endpoints of neurologic change or weight loss. Kaplan Meier survival plots and median survivals were generated using GraphPad Prism version 9.4.1. For antibody localization studies, tumors and normal tissues were harvested 24 hours after a single tqil vein injection of IgG control or 4H2 (40 mg/kg), fixed in 10% neutral buffered formalin, and paraffin embedded. Presence of antibody was examined by IHC probed with anti- mouse IgG-HRP at 1:50 using a previously described protocols (Rattray, et al., JCI Insight 6(14): e145875 (2021)). Signal was developed with DAB and methylgreen counterstain. Results Mice with orthotopic GSC-derived brain tumors confirmed by IVIS were treated with a single dose of IgG control or 4H2 at 40 mg/kg by tail vein injection. Tumors and normal tissues were harvested after twenty-four hours and presence of antibody evaluated by IHC. Significant antibody staining was detected in the cytoplasm of GBM tumor cells after treatment with 4H2, but not IgG control. No antibody stain was detected in normal brain tissue remote from the tumors in mice treated with IgG control or 4H2. In normal tissues, 4H2 showed an increased localization to kidney compared to IgG control, but otherwise similar distribution of antibodies was seen in skeletal muscle. Mice bearing orthotopic GSC-derived GBM tumors were randomized to treatment with IgG control (N=4) or 4H2 (N=5) at 40 mg/kg by tail vein injection weekly for three weeks and monitored for toxicity and survival. No adverse effects were observed.4H2 increased median survival by 66% compared to mice treated with IgG control (**P<0.01, log-rank test). Survival to study completion was 40% in the group treated with 4H2 and 0% in the IgG control group (Fig.3A, Table 1). Table 1: Median and percentage of survival at study completion in C57/BL6 mice with GSC-derived orthotopic GBM tumors treated with IgG control or 4H2.

BM tumors randomized to weekly treatment for three weeks with IgG control (N=6), 4H2 (N=6), anti-PD1 (N=6), anti-PD1 + IgG control (N=7), and anti- PD1 + 4H2 (N=7) were monitored for toxicity and survival. No adverse effects were observed.4H2 yielded a 32% increase in median survival compared to IgG control (*P=0.03, log-rank test). When combined with anti- PD1, 4H2 increased median survival by 50% compared to anti-PD1 + IgG control (*P=0.02, log-rank test). Groups treated with 4H2 alone or 4H2 + anti-PD1 showed 33% and 29% survival to study completion, respectively, compared to 0% in all other groups (Fig.3B, Table 2). These findings demonstrate efficacy of 4H2 as a single agent and in combination with anti- PD1 against GL261 GBM tumors. Table 2: Median and percentage of survival at study completion in C57/BL6 mice with GL261-derived orthotopic GBM tumors treated with combinations of IgG control, 4H2, or anti-PD1. survival caused

by 4H2 could be a consequence of cGAS-mediated senescence/toxicity to GBM tumor cells, cGAS-mediated enhancement of immune response, or a combination thereof. Tumors from mice meeting criteria for euthanasia (N=4 and 3 for IgG control and 4H2 groups, respectively) were evaluated by TUNEL and CD8+ T cell staining.4H2 was associated with an increase in tumor TUNEL signal and CD8+ T cell content by factors of 4.5±0.6 and 1.5±0.2, respectively, as compared to tumors in mice treated with IgG control (P<0.05) (Fig.4A, 4B). Treatment with 4H2 was associated with an increase in CD8 content in tumors by 53%, with relative content of 1.53±0.15 compared to IgG control (*P<0.03) (Fig.4B). This demonstrates an increase in TILs caused by 4H2, and point to an immune mediated component of response to 4H2. To test the importance of the immune system in mediating the anti- tumor effect of 4H2, athymic nude mice bearing intracranial PPQ GBM tumors were randomized to treatment once or twice weekly with IgG control (N=4 and 6, respectively) or 4H2 (N=4 and 6, respectively) and survival measured. No adverse effects of 4H2 were observed.4H2 did not yield any significant improvement in median survival compared to IgG control, and survival to study completion was 0% in all groups (Fig.4C, 4D, Tables 3, 4). These results indicate that the anti-tumor effect of 4H2 in vivo is dependent on T cells in a functional immune system. Table 3: Median and percentage survival at study completion in athymic nude mice with PPQ orthotopic GBM tumors treated with weekly IgG control or 4H2.4H2 did not change survival compared to IgG control (P=ns, log-rank test).

