Compositions and methods for delivering DNA

Abstract

Provided herein are compositions and methods to protect cargo DNA when it is loaded into lipid nanoparticles (LNPs) or similar nanocarrier systems. In certain embodiments, the compositions include a lipid nanoparticle (LNP) that includes a DNA cargo and a molecule capable of condensing and / or compacting DNA. In certain embodiments, the compositions also include a "helper molecule" that provides reduced inflammatory response and reduced DNA degradation by DNAse enzymes and autophagy / xenophagy during and after endosomal escape, upon administration.

Description

[0001] COMPOSITIONS AND METHODS FOR DELIVERING DNA Statement of Government Support This invention was made with government support under HL153510, HL160694, and AI166778 awarded by the National Institutes of Health. The government has certain rights in the invention. Background of the Invention The success of the COVID-19 vaccines showed the unprecedented power of lipid nanoparticles (LNPs) to deliver nucleic acids to target cells, driving levels of expression of encoded proteins far higher than all prior non-viral technologies. This triumph spurred the biopharma industry to invest tens of billions of dollars in LNP-based therapeutics, where LNPs’ ability to be targeted to specific organs and cell types has enabled applications in many types of disease. In the COVID-19 vaccines and many other applications of LNPs, the nucleic acid cardo has been mRNA, which can transiently express encoded proteins. However, LNPs’ sole focus on mRNA delivery may prevent LNPs from reaching their full therapeutic potential, as mRNA has a short half-life (~hours to a couple days)1, lacks a promoter region to achieve cell-type-specific and temporal control, and is not stable for long at room temperature or 4°C. DNA could overcome many of the challenges associated with the use of mRNA, and thereby open up new applications for LNPs. DNA can express proteins in cells for several months2,3, has a promoter that can be made cell-type-specific and / or turned on / off with small molecule drugs (such as a doxycycline-sensitive promoter), is much cheaper to manufacture than mRNA, and can be stored for months or years at 4°C. Such advantages of DNA could open up LNPs’ applications to include long-term expression, including monoclonal antibodies, secreted proteins, or even intracellular proteins, with the half-life of the engineered proteins not being a problem because of constant protein production. Additionally, DNA can be used to express short-hairpin RNA (shRNA) to knockdown proteins long-term, gene editing proteins and guide RNAs, and nearly any other genetically encoded product. For each of these genetic cargo, DNA-loaded LNPs (DNA-LNPs) would offer the advantages of long-term expression (and thus infrequent dosing) and low cost-of- goods-sold (COGS), along with the advantages LNPs already provide, including high levels of expression, low immunogenicity (compared to viral vectors), and fewer limitations on cargo size. These collective benefits of DNA-LNPs would enable treatment of diseases that are less accessible to mRNA-LNPs, such as diseases of chronic autoimmunity, degeneration, pain, and more. While DNA seems a natural fit for LNPs, DNA-LNPs have witnessed very few publications in the 15– 20 years since LNPs were developed. There are 3 main challenges in DNA delivery via lipid nanoparticles (DNA-LNPs): A) toxicity due to the activation of acute inflammatory pathways, B) DNA degradation by DNAse enzymes and autophagy / xenophagy during and after endosomal escape, C) poor nuclear localization of DNA. What is needed are compositions and methods to protect cargo DNA when it is loaded into LNPs or similar nanocarrier systems. Summary of the Invention In one aspect, a composition is provided that includes a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response. In certain embodiments, the helper molecule is an inhibitor of cGAS-STING pathway, optionally cGAS, STING, AIM2, TLR9, TBK1, or IFNAR. In certain embodiments, the molecule capable of complexing or condensing DNA is a cationic lipid, a polyamine, a cationic protein or peptide, or an ionizable lipid, optionally an ionizable lipid that is positively charged at pH 6 - 7.4. In another aspect a composition is provided that includes a lipid nanoparticle (LNP) comprising a DNA cargo and a DNase inhibitor. In another aspect, a composition is provided that includes a lipid nanoparticle (LNP) comprising a DNA cargo, a DNase inhibitor, and an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR. In certain embodiments, the molecule to aid in nuclear localization of DNA is a nuclear localization signal (NLS) peptide. In certain embodiments, the NLS further comprises an oligo. In certain embodiments, the molecule to aid in nuclear localization of DNA is a cell penetrating peptide or Replication Protein A (RPA). In another aspect, a composition is provided that includes a lipid nanoparticle (LNP) comprising a DNA cargo, a DNA-binding domain (DBD) mimicking peptide, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the DNA cargo is in the form of a DNA nanostructure. In another aspect, a composition is provided that includes a lipid nanoparticle (LNP) comprising a DNA cargo, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the LNP comprises an aminolipid. In another aspect, a composition is provided that includes a lipid nanoparticle (LNP) comprising a DNA cargo and a fusion protein comprising dCas9-importin, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR. In another aspect, a method of delivering a DNA cargo to a subject is provided. The method includes administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response. In another aspect, a method of treating a subject in need thereof is provided. The method includes administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response. In another aspect, a method of treating pulmonary fibrosis (IPF) in a subject is provided. The method includes administering to the subject an effective amount of the composition as described herein, wherein the DNA cargo comprises an ORF encoding an anti-fibrotic agent, optionally an antibody to TGFalpha, TGFbeta, VEGF, FGF, CTGF, CCN2, PDGF, Oncostatin M, CCL2, CCL3, or CXCL12. In another aspect, a treatment regimen for a subject in need thereof is provided, comprising: i) delivering to the subject an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR; ii) subsequently delivering to the subject a lipid nanoparticle (LNP) comprising a DNA cargo and a molecule capable of condensing DNA. In another aspect, a method of delivering a DNA cargo to a subject is provided. The method includes administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising the DNA cargo and a molecule capable of complexing or condensing DNA. In another aspect, a method of delivering a DNA cargo to a subject is provided. The method includes administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising the DNA cargo and a DNase inhibitor. Other aspects and advantages of the invention will be apparent from the following detailed description of the invention. Brief Description of the Drawings FIGs.1A-1K demonstrate that unlike modified mRNA-LNP delivery, pDNA-LNP delivery is intolerable in vitro and in vivo. FIGs.1A-1H: Studies done in naïve C57bl / 6 mice. FIGs.1I-1K: Studies done in RAW264.7 macrophages. Survival curve graph of naïve mice treated with 1 mg / kg dose of either mRNA- or pDNA-LNP delivery shows low tolerability of pDNA-LNPs (FIG.1A). Comparison of cumulative distance traveled for 1 hour, 4 hours post 1 mg / kg injection of mRNA- or pDNALNP assessed by AI software, DeepLabCuts (FIG.1B). Compared to mRNA-LNP group, mice that received pDNA-LNP have a significant reduction in total distance traveled, indicating lethargy. Comparison of weight change over time post 5 ug IV dose of mRNA- or pDNALNPs (FIG.1C). Quantification