Table 4: Median and percentage survival at study completion in athymic nude mice with PPQ orthotopic GBM tumors treated with twice weekly IgG control or 4H2.4H2 did not change survival compared to IgG control (P=ns, log-rank test).

Example 8: 4H2 associates with cGAS in nucleic acid dependent manner. Materials and Methods GSC pulldown assay. GSCs treated with 1 mg/mL IgG control or 4H2 for one hour were washed and contents harvested using NE-PER^TM Nuclear and Cytoplasmic Extraction Kit (Thermo Fisher, #78833).50 mL 50% protein G bead slurry was added to the 500 mL final extraction volume for incubation at 4^oC with rotation for 1.5 hours. Beads were washed, and remaining bound proteins eluted in 40 ml SDS loading sample buffer. Samples were analyzed by western blot probed for Ras or cGAS with rabbit anti-mouse cGAS (Cell Signaling #31659) at 1:1000 and secondary goat anti-rabbit HRP (abcam ab205718) at 1:5000. cGAS binding studies. 2 mg recombinant human cGAS (Cayman) was incubated with 8 mg IgG control or 4H2 ± nucleic acid (1.25 mg PvuII-digested pcDNA3 and 50 mM GTP) in a volume of 500 mL PBS with 0.01% Triton X-100 for one hour at 4^oC with rotation.50 mL of 50% protein G bead slurry was added to the reaction and incubation continued for one hour at 4^oC with rotation. Beads were removed, washed five times in PBS + 0.05% Triton X100, and bound protein eluted in 50 mL gentle elution buffer (fisher). Samples were analyzed by western blot probed with rabbit monoclonal antibody against human cGAS (Cell Signaling, #15102) or HRP-linked horse anti-mouse IgG (Cell Signaling, #7076). Results Cyclic GMP-AMP synthase (cGAS) is a cytoplasmic nucleic acid sensor that plays a central role in innate immunity. When activated, cGAS produces cyclic GMP-AMP (cGAMP) to promote stimulator of interferon genes (STING) signaling and a type I interferon response (18). Leading theories on mechanisms responsible for the survival benefit afforded by 4H2 in the GBM models centered on perturbation of cell signaling and on enhanced immune response. An antibody pulldown assay was performed in GSCs after treatment with IgG control or 4H2 to probe for interactions between 4H2 and Ras or cGAS. Ras was chosen as a target based on its role as a key G-protein in cell signaling, and cGAS for its function as a cytoplasmic nucleic acid sensor that catalyzes cGAMP formation from GTP. No 4H2-Ras interaction was observed (Fig.5A), but cGAS yielded a hit with greater pulldown by 4H2 compared to IgG control (Fig.5B).4H2-cGAS binding was further evaluated by incubating purified cGAS with IgG control or 4H2 and testing for competitive inhibition of binding by addition of nucleic acid.4H2 binding to cGAS was confirmed and was reduced in the presence of nucleic acid, consistent with competitive inhibition. Background nonspecific cGAS binding by IgG control was not impacted by the presence of nucleic acid (Fig.5C, 5D). This result indicates that 4H2 may interact with cGAS in the cytoplasm of cells through binding to intermediary nucleic acids such as intrinsic mRNA or nucleic acids ferried into the cell bound to 4H2. Purified recombinant cGAS was incubated with IgG control or 4H2 +/- the nuclease benzonase to degrade any nucleic acid bound to 4H2, and antibodies and their interacting proteins were isolated using protein G.4H2 showed greater association with purified cGAS compared to protein G/IgG control, and addition of nuclease reduced the 4H2-cGAS interaction but not the nonspecific protein G/IgG control-cGAS association (Figs.5D-5F). These findings indicate a 4H2- cGAS interface that is dependent on the presence of nucleic acid. Example 9: 4H2 enhances cGAS activity. Materials and Methods cGAS activity assay. The effect of IgG control or 4H2 (0-160 mg) on relative cGAMP production was assayed using the cGAS Inhibitor Screening Assay Kit (#701930, Cayman) as per the manufacturer’s instructions. NF-kB assay. GSCs were treated with 1 mg/ml IgG control IgG or 4H2 for 18 hours in growth medium (DMEM+10% FBS). Cytoplasmic and nuclear fractions were harvested using with NE-PER^TM Nuclear and Cytoplasmic Extraction Kit (Thermo Fisher, #78833) and evaluated by NF-kB (Cell Signaling, #8242) western blot with Lamin B1 for loading control. cGAS knockdown and colony formation assays. GSCs grown in 6-well plates were transfected with 100 nM control or cGAS siRNA (Dharmacon) by RNAiMax (Thermo Fisher). cGAS knockdown was confirmed by western blot two days later. Cells were treated with IgG control or 4H2 (0-1.6 mM) and evaluated for clonogenic survival by colony formation assay. Results Activated cGAS catalyzes the formation of cGAMP from precursor molecules ATP and GTP. The impact of 4H2 on cGAS activity in vitro was evaluated by measuring relative cGAMP production by cGAS in the presence of IgG control or 4H2. Compared to IgG control, 4H2 increased cGAMP production up to 83%±18 (Fig.6A). cGAMP generated by cGAS promotes nuclear translocation by NF-kB, and experiments were designed to investigate the effect of 4H2 on NF-kB nuclear content in GSCs after treatment with IgG control or 4H2 by western blot. NF-kB nuclear content was increased in cells treated with 4H2 compared to IgG control (Fig.6B). Finally, GSCs were subjected to cGAS knockdown by siRNA, confirmed by western blot (Fig.6C). Control and cGAS-knockdown GSCs were treated with IgG control or 4H2 (0-1.6 mM) and evaluated by colony formation assay. cGAS knockdown significantly reduced sensitivity of the GSCs to 4H2, indicating cGAS-dependent toxicity (Fig.6D). Surviving fractions were 0.16±0.09 and 0.46±0.07 in control or cGAS-knockdown PPQ cells treated with 1.6 µM 4H2, respectively (P<0.05) (Fig.6D). cGAS- knockdown similarly diminished 4H2 impact on Cal12T cell survival (Fig. 6F). Western blots of cytoplasmic and nuclear contents of PPQ cells also revealed an increase in NF-ĸB nuclear content by a factor of 2.2±0.2 in 4H2 compared to IgG control-treated cells (P<0.05) (Fig.6E), consistent with 4H2-mediated cGAS activation. Example 10: 4H2 delivers nucleic acids to cells. Materials and Methods DNA binding assay. 0.5 mg circular or linearized pcDNA3 plasmid DNA (5.4 kb) was incubated with 10 mg IgG control or 4H2 in 50 ml buffer (PBS or binding buffer containing 10 mM Mg or 1 mM EDTA) for one hour at room temperature. Samples were evaluated by EMSA on 1% agarose gels stained with SYBR^TM Green I (Thermo Fisher). RNA binding assay. 0.2 mg total RNA or GFP mRNA was incubated with IgG control or 4H2 (0-4 mg) for one hour at room temperature. Samples were evaluated by EMSA on 1% agarose gels stained with SYBR^TM Green I (Thermo Fisher). Results cGAS is a cytoplasmic nucleic acid sensor that initiates an innate immune response. The findings above indicate that 4H2 interacts with cGAS and promotes its activity. The specifics of this interaction are unknown and may include direct binding or alternatively an indirect association through common binding to GUO-containing nucleic acid carried into the cytoplasm by 4H2. In considering this possibility, experiments were designed to explore the ability of 4H2 to carry exogenous DNA and RNA into cells.4H2 binding to circular and linearized plasmid DNA and to total and mRNA was confirmed by EMSA (Fig.7A, 7B). A luciferase expression plasmid mixed with 4H2 or DX1 was added to U87 glioma cells in culture, and luciferase signal measured after twenty-four hours. Minimal luciferase signal was seen in cells treated with DX1 + plasmid, while 4H2 + plasmid yielded a much stronger signal (Fig.8A). Luciferase mRNA was encapsulated into lipid nanoparticles (MC3-LNP) or mixed with DX1 or 4H2 and added to U87 glioma cells in culture, and luciferase signal measured after twenty-four hours.4H2 + mRNA and mRNA loaded MC3-LNPs yielded similar luciferase signal, while DX1 + mRNA showed no apparent signal (Fig.8B). Example 11: 4H2 mediates local gene delivery in vivo. Materials and Methods Nucleic acid delivery assays. For DNA, pGL4.13 (luc2/SV40) plasmid was incubated with DX1 or 4H2 and added to U87 glioma cells in culture. Luciferase activity was assayed after 24 hours. For RNA, Luc mRNA was incubated with DX1 or 4H2 or was encapsulated into MC3-LNP lipid nanoparticles. Samples were added to U87 glioma cells in culture. Luciferase activity was assayed after 24 hours. mRNA delivery to brain and retina. Studies were conducted under a Yale University IACUC approved protocol. Female Ai9 Cre reporter mice ages 5-6 weeks (The Jackson Laboratory) were treated with intracranial or intraocular injection of 4H2/Cre mRNA (w/w 3). Brains and eyes were harvested after twenty-four hours and sectioned for immunofluorescence. Functional Cre recombinase activity is detected by visualizing RFP fluorescence. mRNA delivery to tumors. Studies were conducted under a Yale University IACUC approved protocol. H358 tumors were generated by subcutaneous injection into the flanks of female nude mice ages 5-6 weeks using a previously described protocol (Chen, et al., Oncotarget 7(37): 59965-59975 (2016)). Tumor formation was followed by caliper measurement. Once tumors reached ~100 mm³ mice were administered intratumoral injection of mixtures of luciferase (Luc) mRNA with DX1 or 4H2 at w/w of 3. Luciferase signal was visualized by IVIS as previously described (Rattray, et al., JCI Insight 6(14): e145875 (2021)). mRNA delivery to skeletal muscle. Studies were conducted under a Yale University IACUC approved