of plasma cytokines 4 hours post 5 ug dose of mRNA- or pDNA-LNPs using flow cytometry based multiplexing assay indicates pDNA-LNP induced acute inflammation (FIG.1D-1F). Specifically, IFN-b (FIG.1E) and IL-6 (FIG.1F) levels are ~1400x and ~1000x higher (respectively) for mice injected with pDNA-LNP compared to mRNA-LNP control.5 ug of pDNA formulated with three FDA-approved formulations (ONPATTRO, mRNA- 1273, and Comirnaty) were IV injected and plasma was collected 4 hours post dose for cytokine quantification, which indicated this toxicity occurs across various LNP formulations (FIG.1G). Plasma was collected from mice 4 and 24 hours post 5 ug of pDNA- LNP, showing acute inflammation with majority of pro-inflammatory cytokine levels back to baseline at the 24-hour timepoint (FIG.1H). RAW264.7 macrophages’ cell viability over time post mRNA- or pDNA-LNP incubation (FIG.1I). IFN-b levels in cell supernatant 4 hours post LNP dose (FIG.1J). IFN-b levels as a function of pDNA-LNP dose (FIG.1K). FIGs.2A-2F show pDNA-LNP inflammation is driven by the cGAS-STING pathway. a. The proposed mechanism that drives pDNA-LNP inflammation (FIG.2A). Any cytosolic DNA (endogenous or exogenous) is detected by cGAS leading to downstream activation of STING causing acute inflammatory response. BALB / c STING Knockout (STING KO) mice injected with 5 ug pDNA-LNP have lower levels of pro-inflammatory cytokines in plasma compared to naïve BALB / c mice with specifically IFN-b (FIG.2C) and IL-6 (FIG.2D) back to baseline (FIGs.2B-2D). Representative images of phosphorylated STING (pSTING) 4 hours post treatment indicates STING activation for pDNA groups (FIGs.2E-2F). Quantification of pSTING mean fluorescence intensity (MFI) (FIG.2F). FIGs.3A-3E demonstrate developing a platform technology: co-loading of anti- inflammatory lipids with anti-STING activity into standard pDNA-LNP formulations. a. Schematic showing cell stress caused by virus infections leads to nitration of endogenous fatty acids to form nitrated fatty acids that have anti-inflammatory properties (FIG.3A). Development of platform technology by loading in anti-inflammatory lipids into standard LNP formulation (FIG.3B). Size distribution of pDNA-LNPs loaded with various anti- inflammatory lipids determined by dynamic light scattering (DLS) shows no significant differences in LNP size (FIG.3C). Loading in various antiinflammatory lipids do not significantly impact pDNA encapsulation as measured by PicoGreen assay (FIG.3D). Drug loading as measured by HPLC after size exclusion purification shows >80% drug encapsulation for all LNP formulations. pDNA-LNPs loaded with various antiinflammatory lipids have reduced IFN-b in cell supernatant indicating lower inflammation (FIG.3E). Anti- inflammatory lipids that are nitrate prior to LNP formation (NCLA and NOA) are more effective than lipids that are nitrated in cell (DHA and EPA). FIGs.4A-4L demonstrate nitro-oleic acid (NOA) loaded pDNA-LNPs (+NOA- LNPs) show superior safety profiles in vitro and in vivo. Confocal imaging of pSTING reveals no activation of STING for +NOA-LNPs compared to standard pDNA-LNP control in RAW264.7 macrophages (FIGs.4A-4B). Quantification of pSTING MFI (FIG.4B) shows significant decrease for +NOA-LNP group. Confocal imaging of STING’s downstream marker phosphorylated TBK1 (pTBK1) also is not activated for +NOA-LNPs compared to standard pDNA-LNP control (FIGs.4C-4D). Cell viability measured over time indicates better cell tolerability of +NOA-LNPs compared to standard pDNA-LNPs (FIG.4E). IFN-b levels in cell supernatant are lower for +NOA-LNPs compared to standard pDNA-LNP 4 hours post 1000 ng / mL dose, irrespective of LNP formulation (FIGs.4F-4H) [(FIG.4F) ONPATTRO, (FIG.4G) mRNA-1273, (FIG.4H) Comirnaty: all FDA-approved LNP formulations]. Quantification of plasma cytokines 4 hours post 5 ug dose of pDNA- or +NOA-LNPs using flow cytometry based multiplexing assay indicates amelioration of inflammation in +NOA-LNPs group (FIGs.4I-4K). Specifically, IFN-b (FIG.4E) and IL-6 (FIG.4F) levels are ~4x and ~8x lower (respectively) for mice injected with +NOA-LNP compared to standard pDNA-LNP control. Survival curve comparing dose of 1 mg / kg of pDNA-LNP and +NOA-LNPs indicates better tolerability for +NOA-LNPs (FIG.4L). FIGs.5A-5G shows optimization of +NOA-pDNA expression in vitro using DoE and sustained transgene expression in vivo. Full factorial design of experiments (DoE) screen was performed using JMP software. Ionizable lipid mol%, type of helper lipid (DSPC, DOPE, DOTAP, and 18:0 PG), and total lipid to pDNA (w / w) were varied and screened for luciferase expression in RAW264.7 macrophages 24-hour post 1000 ng / ml dose (FIG.5A). Representative images of RAW264.7 macrophages treated with eGFP pDNA were obtained using confocal imaging 24 hours post treatment and MFI quantified using ImageJ software (FIG.5B-5C). Similarly to FIG.5B-5C, confocal images were also taken at 48 hours that shows improved expression in optimized +NOA-LNP (FIG.5D-5E). Mice treated with either standard pDNA- or +NOA-LNPs encoding luciferase were injected with d-luciferin sodium salt prior to imaging with IVIS bioluminescence imaging system (PerkinElmer) over time showing sustained transgene expression (FIG.5F-5G). Images were quantified (FIG.5G) indicating inclusion of NOA does not hinder pDNA expression. Note, 2 mice died prior to 48h timepoint for standard pDNA-LNP group due to pDNA toxicities. FIG.6 shows compound structures of cGAS inhibitors. FIG.7 shows compound structures of STING inhibitors. FIGs.8A-8K demonstrate that unlike mRNA-LNP, pDNA-LNP delivery causes acute inflammation and death in vivo. Survival curve graph of naïve C57BL / 6 (“Black-6”) mice IV-injected with 1 mg / kg of either mRNA- or pDNA-LNP shows 100% mortality in the pDNA-LNPs group (FIG.8A).4-hours after 1 mg / kg IV injection of LNPs, movement of mice was tracked for 1 hour and total distance walked was assessed by AI software (DeepLabCuts), a validated metric of an infusion reaction (FIG.8B). Mice treated with pDNA-LNPs have significantly lower total distance walked compared to mRNA-LNP control, indicating severe lethargy. Weight change over time in mice given a much lower IV dose of LNPs (5 µg) of mRNA- or pDNA-LNPs (FIG.8C). Multiplex analysis of pro- inflammatory plasma cytokines 4-hours post 5 µg IV dose of pDNA-LNP indicates acute systemic inflammation compared to PBS and mRNA-LNP controls (FIG.8D-F). Specifically, IFN-β (FIG.8E) and IL-6 (FIG.8F) levels are ~1400x and ~1000x higher (respectively) for mice injected with pDNA-LNP compared to mRNA-LNP.5 µg of pDNA formulated with three FDA-approved LNP formulations (patisiran, mRNA-1273, and BNT162b2) were IV injected and plasma was collected 4-hours post dose for cytokine quantification, which indicated this toxicity occurs across various LNP formulations (FIG. 8G). Cytokine levels in mouse plasma collected 4- or 24-hours after IV injection of 5 µg of pDNA-LNPs, highlighting acute-but-transient inflammation, with the majority of pro- inflammatory cytokine levels back to baseline at the 24-hour time point (FIG.8H). In vitro studies in a macrophage-derived cell line, RAW264.7 (FIGs.8I-8K). Effect of 1000 ng / mL mRNA- or pDNA-LNP on cell viability over time (FIG.8I). IFN-β levels in cell supernatant 4-hours after exposure to 1000 ng / mL empty-, mRNA-, and pDNA-LNP dose shows DNA- cargo-specific inflammatory cytokine production (FIG.8J). IFN-β levels in cell supernatant as a function of pDNA-LNP dose shows an exponential increase within the estimated dose range needed for in vivo efficacy (FIG.8K). Statistics: n=5 / group for (A, C), n=3-4 / group for rest. Data shown represents mean ± SEM. B, C, I, Unpaired t-tests were performed. For all other graphs, comparisons were made using one-way ANOVA with Tukey’s post-hoc test. FIGs.9A-9C demonstrate pDNA-LNPs induce acute inflammation regardless of plasmid size. Multiplex analysis of pro-inflammatory plasma cytokines 4-hours post 5 µg IV dose of pDNA-LNPs indicates acute systemic inflammation regardless of plasmid size with no significant change in IFN-β (FIG.9B) and IL-6 (FIG.9C) levels. FIGs.10A-10C demonstrate pDNA-LNPs inflammation does not reappear 5-days after IV dose. Multiplex analysis of pro-inflammatory plasma cytokines 5-days post 25 µg IV dose of mRNA- or pDNA-LNPs indicates all cytokines levels back to baseline, specifically IFN-β (FIG.10B) and IL-6 (FIG.10C) levels. FIGs.11A-11B show cell viability after pDNA-LNP treatment in RAW264.7 cells. Cell viability measured 4-hours after various doses of pDNA-LNPs shows good tolerability (FIG.11A). Note, all studies measuring cell supernatant cytokines 4-hours after 1000 ng / mL dose where cell viability is ~100%. Cell viability as a function of dose- and time-response of pDNA-LNPs (FIG.11B). FIG.12A-12C show cargo inflammation from LNPs when delivered intratracheally in naïve C57BL / 6 mice. A, B, C. After intratracheally administering 5 µg mRNA- or pDNA- LNPs, inflammation specific to the lungs was examined by examining protein and leukocyte levels in the bronchoalveolar lavage (BAL) fluid, which indicates capillary leakage and leukocyte penetration into the alveoli (air sacs) (FIGs.12A-12C). Protein (FIG.12A), total cells (FIG.12B), and pro-inflammatory cytokines (FIG.12C) were higher in the BAL fluid from mice that were administered pDNA-LNPs compared to the ones given mRNA-LNPs. FIGs.13A-13F demonstrate pDNA-LNP inflammation is driven by STING. The proposed mechanism that drives pDNA-LNP inflammation. Any cytosolic DNA (endogenous or exogenous) is detected - independent of DNA-sequence - by cGAS, leading to downstream activation of STING which induces an acute inflammatory response (FIG. 13A). STING Knockout (STING-KO) mice IV-injected with 5 µg pDNA-LNPs have reduced levels of pro-inflammatory cytokines in plasma 4-hours post dose compared to naïve BALB / c mice with IFN-β and IL-6 levels back to baseline (FIG.13B). pDNA-LNPs injected in C57bl / 6 (“Black-6”) and BALB / c have varying levels of inflammation with ~2x lower IFN-β in BALB / c mice leading to improved survival rates at 1 mg / kg dose (FIG.13C-13D). Representative images of phosphorylated STING (pSTING) 4-hours post treatment indicates STING activation for pDNA group (1000 ng / mL dose) in RAW264.7 cells (FIG.13E-13F). Quantification of pSTING mean fluorescence intensity (MFI) (FIG.13F). Statistics: n=3 / group for (B, C), n=10 / group for (D). Data shown represents mean ± SEM. C. Unpaired t-test was performed. F. Comparisons were made using one-way ANOVA with Tukey’s post-hoc test. FIG.14 shows pDNA-LNPs cause extreme weight loss in naïve BALB / c mice. Naive BALB / c mice that survival when IV-injected with 1 mg / kg (~25 µg) of pDNA-LNPs were monitored over time. All mice that survived visually looked healthy 3 days post LNP, though extreme weight loss (~17% in 2 days) was observed. FIGs.15A-15E show co-loading anti-inflammatory lipids with STING inhibitory activity into standard pDNA-LNP formulations. Schematic showing cell stress caused by virus infections leads to nitration of endogenous unsaturated fatty acids to form nitrated fatty acids that have anti-inflammatory properties, especially potent inhibition of STING (FIG. 15A). Development of platform technology by adding anti-inflammatory lipids as the 5th component in the lipid mixture prior to LNP formulation using microfluidics (FIG.15B). Size distribution of pDNA-LNPs loaded with various anti-inflammatory lipids determined by dynamic light scattering (DLS) shows no differences in LNP size or polydispersity index (PDI) (FIG.15C). All anti-inflammatory lipids tested load >80% (drug to lipid ratio of 0.2, mole-to-mole) and have no impact on pDNA encapsulation (FIG.15D). pDNA-LNPs loaded with various anti-inflammatory lipids reduce IFN-β secretion in cell supernatant 4-hours after 1000 ng / mL dose (FIG.15E). Anti-inflammatory lipids that are nitrated prior to LNP formation (NLA and NOA) are more effective than lipids that are nitrated in cells (DHA and EPA). Statistics: E, n=4 / group. Data shown represents mean ± SEM and comparisons were made using one-way ANOVA with Tukey’s post-hoc test. FIGs.16A-16B show cell viability after +NOA-pDNA-LNP treatment in RAW264.7 cells. Cell viability measured 4-hours after various doses of +NOA-pDNA-LNPs shows good tolerability (FIG.16A). Note, all studies measuring cell supernatant cytokines 4-hours after 1000 ng / mL dose where cell viability is ~100%. Cell viability as a function of dose- and time-response of +NOA-pDNA-LNPs (FIG.16B). FIGs.17A-17L demonstrate nitro-oleic acid (NOA) loaded pDNA-LNPs (+NOA- pDNA-LNPs) show superior safety profiles in vitro and completely prevent mortality in vivo. Representative confocal images of phosphorylated STING (pSTING) shows +NOA- pDNA-LNPs do not activate STING compared to standard pDNA-LNPs in RAW264.7 cells (FIGs.17A-17B). Quantification of pSTING MFI (FIG.17B) shows significant decrease for +NOA-pDNA-LNP group relative to standard pDNA-LNP. Similar to FIG.17A and FIG. 17B, downstream marker of STING activation, phosphorylated TBK1 (pTBK1) is also not activated for cells treated with +NOA-pDNA-LNPs compared to standard pDNA-LNPs. E. RAW264.7 cell viability measured over time indicates better tolerability of +NOA-pDNA- LNPs compared to standard pDNA-LNPs (FIGs.17C-17D). IFN-β levels in cell supernatant are lower for +NOA-pDNA-LNPs compared to standard pDNA-LNP 4-hours post 1000 ng / mL dose, irrespective of LNP formulation (FIGs.17F-17H) [(FIG.17F) Patisiran, (FIG. 17G) mRNA-1273, and (FIG.17H) BNT162b2: all FDA-approved LNP formulations]. Quantification of plasma cytokines 4-hours post 5 µg dose of pDNA- or +NOA-pDNA- LNPs (FIGs.17I-17K). Specifically, IFN-β (FIG.17J) and IL-6 (FIG.17K) levels are ~4x and ~8x lower, respectively, for mice injected IV with +NOA-pDNA-LNP compared to standard pDNA-LNP control. Survival curve in C57BL / 6 (“Black-6”) mice, comparing IV dose of 1 mg / kg of pDNA-LNP and +NOA-pDNA-LNPs shows loading of NOA in pDNA- LNPs completely prevents mortality (FIG.17L). Statistics: n=3 / group for (E-K), n=5 / group for (L). Data shown represents mean ± SEM. E-H, J, K. Unpaired t-tests were performed. B, D. Comparisons were made using one-way ANOVA with Tukey’s post-hoc test. FIG.18A-18C demonstrate more endosomal escape of pDNA-LNPs leads to higher levels of IFN-b in RAW264.7 cells. RAW264.7 cells were incubated with 1000 ng / mL of pDNA-LNPs made from 3 FDA-approved formulations (Patisiran [D-Lin-MC3-DMA], mRNA-1273 [SM-102], and BNT162b2 [ALC-0315]). pDNA-LNPs that lead to higher endosomal escape, indicated by higher transgene expression (FIG.18A) leads to greater levels of IFN-β (FIG.18B) showing a linear correlation (FIG.18C). FIGs.19A-19C show dose-response of +NOA-pDNA-LNPs.5 µg of pDNA-LNPs were formulated with were IV-injected into naïve mice. Multiplex analysis of pro- inflammatory plasma cytokines 4-hours post 5 µg IV dose of pDNA-LNPs (formulated with NOA to total lipid ratio of 0.2-1.2 mole-to-mole) indicates 0.2-0.4 NOA to total lipid ratio as the optimal ratio for best reduction of all pro-inflammatory cytokines (FIG.19A), specifically IFN-β (FIG.19B) and IL-6 (FIG.19C). FIGs.20A-20C demonstrate A151, oligonucleotide inhibitor of other DNA sensors (AIM2 and TLR9), reduces pDNA-LNP inflammation in vitro but not in vivo. Dose- response of A151 loaded pDNA-LNPs show reduction of IFN-β release in RAW264.7 macrophages (FIG.20A). Co-loaded A151 with +NOA-pDNA-LNPs does not have an additive or synergistic effect of reducing pDNA-induced inflammation in naïve mice (FIGs. 20B-20C). FIG.21 shows weight loss of C57BL / 6 mice treated with mRNA-LNP and NOA- pDNA-LNPs. expression (at least 1 month) in vivo. Representative IVIS images of BALB / c mice that were IV-injected (retro-orbitally) with 25 µg of pDNA-LNP or +NOA-pDNA-LNPs (encoding