protocol. Female C57/BL6 mice ages 5-6 weeks were treated with intramuscular injection of mixtures of luciferase (Luc) mRNA with DX1 or 4H2 at w/w of 3 (left quadriceps) or 1 (right quadriceps). Luciferase signal was visualized by IVIS as previously described (Rattray, et al., JCI Insight 6(14): e145875 (2021)). Results Systemically administered 4H2 showed increased localization to orthotopic brain tumors compared to IgG control, but not to normal brain (Fig.3A, 3B). This is believed to reflect DNA/nucleoside release by necrotic GBM tumors promoting tumor localization by 4H2 through nucleoside transporters. Nucleoside transporters are expressed in normal brain (Chang, et al., Acta neuropathol Commun 9: 112 (2021)), and experiments were designed to test if direct injection of a mix of 4H2 and nucleic acid would promote uptake to yield local gene expression. Ai9 mice engineered to generate RFP in tissues upon expression of Cre recombinase were used to examine 4H2-mediated gene delivery in the brain. Mice were treated by injection of 4H2 + Cre mRNA into the brain, and RFP signal measured after twenty-four hours. RFP signal reflecting Cre activity was detected along the injection track in the brain (Fig.9A). In a separate experiment, Ai9 mice were treated by intraocular injection of 4H2 + Cre mRNA, and visualization of RFP signal twenty-four hours later revealed strong Cre activity in the retina, consistent with known expression of retinal nucleoside transporters (Dos Santos-Rodrigues, et al., Vitam Horm 98: 487-523 (2015)) and demonstrating retinal gene therapy mediated by 4H2 (Fig.9B). 4H2 delivery of mRNA to extracranial tissues was evaluated in tumors and skeletal muscle known to abundantly express nucleoside transporters. Nude mice with subcutaneous H358 flank tumors treated with intratumoral injection of DX1 + luciferase mRNA or 4H2 + luciferase mRNA were monitored for luciferase expression by serial IVIS. No signal was detected in tumors treated with DX1 + luciferase mRNA, but 4H2 + luciferase mRNA yielded strong and durable signal in tumors at 6, 24, and 72 hours (Fig.10A). No significant signal outside of tumors was observed. In a separate experiment, non-tumor bearing C57/BL6 mice that were treated by quadriceps injection of 4H2 + luciferase mRNA exhibited luciferase signal at 6 and 24 hours, localized to the injected muscles (Fig.10B). Example 12: 4H2 as a gene delivery carrier for treatment of NF2 Mouse xenografts were established through inoculation of luciferase- expressing HEI193 cells in the sciatic nerve.17 days later, the mice were imaged using IVIS. Based on the luciferase expression, the mice were grouped into 4 groups, which were treated with saline, 4H2 alone, 4H2 with plasmid carrying NF2 cDNA, and 4H2 mRNA through direct injection. The second treatment was given on day 42 after tumor inoculation. The growth of tumors was monitored by IVIS. Representative IVIS images (Fig.11A) and plot (Fig.11B) of luminescence over time are shown.4H2+DNA and 4H2+mRNA reduced tumor growth relative to untreated control and 4H2 alone, and further illustrates that ability of 4H2 to treat disease by delivery of therapeutic nucleic acids. Example 13: 4H2-CD5 bispecific antibody for targeted gene delivery to T cells. Figures 12A-12C exemplify the design and use of a 4H2-CD5 bispecific antibody for targeted gene delivery to T cells. 4H2 sequences VL: DIVLTQSPATLSVTPGDRVSLSCRASQSISNYLHWYQQKSHESPRLLIKYA SQSISGIPSRFSGSGSGTDFTLSIISVETEDFGMYFCQQSNSWPLTFGAGT KLELK (SEQ ID NO:1) VH: EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGRV NPSNGGISYNQKFKGKATLTVDKSLSTAYMQLNSLTSEDSAVYYCARGPYT MYYWGQGTSVTVSS (SEQ ID NO:5) CD5 sequences VL: NIVMTQSPSSLSASVGDRVTITCQASQDVGTAVAWYOQKPDQSPKLLIYWT STRHTGVPDRFTGSGSGTDFTLTISSLOPEDIATYFCHQYNSYNTFGSGTK LEIK (SEQ ID NO:23) VH: QVTLKESGPVLVKPTETLTLTCTFSGFSLSTSGMGVGWIRQAPGKGLEWVA HIWWDDDVYYNPSLKSRLTITKDASKDQVSLKLSSVTAADTAVYYCVRRRA TGTGFDYWGQGTLVTVSS (SEQ ID NO:24) Fig.12A is a schematic showing design of the 4H2-CD5 bispecific antibody. The Ai9 mouse model allows measurement of delivery of Cre recombinase through detection of DeRed expression. Ai9 mice bearing MC38 tumors were treated with control, 4H2 + Cre mRNA, or 4H2-CD5 bispecific antibody + Cre mRNA through intratumoral injection. After 48 hours, the mice were euthanized. The tumors were isolated and dissociated into single cells. T cells within the tumors were analyzed by flow cytometry for expression of DeRed. T cells in tumors treated with 4H2-CD5 + Cre mRNA showed increased DeRed signal compared to control or 4H2 + Cre mRNA. Representative FACS plots are shown in Fig.12B and combined analysis in Fig.12C. These experiments exemplify 4H2-based bispecific antibodies for use in strategies