luciferase) (FIG.22A). Quantified total flux (photons / s) from IVIS images show addition of NOA does not hinder pDNA transgene expression capacity and shows prolonged expression of pDNA-LNPs and +NOA-pDNA-LNPs (at least 1 month) (FIG.22B). Of note, two mice that received 25 µg of pDNA-LNPs died within 2 days. Total transgene expression levels of +NOA-pDNA-LNPs at day 15 compared to PBS and mRNA-LNP controls (FIG.22C). FIG.23 shows mRNA-LNP control for IVIS imaging. FIGs.24A-24D demonstrate small lipid screen significantly boosts transgene expression of +NOA-pDNA-LNPs, enabling transfection of difficult-to-transfect cells. Design of experiment (DoE) screening to optimize +NOA-pDNA-LNP formulation in RAW264.7 cells (FIGs.24A-24B). Using JMP software, a full factorial screen was designed by varying ionizable lipid mol% (30 to 50), total lipid to pDNA w / w ratio (20:1 to 40:1), and the type of helper lipid used (DSPC, DOPE, DOTAP, and 18:0 PG). All LNPs contained 0.2 D / L of NOA. +NOA-pDNA-LNP optimized with DSPC or DOTAP as the helper lipid led to 3.5x or 23x increase in transgene expression, respectively, when compared to standard +NOA-pDNA-LNP (b).2D monoculture of difficult-to-transfect cell line, human induced- pluripotent-stem-cell-derived type II alveolar epithelial cells (iAT2s), were treated with 1000 ng of eGFP encoding pDNA - using lipofectamine, unoptimized +NOA-pDNA-LNPs, or DOTAP optimized +NOA-pDNA-LNPs - and imaged after 48-hours (FIGs.24C-24D). mCherry signal indicates iAT2 positively, while eGFP signal indicates successfully transfected cells (FIG.24C).120-hours post transfection, mCherry + cells that were also eGFP + were quantified using flow cytometry indicating similar transfection levels (trending higher) for DOTAP optimized +NOA-pDNA-LNPs to the gold standard, lipofectamine 2000 (FIG.24D). FIGs.25A-25F demonstrates that Linear DNA delivered by LNPs is less inflammatory than pDNA in vitro. FIG.25A is a schematic showing cutting plasmid DNA (pDNA) into linear DNA (LinDNA). FIG.25B shows forming LNPs with either pDNA or LinDNA encapsulated. FIG.25C shows that encapsulating LinDNA does not lead to spontaneous re-ligation. FIG.25D is a graph showing cell viability as a percentage of control. LinDNA-LNPs have improved cell viability than pDNA. FIG.25E is a graph showing normalized luminescence and demonstrates that LinDNA-LNPs have improved gene expression than pDNA. FIG.25F shows that LinDNA-LNPs has undetectable levels of STING in raw cells. FIGs.26A and 26B show that histone proteins H2A and H3 are effective in condensing DNA. We loaded H2A- and H3-condensed plasmids into LNP and observed cell viability and expression of transfected RAW264.7 cells. While there was no cell death observed with either preparation (A), loading H2A-condensed plasmids into LNP resulted in expression at least comparable to lipofectamine (B). FIG.27 RESERVED. FIG.28 shows that phagocytes play a key role in pDNA-LNP-induced inflammation. Wild type and macrophage-depleted mice were treated with 5ug pDNA-LNP via IV and plasma cytokines tested 4 hours later. Macrophage-depleted mice had a significantly reduced inflammatory response than wild type in response to pNDA-LNP treatment. FIG.29 shows that indirectly avoiding phagocytes reduces pNDA-LNP toxicity. Mice were treated with 5ug pDNA-LNP (SM-102), NOA-pDNA-LNP, GalNAc-pDNA- LNP, NOA / GalNAc-pDNA-LNP (combo-pDNA-LNP), or pDNA-LNP (4A3-Sc8) via IV and plasma cytokines tested 4 hours later. Adding a GalNAc peg lipid (with or without NOA) reduced inflammatory cytokines. FIG.28 altering mol % of GalNAc-PEG lipid affects LNP formulation. Mice were treated with 5ug GalNAc-pDNA-LNP at 0.25%, 0.75% or 1.5% GalNAc. We found that higher mol% GalNAc-PEG-lipid leads to low pDNA encapsulation and smaller particle size. FIG.30 shows that various excipients improved pDNA transfection with LNPs. RAW264.7 cells were treated with 500ng / mL DNA-LNP and an excipient selected from tannic acid, punicalagin, vitamin B9, vitamin C, vitamin B12, vitamin D, davunetide, chlorogenic acid, ferulic acid, melatonin, and vitamin K3.24 h later luciferase measurements were obtained. Tannic acid, vitamin B12, davunetide, and chlorogenic acid improved transfection of RAW264.7 cells. FIG.31 shows improvement of expression of pDNA-LNP when listed excipient is administered. FIG.32 is a schematic showing experimental scheme for cssDNA-NLS peptide of Example 22. FIG.33 shows that NLS-peptide improves expression of transgene as described in Example 22. FIG.34 shows that css-DNA-RPA improves expression of transgene as described in Example 22. FIG.35 shows that TCF1 transgene expression in DNA-LNPs. FIG.36 shows that TREX1 degrading molecules improved expression in DNA- LNPs. Detailed Description of the Invention Provided herein are compositions, kits, and methods that improve on prior art methods of delivering DNA. The compositions and methods augment the delivery of DNA to cells in different ways. These compositions and methods can be used alone, or in combination, depending on the application for which they are being used. In certain embodiments, the compositions, kits, and methods prevent or reduce DNA degradation to improve pDNA transfection efficiency. In certain embodiments, the compositions, kits, and methods provide for LNP delivery of DNA cargoes, with reduced inflammatory response in vivo. In certain embodiments, the composition comprises a lipid nanoparticle (LNP) comprising a DNA cargo, a molecule capable of complexing or condensing DNA, and an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR. Unless defined otherwise in this specification, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art and by reference to published texts, which provide one skilled in the art with a general guide to many of the terms used in the present application. As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” cell can mean a single cell or a multiplicity of cells. As used herein, the term “about” refers to a variant of ±10% from the reference integer and values therebetween. For example, “about” 40 base pairs, includes ±4 (i.e., 36 – 44, which includes the integers 36, 37, 38, 39, 40, 41, 42, 43, 44). For other values, particularly when reference is to a percentage (e.g., 90% identity, about 10% variance, or about 36% mismatches), the term “about” is inclusive of all values within the range including both the integer and fractions. As used throughout this specification and the claims, the terms “comprising”, “containing”, “including”, and its variants are inclusive of other components, elements, integers, steps and the like. Conversely, the term “consisting” and its variants are exclusive of other components, elements, integers, steps and the like. Nucleotides are referred to by their commonly accepted single-letter codes. Unless otherwise indicated, nucleic acids are written left to right in 5′ to 3′ orientation. Nucleotides are referred to herein by their commonly known one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Accordingly, A represents adenine, C represents cytosine, G represents guanine, T represents thymine, U represents uracil. Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. As used herein, the term “administered in combination” or “combined administration” means that two or more agents (e.g., LNPs) are administered to a subject at the same time or within an interval such that there can be an overlap of an effect of each agent on the patient. In some embodiments, they are administered within about 60 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved. In some embodiments, the administration in combination can be concurrent (i.e., all the LNPs are administered as part of a single formulation, or different LNPs in different formulation are administered simultaneous), or consecutive (e.g., several LNPs in several formulations are administered consecutively). In the context of the present disclosure, substitutions (even when they are referred to as amino acid substitution) are conducted at the nucleic acid level, i.e., substituting an amino acid residue with an alternative amino acid residue is conducted by substituting the codon encoding the first amino acid with a codon encoding the second amino acid. When used with respect to two or more moieties, the terms “associated with,” “conjugated,” “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization-based connectivity sufficiently stable such that the “associated” entities remain physically associated. Codon optimization refers to various approaches designed to improve the codon composition of a recombinant gene based on various criteria without altering the amino acid sequence. Various methods of codon optimization are known in the art. As used herein, the terms “coding region” and “region encoding” and variants thereof, refer to an Open Reading Frame (ORF) in a polynucleotide that upon expression yields a polypeptide or protein. As used herein, the term “effective amount” of an agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied. For example, in the context of administering an agent that treats a tumor, an effective amount of an agent is, for example, an amount sufficient to reduce or decrease a size of a tumor or to inhibit a tumor growth, as compared to the response obtained without administration of the agent. The term “effective amount” can be used interchangeably with “effective dose,” “therapeutically effective amount,” or “therapeutically effective dose.” As used herein, the term “helper lipid” refers to a compound or molecule that includes a lipidic moiety (for insertion into a lipid layer, e.g., lipid bilayer) and a polar moiety (for interaction with physiologic solution at the surface of the lipid layer). Typically, the helper lipid is a phospholipid. A function of the helper lipid is to “complement” the amino lipid and increase the fusogenicity of the bilayer and / or to help facilitate endosomal escape, e.g., of nucleic acid delivered to cells. Helper lipids are also believed to be a key structural component to the surface of the LNP. The term “ionizable amino lipid” includes those lipids having one, two, three, or more fatty acid or fatty alkyl chains and a pH-titratable amino head group (e.g., an alkylamino or dialkylamino head group). An ionizable amino lipid is typically protonated (i.e., positively charged) at a pH below the pKa of the amino head group and is substantially not charged at a pH above the pKa. In certain embodiments, the ionizable lipid is partially charged, due to the presence of amide bonds. In certain embodiments, the ionizable lipid is positively charged at pH 6 - 7.4, which is the pH range these LNPs face during storage, when in blood, etc. Being positively charged at these pHs allows these ionizable lipids to condense DNA compactly. In certain embodiments, the ionizable lipid is 98N-12. In certain embodiments, the ionizable lipid is 306-N16B. The terms “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence” are used interchangeably and refer to a contiguous nucleic acid sequence. The sequence can be either single stranded or double stranded DNA or RNA, e.g., an mRNA. The phrase “nucleotide sequence encoding” refers to the nucleic acid (e.g., an mRNA or DNA molecule) coding sequence which encodes a polypeptide. The coding sequence can further include initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of an individual or mammal to which the nucleic acid is administered. The coding sequence can further include sequences that encode signal peptides. As used herein, the term “open reading frame”, abbreviated as “ORF”, refers to a segment or region of DNA or mRNA molecule that encodes a polypeptide. The ORF comprises a continuous stretch of non-overlapping, in-frame codons, beginning with the initiation codon and ending with a stop codon, and is translated by the ribosome. The term “polynucleotide” as used herein refers to polymers of nucleotides of any length, including ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. This term refers to the primary structure of the molecule. Thus, the term includes triple-, double- and single-stranded deoxyribonucleic acid (“DNA”), as well as triple-, double- and single-stranded ribonucleic acid (“RNA”). It also includes modified, for example by alkylation, and / or by capping, and unmodified forms of the polynucleotide. More particularly, the term “polynucleotide” includes polydeoxyribonucleotides (containing 2- deoxy-D-ribose), polyribonucleotides (containing D-ribose), including tRNA, rRNA, hRNA, siRNA and mRNA, whether spliced or unspliced, any other type of polynucleotide which is an N- or C-glycoside of a purine or pyrimidine base, and other polymers containing normucleotidic backbones, for example, polyamide (e.g., peptide nucleic acids “PNAs”) and polymorpholino polymers, and other synthetic sequence-specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA. In particular aspects, the polynucleotide comprises an mRNA. In other aspect, the mRNA is a synthetic mRNA. In some aspects, the synthetic mRNA comprises at least one unnatural nucleobase. In some aspects, all nucleobases of a certain class have been replaced with unnatural nucleobases (e.g., all uridines in a polynucleotide disclosed herein can be replaced with an unnatural nucleobase, e.g., 5-methoxyuridine). In some aspects, the polynucleotide (e.g., a synthetic RNA or a synthetic DNA) comprises only natural nucleobases, i.e., A, C, T and U in the case of a synthetic DNA, or A, C, T, and U in the case of a synthetic RNA. The skilled artisan will appreciate that the T bases in the codon maps disclosed herein are present in DNA, whereas the T bases would be replaced by U bases in corresponding RNAs. For example, a codon-nucleotide sequence disclosed herein in DNA form, e.g., a vector or an in-vitro translation (IVT) template, would have its T bases transcribed as U based in its corresponding transcribed mRNA. In this respect, both codon- optimized DNA sequences (comprising T) and their corresponding RNA sequences (comprising U) are considered codon-optimized nucleotide sequence of the present disclosure. A skilled artisan would also understand that equivalent codon-maps can be generated by replaced one or more bases with non-natural bases. Thus, e.g., a TTC codon (DNA map) would correspond to a UUC codon (RNA map), which in turn would correspond to a ΨΨ codon (RNA map in which U has been replaced with pseudouridine). Standard A-T and G-C base pairs form under conditions which allow the formation of hydrogen bonds between the N3-H and C4-oxy of thymidine and the N1 and C6-NH2, respectively, of adenosine and between the C2-oxy, N3 and C4-NH2, of cytidine and the C2- NH2, N′—H and C6-oxy, respectively, of guanosine. Thus, for example, guanosine (2- amino-6-oxy-9-β-D-ribofuranosyl-purine) can be modified to form isoguanosine (2-oxy-6- amino-9-β-D-ribofuranosyl-purine). Such modification results in a nucleoside base which will no longer effectively form a standard base pair with cytosine. However, modification of cytosine (1-β-D-ribofuranosyl-2-oxy-4-amino-pyrimidine) to form isocytosine (1-β-D- ribofuranosyl-2-amino-4-oxy-pyrimidine-) results in a modified nucleotide which will not effectively base pair with guanosine but will form a base pair with isoguanosine (U.S. Pat. No.5,681,702 to Collins et al.). Isocytosine is available from Sigma Chemical Co. (St. Louis, Mo.); isocytidine can be prepared by the method described by Switzer et al. (1993) Biochemistry 32:10489-10496 and references cited therein; 2′-deoxy-5-methyl-isocytidine can be prepared by the method of Tor et al., 1993, J. Am. Chem. Soc.115:4461-4467 and references cited therein; and isoguanine nucleotides can be prepared using the method described by Switzer et al., 1993, supra, and Mantsch et al., 1993, Biochem.14:5593-5601, or by the method described in U.S. Pat. No.5,780,610 to