of nucleic acid delivery to specific cells based on the cell-penetrating and nucleic acid binding of 4H2 combined with the homing specificity provided by the second antibody component, in this case CD5 for T cells. Example 14: 4H2 binds and activates toll-like receptor 7 (TLR7) TLR7 is an intracellular pattern recognition receptor that recognizes RNA and initiates an innate immune response. TLR7 responds particularly well to GU-rich RNA.4H2 is an anti-G autoantibody. Experiment were designed to determine if 4H2 interacts with TLR7 in a nucleic acid- dependent manner similar to results found for the 4H2-cGAS interaction as exemplifed above. Cell lysates from glioma stem-like cells (GSCs) treated with IgG control or 4H2 were probed for TLR7 by western blot. The band representing activated cleaved TLR7 was significantly increased in cells treated with 4H2. Representative blot is shown in (Fig.13A) and cleaved TLR7 content relative to IgG control determined by ImageJ in (Fig.13B). These results indicate that 4H2 induces cleavage of TLR7. Antibodies and bound proteins were pulled down from lysates of GSCs treated with IgG control or 4H2 by protein G beads and then analyzed by TLR7 western blot (Fig.13C).4H2, but not IgG control, showed strong binding to cleaved TLR7 demonstrated by its pulldown with 4H2 in this assay. Blot is representative of two independent experiments. These results indicate that 4H2 binds cleaved TLR7. This adds another dimension to the use of 4H2 as a stimulator of immunity because 4H2 activates both cGAS and TLR7. TLR7 agonists have been sought for use in immunotherapy, but the combined activation of cGAS and TLR7 distinguishes 4H2 from other agonists that activate either TLR7 or cGAS, but not both. Summary This study reveals a previously unknown interaction between a lupus anti-GUO autoantibody and cGAS. Specifically, the cell-penetrating lupus anti-GUO autoantibody 4H2 localizes to cytoplasm and avoids endosomes, binds nucleic acid and delivers it to cells and tissues, activates cGAS, and causes cGAS-dependent toxicity to glioma cells and increases survival in orthotopic GBM models. These findings indicate opportunities to deploy anti-GUO autoantibodies in biotechnology and raise the possibility that such antibodies contribute to cGAS activation and the type I interferon signature associated with SLE. Nucleoside transporter-dependent cellular penetration by 4H2 is indicated by the inhibitory effects of the nucleoside transport inhibitor DP and the enhancement of 4H2 penetration by free GUO. Consistent with this, systemically administered 4H2 localized to brain tumors where DNA/nucleosides are released, but not to normal brain tissue. However, 4H2 was able to mediate gene delivery to normal brain when directly injected as a complex with mRNA. Similarly, 4H2/mRNA yielded local gene expression in the retina after intraocular injection and in extracranial target tissues including tumors and skeletal muscle. Taken together these findings link cellular penetration by 4H2 to nucleoside transport and establish 4H2 as a non-covalent cytoplasmic delivery ligand for nucleic acids. 4H2 and 3E10 were isolated from the same lupus model, and it is intriguing that they appear to share a nucleoside transporter-dependent mechanism of penetrating cells and crossing the BBB but at the same time they localize to completely different cellular compartments. Both avoid endosomes and lysosomes, but 3E10 localizes into nuclei and 4H2 to cytoplasm. The reason for the difference is presently unknown, but it may explain the greater ability of 4H2 to deliver functional mRNA to cells compared to 3E10 found here, because mRNA translation occurs in the cytoplasm and not the nucleus. The precise mechanism by which 4H2 activates cGAS and TLR7 is unknown. Possibilities include direct binding and activation by 4H2 or indirect binding through simultaneous interactions between cGAS and TLR7, 4H2, and cytoplasmic nucleic acid and/or GTP. Overall, with a nucleoside transporter-dependent method of cytoplasmic penetration and an ability to deliver nucleic acids to cells and activate cGAS and TLR7, 4H2 is a compelling agent for use in oncology as a stimulator of immunity, in gene therapy as a non-covalent cytoplasmic delivery ligand for nucleic acids, and in vaccine design for simultaneous gene delivery and activation of immune receptors such as cGAS and TLR7 to potentiate response. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim: 1. A composition comprising or consisting of (a) an intact 4H2 monoclonal antibody or a cell- penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) a nucleic acid cargo comprising a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof.

2. The composition of claim 1, wherein (a) comprises: (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv).

3. The composition of claims 1 or 2, wherein (a) comprises the same or different epitope specificity as monoclonal antibody 4H2.

4. The composition of any one of claims 1-3, wherein (a) is a recombinant antibody having the paratope of monoclonal antibody 4H2.

5. A composition comprising (a) a binding protein comprising (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv), and (b) a nucleic acid cargo comprising a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof.

6. The composition of any one of claims 1-5, wherein (a) is bispecific.

7. The composition of claim 6, wherein (a) targets a cell type of interest.

8. The composition of any one of claims 1-7, wherein (a) and (b) are non-covalently linked or associated.

9. The composition of any one of claims 1-8, wherein (a) and (b) are in a complex.

10. The composition of any one of claims 1-9 wherein (b) comprises DNA, RNA, PNA or other modified nucleic acids, or nucleic acid analogs, or a combination thereof.

11. The composition of any one of claims 1-10, wherein (b) comprises mRNA.

12. The composition of any one of claims 1-11, wherein (b) comprises a vector.

13. The composition of claim 12, wherein the vector comprises a nucleic acid sequence encoding a polypeptide of interest operably linked to expression control sequence.

14. The composition of claim 13, wherein the vector is a plasmid.

15. The composition of any one of claims 1-14, wherein (b) comprises a nucleic acid encoding a Cas endonuclease, a gRNA, or a combination thereof.

16. The composition of any one of claims 1-15, wherein (b) comprises a nucleic acid encoding a chimeric antigen receptor polypeptide.

17. The composition of any one of claims 1-16, wherein (b) comprises a functional nucleic acid.

18. The composition of any one of claims 1-17, wherein (b) comprises a nucleic acid encoding a functional nucleic acid.

19. The composition of claims 17 or 18, wherein the functional nucleic acid is antisense molecules, siRNA, miRNA, aptamers, ribozymes, RNAi, or external guide sequences.

20. The composition of any one of claims 1-19, wherein (b) comprises a plurality of a single nucleic acid molecules.

21. The composition of any one of claims 1-19, wherein (b) comprises a plurality of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different nucleic acid molecules.

22. The composition of any one of claims 1-21, wherein (b) comprises or consists of nucleic acid molecules between about 1 and 25,000 nucleobases in length.

23. The composition of any one of claims 1-22, wherein (b) comprises or consists of single stranded nucleic acids, double stranded nucleic acids, or a combination thereof.

24. The composition of any one of claims 1-23, further comprising carrier DNA.

25. The composition of claim 24, wherein the carrier DNA is non-coding DNA.

26. The composition of claims 24 or 25, wherein (b) is composed of RNA.

27. A pharmaceutical composition comprising the composition of any one of claims 1-26 and a pharmaceutically acceptable excipient.