Collins et al. Other nonnatural base pairs can be synthesized by the method described in Piccirilli et al., 1990, Nature 343:33-37, for the synthesis of 2,6-diaminopyrimidine and its complement (1-methylpyrazolo- [4,3]pyrimidine-5,7-(4H,6H)-dione. Other such modified nucleotide units which form unique base pairs are known, such as those described in Leach et al. (1992) J. Am. Chem. Soc. 114:3675-3683 and Switzer et al., supra. As used herein, the term “polypeptide” refers to a polymer of amino acid residues typically joined by peptide bonds that can be produced naturally (e.g., isolated or purified) or synthetically. “Fragments” of proteins or peptides in the context of the present invention may, typically, comprise a sequence of a protein or peptide as defined herein, which is, with regard to its amino acid sequence (or its encoded nucleic acid molecule), N-terminally and / or C-terminally truncated compared to the amino acid sequence of the original (native) protein (or its encoded nucleic acid molecule). Such truncation may thus occur either on the amino acid level or correspondingly on the nucleic acid level. A sequence identity with respect to such a fragment as defined herein may therefore preferably refer to the entire protein or peptide as defined herein or to the entire (coding) nucleic acid molecule of such a protein or peptide. A fragment of a protein may typically comprise an amino acid sequence having a sequence identity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, more preferably of at least 80%, even more preferably at least 85%, even more preferably of at least 90% and most preferably of at least 95% or even 97%, with an amino acid sequence of the respective naturally occurring full-length protein. Fragments of proteins or peptides may furthermore comprise a sequence of a protein or peptide as defined herein, which has a length of for example at least 5 amino acids, preferably a length of at least 6 amino acids, preferably at least 7 amino acids, more preferably at least 8 amino acids, even more preferably at least 9 amino acids; even more preferably at least 10 amino acids; even more preferably at least 11 amino acids; even more preferably at least 12 amino acids; even more preferably at least 13 amino acids; even more preferably at least 14 amino acids; even more preferably at least 15 amino acids; even more preferably at least 16 amino acids; even more preferably at least 17 amino acids; even more preferably at least 18 amino acids; even more preferably at least 19 amino acids; even more preferably at least 20 amino acids; even more preferably at least 25 amino acids; even more preferably at least 30 amino acids; even more preferably at least 35 amino acids; even more preferably at least 50 amino acids; or most preferably at least 100 amino acids. For example such fragment may have a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g.8, 9, or 10, (or even 6, 7, 11, or 12 amino acids), or fragments as processed and presented by MHC class II molecules, preferably having a length of about 13 or more amino acids, e.g.13, 14, 15, 16, 17, 18, 19, 20 or even more amino acids, wherein these fragments may be selected from any part of the amino acid sequence. These fragments are typically recognized by T-cells in form of a complex consisting of the peptide fragment and an MHC molecule, i.e. the fragments are typically not recognized in their native form. Fragments of proteins or peptides may comprise at least one epitope of those proteins or peptides. Furthermore, domains of a protein, like the extracellular domain, the intracellular domain or the transmembrane domain and shortened or truncated versions of a protein may be understood to comprise a fragment of a protein. “Variants” of proteins or peptides as defined in the context of the present invention may be generated, having an amino acid sequence which differs from the original sequence in one or more mutation(s), such as one or more substituted, inserted and / or deleted amino acid(s). Preferably, these fragments and / or variants have the same biological function or specific activity compared to the full-length native protein, e.g. its specific antigenic property. “Variants” of proteins or peptides as defined in the context of the present invention may comprise conservative amino acid substitution(s) compared to their native, i.e. non- mutated physiological, sequence. Those amino acid sequences as well as their encoding nucleotide sequences in particular fall under the term variants as defined herein. Substitutions in which amino acids, which originate from the same class, are exchanged for one another are called conservative substitutions. In particular, these are amino acids having aliphatic side chains, positively or negatively charged side chains, aromatic groups in the side chains or amino acids, the side chains of which can enter into hydrogen bridges, e.g. side chains which have a hydroxyl function. This means that e.g. an amino acid having a polar side chain is replaced by another amino acid having a likewise polar side chain, or, for example, an amino acid characterized by a hydrophobic side chain is substituted by another amino acid having a likewise hydrophobic side chain (e.g. serine (threonine) by threonine (serine) or leucine (isoleucine) by isoleucine (leucine)). Insertions and substitutions are possible, in particular, at those sequence positions which cause no modification to the three- dimensional structure or do not affect the binding region. Modifications to a three- dimensional structure by insertion(s) or deletion(s) can easily be determined e.g. using CD spectra (circular dichroism spectra) (Urry, 1985, Absorption, Circular Dichroism and ORD of Polypeptides, in: Modern Physical Methods in Biochemistry, Neuberger et al. (ed.), Elsevier, Amsterdam). A “variant” of a protein or peptide may have at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid identity over a stretch of 10, 20, 30, 50, 75 or 100 amino acids of such protein or peptide. Furthermore, variants of proteins or peptides as defined herein, which may be encoded by a nucleic acid molecule, may also comprise those sequences, wherein nucleotides of the encoding nucleic acid sequence are exchanged according to the degeneration of the genetic code, without leading to an alteration of the respective amino acid sequence of the protein or peptide, i.e. the amino acid sequence or at least part thereof may not differ from the original sequence in one or more mutation(s) within the above meaning. As used herein, the term ligand (sometimes referred to herein as targeting or binding moiety) refers to any molecule that specifically binds to another molecule, which is sometimes referred to herein as the partner molecule or target. In one embodiment, the binding moiety is an antibody. As used herein, an “antibody” is a monoclonal antibody, a synthetic antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, a multi-specific binding construct that can bind two or more targets, a dual specific antibody, a bi-specific antibody or a multi-specific antibody, or an affinity matured antibody, a single antibody chain or an scFv fragment, a diabody, a single chain comprising complementary scFvs (tandem scFvs) or bispecific tandem scFvs, an Fv construct, a disulfide-linked Fv, a Fab construct, a Fab' construct, a F(ab')2 construct, an Fc construct, a monovalent or bivalent construct from which domains non-essential to monoclonal antibody function have been removed, a single-chain molecule containing one VL, one VH antigen-binding domain, and one or two constant “effector” domains optionally connected by linker domains, a univalent antibody lacking a hinge region, a single domain antibody, a dual variable domain immunoglobulin (DVD-Ig) binding protein or a nanobody. Also included in this definition are antibody mimetics such as affibodies, i.e., a class of engineered affinity proteins, generally small (~6.5 kDa) single domain proteins that can be isolated for high affinity and specificity to any given protein target. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. The term antibody also encompasses molecules comprising an immunoglobulin domain from an antibody (e.g., a VH, CL, CL, CH1, CH2 or CH3 domain) fused to other molecules, i.e., fusion proteins. In some embodiments, such fusion protein comprises an antigen-binding moiety (e.g., an scFv). The antibody moiety of a fusion protein comprising g an antigen-binding moiety can be used to direct a therapeutic agent (e.g., a cytotoxin) to a desired cellular or tissue location determined by the specificity of the antigen-binding moiety. Compositions In certain aspects, provided herein are compositions that include a lipid nanoparticle (LNP) that includes a DNA cargo and one or more of i) a molecule capable of condensing and / or compacting DNA, ii) a molecule to aid in nuclear localization of DNA, and iii) a “helper molecule” that provides reduced inflammatory response, upon administration. In certain embodiments, the molecule of i), ii), or iii) is contained in the same LNP as the DNA cargo. In other embodiments, the molecule of i), ii), or iii) is contained in the LNP separate from the DNA cargo, i.e., in a “helper” LNP. In one embodiment, compositions that include a lipid nanoparticle (LNP) that includes a DNA cargo and at least a molecule to aid in nuclear localization of DNA. Molecules that aid in nuclear localization include nuclear localization signal peptides, cell penetrating peptides, DNA-binding domain (DBD) mimicking peptide. Nuclear Localization Signal Peptide In certain embodiments, the compositions provided herein incorporate one or more nuclear localization signal peptide. Nuclear localization signals (NLS) are generally short peptides that act as a signal fragment that mediates the transport of proteins from the cytoplasm into the nucleus. The classic NLS encompass two categories, termed “monopartite” (MP) and “bipartite” (BP). MP NLS are a single cluster composed of 4–8 basic amino acids, which generally contains 4 or more positively charged residues, that is, arginine (R) or lysine (K). The characteristic motif of MP NLS is usually defined as K (K / R) X (K / R), where X can be any residue. See, e.g., Lu, J., Wu, T., Zhang, B. et al. Types of nuclear localization signals and mechanisms of protein import into the nucleus. Cell Commun Signal 19, 60 (2021) which is incorporated herein by reference. In certain embodiments, the NLS is one listed in the table below. Nuclear Localization Signal peptides Category Source Sequence Seq ID Transport No. receptors Importin α / β1 βs Cell-Penetrating Peptides In certain embodiments, the compositions provided herein incorporate one or more cell-penetrating peptide. Cell-penetrating peptides (CPPs) or protein transduction domains (PTDs) are relatively short and, in many cases, cationic amino acids that possess the ability to penetrate the cellular membrane. Useful peptides include those in the table below. Cell-penetrating peptides SE Peptide Q e s pi se ) c n Peptides useful herein include those discussed in, see, e.g., Bottens RA, Yamada T. Cell-Penetrating Peptides (CPPs) as Therapeutic and Diagnostic Agents for Cancer. Cancers (Basel).2022 Nov 11;14(22):5546. doi: 10.3390 / cancers14225546. PMID: 36428639; PMCID: PMC9688740, which is incorporated herein by reference. In certain embodiments, the compositions provided herein incorporate one or more transcription factor, such as, e.g., TCF-1. In one embodiment, a composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, a DNA-binding domain (DBD) mimicking peptide, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR is provided. In certain embodiments, the DBD- mimicking peptide is fused with a nuclear localization signal peptide. In certain embodiments, the DBD-mimicking peptide mimics helix-turn helix (HTH), zinc finger, leucine zipper, or basic region leucine zipper (bZIP). In another embodiment, the DNA cargo is in the form of a DNA nanostructure. In one embodiment, a composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, a DNA-binding domain (DBD) mimicking peptide, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the DNA cargo is in the form of a DNA nanostructure is provided. In one embodiment, the DNA cargo is comprised in a plasmid that comprises one or more tandem repeats of the SV40 DNA targeting sequence (DTS). In another embodiment, the LNP comprises a short-chain aminolipid. “Molecules Capable of Condensing and / or Compacting DNA” In certain embodiments, the compositions provided herein incorporate one or more molecules capable of condensing and / or compacting DNA. DNA can be protected from damage during the many steps on its journey from LNP formation to storage in LNPs, to its time in endosomes, to release from endosomes, and uptake into nucleus if it is complexed with other molecules that shield the DNA from damaging agents. Alternatively, the DNA can be protected from damage via condensation of DNA into a more tightly packed structure (decreased hydrodynamic radius). In nature, there are many molecules which complex with DNA to provide such protection and sometimes compactification. Examples include the compaction of DNA into sperm, which is accomplished by complexation with polyamines (spermine & spermidine) and cationic proteins, such as protamine. Additionally, compaction of DNA aids with its crossing of the nuclear pore complex. In certain embodiments, the molecule capable of condensing and / or compacting DNA is a protein (e.g., histone), peptide (especially those that are cationic), or charged lipids. In certain embodiments, the molecule capable of condensing and / or compacting DNA is a cationic lipid. Cationic lipids are amphiphilic molecules, which consist of a hydrophilic and a hydrophobic region connected by a linker structure

[0033] . DOTMA and DOTAP (1,2-dioleoyl-3-trimethylammonium propane) are two most commonly investigated cationic lipids for transfection. A number of commercial preparations of cationic lipids are available which can be used to condense / compact the DNA. These include, for example, LIPOFECTIN® (commercially available cationic liposomes comprising DOTMA and 1,2-dioleoyl-sn- 3phosphoethanolamine (DOPE), from GIBCO / BRL, Grand Island, N.Y.); LIPOFECTAMINE® (commercially available cationic liposomes comprising N-(1- (2,3dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoroacetate (DOSPA) and (DOPE), from GIBCO / BRL); and TRANSFECTAM® (commercially available cationic lipids comprising dioctadecylamidoglycyl carboxyspermine (DOGS) in ethanol from Promega Corp., Madison, Wis.). The following lipids are cationic and have a positive charge at below physiological pH: DODAP, DODMA, DMDMA, 1,2- dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N- dimethylaminopropane (DLenDMA). In certain embodiments, the cationic lipid is DOTAP. In certain embodiments, the cationic lipid is DOSPA. In certain embodiments, the cationic lipid is a spermine or spermidine-conjugated lipid. Polyamines are also useful in condensing / compacting DNA. Polyamines include spermine, spermidine, cadaverine, 1,3-diaminopropane, and putrescine. See, e.g., van Dam L, Korolev N, Nordenskiöld L. Polyamine-nucleic acid interactions and the effects on structure in oriented DNA fibers. Nucleic Acids Res.2002 Jan 15;30(2):419-28. doi: 10.1093 / nar / 30.2.419. PMID: 11788703; PMCID: PMC99836, which is incorporated herein by reference. Cationic peptides and proteins from natural or non-natural sources are also useful in condensing / compacting DNA. Cationic peptides and other basic polymers are positively charged and interact with the negatively charged phosphate backbone of DNA through electrostatic interactions. Cationic proteins useful herein include Poly-L-lysines and polylysine-containing peptides, histones, protamine, Brdt (sperm protein), RVG-9R, R15, µ, Pep