28. The composition of claim 27 further comprising polymeric nanoparticles encapsulating a complex of (a) and (b).

29. The composition of claim 28, wherein a targeting moiety, a cell penetrating peptide, or a combination thereof is associated with, linked, conjugated, or otherwise attached directly or indirectly to the nanoparticle.

30. A method of delivering a nucleic acid cargo to a cell comprising contacting the cell with an effective amount of the composition of any one of claims 1-29.

31. The method of claim 30, wherein the contacting occurs ex vivo.

32. The method of claim 31, wherein the cells are hematopoietic stem cells, or T cells.

33. The method of any one of claims 30-32, further comprising administering the cells to a subject in need thereof.

34. The method of claim 33, wherein the cells are administered to the subject in an effective amount to treat one or more symptoms of a disease or disorder.

35. The method of claim 30 wherein the contacting occurs in vivo following administration to a subject in need thereof.

36. The method of any one of claims 33-35, wherein the subject has a disease or disorder.

37. The method of claim 36, wherein the disease or disorder is a genetic disorder, cancer, or an infection or infectious disease.

38. The method of claims 36 or 37, wherein (b) is delivered into cells of the subject in an effective amount to reduce one or more symptoms of the disease or disorder in the subject.

39. A method of making the composition of any one of claims 1- 29 comprising incubating and/or mixing of (a) and (b) for an effective amount of time and at a suitable temperature to form complexes of (a) and (b), prior to contact with cells.

40. A method of making the composition of any one of claims 1- 29, comprising incubating and/or mixing of (a) and (b) for between about 1 min and about 30 min, about 10 min and about 20 min, or about 15 min, optionally at room temperature or 37 degrees Celsius.

41. The composition or method of any one of foregoing claims wherein the ratio of (a):(b) is between 1:3 and 5:1, optionally wherein the ratio is 1:1 or 3:1.

42. A method of increasing activation of an immune receptor in cells of a subject in need thereof comprising administering an effective amount of (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof, optionally wherein the immune receptor is cGAS or another Pattern Recognition Receptor (PRR) optionally a toll-like receptor optionally TLR7.

43. The method of claim 42, wherein the subject has cancer or an infection.

44. The method of claims 42 or 43, wherein the subject does not have cancer.

45. The method of any one of claims 42-44, wherein the subject has a wound that needs healing.

46. The method of any one of claims 42-44, wherein the subject has an immune dysregulation, optionally wherein the immune dysregulation is multiple sclerosis.

47. The method of any one of claims 42-46, further comprising administering the subject (b) an additional agent.

48. The method of claim 47, wherein (b) is selected from a nucleic acid cargo, immunostimulatory nucleic acids, one or more vaccine component, an immune checkpoint modulator that induces, increases, or enhances an immune response, and combinations thereof.

49. A method of treating cancer or an infection comprising administering to a subject in need thereof an effective amount of the combination of (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) an immune checkpoint modulator that induces, increases, or enhances an immune response.

50. The method of any one of claims 48-49, wherein the immune checkpoint modulator induces an immune response against the cancer or infection.

51. The method of any one of claims 48-50, wherein the immune checkpoint modulator reduces an immune inhibitory pathway.

52. The method of claim 51, wherein the immune inhibitory pathway is the PD-1 pathway.

53. The method of any one of claims 48-52, wherein the immune checkpoint modulator is selected from the group consisting of PD-1 antagonists, PD-1 ligand antagonists, and CTLA4 antagonists.

54. The method of any one of claims 48-50, wherein the immune checkpoint modulator increases an immune activating pathway.

55. The method of any one of claims 48-54, wherein the immune checkpoint modulator is an antibody.

56. The method of any one of claims 48-54, wherein the immune checkpoint modulator is a CAR-T cell.

57. The method of any one of claims 48-54, wherein the immune checkpoint modulator is an oncolytic virus.

58. A method of treating cancer or an infection comprising administering to a subject in need thereof an effective amount of the combination of (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) an immunostimulatory nucleic acid.

59. The method of claims 48 or 58, wherein the immunostimulatory nucleic acid is a STING agonist.

60. A method of vaccinating a subject comprising administrating the subject (a) an intact 4H2 monoclonal antibody or a cell-penetrating fragment thereof, optionally selected from a monovalent, divalent, or multivalent single chain variable fragment (scFv), or a diabody; or humanized form, chimeric form, or variant thereof; and (b) one or more vaccine components.

61. The method of claims 48 or 60, wherein the one or more vaccine components include an antigen, a nucleic acid encoding an antigen, an adjuvant, a nucleic acid encoding an adjuvant, or a combination thereof.

62. The method of claim 61, wherein the antigen is derived from a bacteria or virus.

63. The method of any one of claims 48-62, wherein administration of the combination (a) and (b) to the results in a more than additive reduction in one or more symptoms of cancer or infection compared to the reduction achieved by administering (a) or (b) in the absence of the other.

64. The method of any one of claims 48-63, wherein (a) is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of (b) to the subject.

65. The method of any one of claims 48-63 wherein (b) is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of (a) to the subject.

66. The method any one of claims 42-65 further comprising administering to the subject one or more additional active agents selected from the group consisting of a chemotherapeutic agent, an anti-infective agent, and combinations thereof.

67. The method of any one of claims 42-66 further comprising surgery or radiation therapy.

68. The method of any one of claims 42-67 comprising a nucleic acid cargo.

69. The method of claims 68, wherein the (a) and the nucleic acid cargo are in a complex.

70. The method of claims 68 or 69, wherein (b) is the nucleic acid cargo, optionally wherein the nucleic acid cargo is composed of comprises DNA, RNA, PNA, PMO, or other modified nucleic acids, or nucleic acid analogs, or a combination thereof.

71. The method of claims 68 or 69, wherein (b) is not the nucleic acid cargo.

72. The method of any one of claims 42-71, wherein (a) comprises: (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv).

73. The method of claims any one of claims 42-72, wherein (a) comprises the same or different epitope specificity as monoclonal antibody 4H2.

74. The method of any one of claims 42-73, wherein (a) is a recombinant antibody having the paratope of monoclonal antibody 4H2.

75. The method of any one of claims 42-74, wherein (a) comprise: (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv)

76. The method of any one of claims 42-75, wherein (a) is bispecific.

77. The method of claim 76, wherein (a) targets a cell type of interest.

78. A pharmaceutical composition comprising (a) and (b) of any one of claims 48-77 and a pharmaceutically acceptable excipient.

79. The pharmaceutical composition of claim 78 comprising a nucleic acid cargo.

80. The pharmaceutical composition of claim 79, wherein (b) is the nucleic acid cargo.

81. The pharmaceutical composition of claim 79, wherein (b) is not the nucleic acid cargo.

82. The pharmaceutical composition of any one of claims 79-81, wherein (a) and nucleic acid cargo are in a complex.

83. The pharmaceutical composition of claim 82 further comprising polymeric nanoparticles encapsulating (a), (b), the nucleic acid cargo, or a combination thereof.

84. The pharmaceutical composition of any one of claims 78-83, wherein a targeting moiety, a cell penetrating peptide, or a combination thereof is associated with, linked, fused, conjugated, or otherwise attached directly or indirectly to (a), (b), the nucleic acid cargo, the nanoparticle, or a combination thereof.

85. A composition comprising (a) a bispecific binding protein comprising (i) the CDRs of SEQ ID NO:5 in combination with the CDRs of SEQ ID NO:1; (ii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:6-8, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:2-4, respectively; (iii) a humanized form of (ai) or (aii); (iv) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:5 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:1; or (v) a humanized form of (iv), and a binding domain that binds to an immune cell marker.

86. The composition of claim 85, wherein the immune cell marker is CD5.

87. The composition of claim 86, wherein the binding domain that binds to CD5 comprises (vi) the CDRs of SEQ ID NO:24 in combination with the CDRs of SEQ ID NO:23; (vii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:25-27, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:28-30, respectively; (viii) a humanized form of (iv) or (iiv); (ix) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:24 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:23; or (x) a humanized form of (ix).

88. The composition of any one of claims 85-87 comprising (b) a nucleic acid cargo comprising a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof.

89. A method of increasing an immune response in a subject in need thereof comprising administering the subject an effective amount of the composition of any one of claims 85-88.

90. The method of claim 89, wherein the subject has cancer or an infection.

91. A binding protein optionally an antibody comprising (i) the CDRs of SEQ ID NO:24 in combination with the CDRs of SEQ ID NO:23; (ii) first, second, and third heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:25-27, respectively in combination with first, second and third light chain CDRs comprising the amino acid sequences of SEQ ID NOS:28-30, respectively; (iii) a humanized form of (i) or (ii); (iv) a heavy chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:24 in combination with a light chain comprising an amino acid sequence comprising at least 85% sequence identity to SEQ ID NO:23; or (v) a humanized form of (iv).