V, Tat49–57 derivatives, POLYTAT, L-Arg, D-Arg, and RPC. See, e.g., Tecle M, Preuss M, Miller AD. Kinetic study of DNA condensation by cationic peptides used in nonviral gene therapy: analogy of DNA condensation to protein folding. Biochemistry.2003 Sep 9;42(35):10343-7. doi: 10.1021 / bi034325e. PMID: 12950160, and Saccardo P, Villaverde A, González-Montalbán N. Peptide-mediated DNA condensation for non-viral gene therapy. Biotechnol Adv.2009 Jul-Aug;27(4):432-8. doi: 10.1016 / j.biotechadv.2009.03.004. Epub 2009 Mar 31. PMID: 19341789, which are incorporated herein by reference. In certain embodiments, ionizable lipids that maintain a positive charge when in LNPs, even when the LNPs are not in an external buffer that is acidic are useful as condensing / compacting agents. In certain embodiments, the ionizable lipid is 98N-12. In certain embodiments, the ionizable lipid is 306-N16B. “DNase Inhibitors” In certain embodiments, the compositions provided herein incorporate one or more DNase inhibitors. DNA can be protected from damage during the many steps on its journey from LNP formation to storage in LNPs, to its time in endosomes, to release from endosomes, and uptake into nucleus if it is complexed with other molecules that shield the DNA from damaging agents. Deoxyribonucleases (DNases) are a heterogeneous class of enzymes which catalyze hydrolysis of deoxyribonucleic acid (DNA). Two main types of DNase are DNase I and DNase II, both endonucleases, which produce 3’-oligonucleotides and 5’-oligonucleotides, respectively. See, e.g., Kolarevic A, Yancheva D, Kocic G, Smelcerovic A. Deoxyribonuclease inhibitors. Eur J Med Chem.2014 Dec 17;88:101-11. doi: 10.1016 / j.ejmech.2014.07.040. Epub 2014 Jul 15. PMID: 25042005, which is incorporated herein by reference. DNase III, also known as TREX1 (three prime repair exonuclease 1), is a human enzyme encoded by the TREX1 gene. It belongs to the family of 3’-5’ DNA exonucleases, which means it cleaves DNA from the 3’ end to the 5’ end. Natural DNase inhibitors have been isolated from various sources and include, without limitation, somatostatin, cholesterol sulfate in concert with bile acids, inhibitor in human leucocytes, and protein from KB cells; actin, anti-DNase antisera [27,28], proteins from calf spleen, and thymus; antibiotics isolated from bacteria of the genus Streptomyces (actinomycin D, nogalamycin, daunomycin, neomycin B and paromomycin), and a metabolite from Micromonospora echinospora. Other DNase inhibitors include EDTA, sodium orthovanadate, heparin, aprotinin, and zinc ions. Other DNase inhibitors include siRNA, aptamers, or antisense oligonucleotides designed to bind to DNase mRNA or protein. In another embodiment, the DNase inhibitor is a DNase-degrading molecule, such as a PROTAC. In one embodiment, the DNase inhibitor is a TREX1-degrading molecule, such as a PROTAC that binds TREX1. “Helper Molecules” In certain embodiments, the compositions provided herein incorporate one or more molecules that attenuates the inflammatory response associated with DNA delivery. These helper molecules vary, but are, in some embodiments, associated with inhibition of the cGAS-STING pathway, and related molecules. Each of the helper molecules described herein, also includes, in a separate embodiment, an embodiment utilizing a pro-drug thereof. The helper molecule may be a nitrated fatty acid. Nitrated fatty acids are the product of nitrogen dioxide reaction with unsaturated fatty acids. The identity and synthesis of nitrated fatty acids are known in the art. See, e.g., Woodcock SR, Bonacci G, Gelhaus SL, Schopfer FJ. Nitrated fatty acids: synthesis and measurement. Free Radic Biol Med.2013 Jun;59:14-26. doi: 10.1016 / j.freeradbiomed.2012.11.015. Epub 2012 Nov 29. PMID: 23200809; PMCID: PMC4020000, which is incorporated herein by reference. In certain embodiments, the nitrated fatty acid is nitro-oleic acid or a pro-drug or derivative thereof. In certain embodiments, the nitrated fatty acid is nitro-conjugated linoleic acid or a pro-drug or derivative thereof. In certain embodiments, the nitrated fatty acid is docosahexaenoic acid or a pro-drug or derivative thereof. In certain embodiments, the nitrated fatty acid is eicosapentaenoic acid or a pro-drug or derivative thereof. In certain embodiments, the nitrated fatty acid is 4-octyl itaconate or a pro-drug or derivative thereof. In certain embodiments, the nitrated fatty acid is nitro-arachidonic acid or a pro-drug or derivative thereof. The helper molecule may be a cGAS inhibitor. Cyclic GMP-AMP synthase (cGAS) acts as a key DNA sensor. It directly binds double-stranded DNA (dsDNA), inducing the formation of liquid-like droplets in which cGAS is activated, leading to synthesis of 2',3'- cGAMP, a second messenger that binds to and activates STING1, thereby triggering type-I interferon production. Various cGAS inhibitors are known, and useful herein. See, e.g., Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol.2021 Sep;21(9):548-569. doi: 10.1038 / s41577-021-00524-z. Epub 2021 Apr 8. PMID: 33833439; PMCID: PMC8029610, which is incorporated herein by reference. In certain embodiments, the cGAS inhibitor is PF-06928215 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is PF-06928215 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is RU.365 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is RU.521 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is G150 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is compound S3 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is hydroxychloroquine or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is quinacrine or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is X6 or a pro- drug or derivative thereof. In certain embodiments, the cGAS inhibitor is suramin or a pro- drug or derivative thereof. In certain embodiments, the cGAS inhibitor is ODN A151 or a pro-drug or derivative thereof. In certain embodiments, the cGAS inhibitor is CU-76 or a pro-drug or derivative thereof. The helper molecule may be a STING inhibitor. Stimulator of interferon genes (STING) is a facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Various STING inhibitors are known, and useful herein. See, e.g., Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol.2021 Sep;21(9):548-569. doi: 10.1038 / s41577- 021-00524-z. Epub 2021 Apr 8. PMID: 33833439; PMCID: PMC8029610, which is incorporated herein by reference. In certain embodiments, the STING inhibitor is Astin C or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is C-176 or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is C178 or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is C170 or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is C171 or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is H151 or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is NO2-cLA or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is NO2-OA or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is BPK-21 or a pro-drug or derivative thereof. In certain embodiments, the STING inhibitor is BPK-25 or a pro-drug or derivative thereof. The helper molecule may be an AIM2 inhibitor. Sensor component of the AIM2 inflammasome, which mediates inflammasome activation in response to the presence of double-stranded DNA (dsDNA) in the cytosol, leading to subsequent pyroptosis. AIM2 inhibitors are known, and useful herein. See, e.g., Green et al, Discovery of an inhibitor of DNA-driven inflammation that preferentially targets the AIM2 inflammasome, iScience 26, 106758, May 19, 2023. In certain embodiments, the AIM2 inhibitor is a sulfonic calixarene or a pro-drug or derivative thereof. In certain embodiments, the AIM2 inhibitor is shikonin or a pro-drug or derivative thereof. In certain embodiments, the AIM2 inhibitor is NLPR3 / AIM2-IN-3 or a pro-drug or derivative thereof. In certain embodiments, the AIM2 inhibitor is JC2-11 or a pro-drug or derivative thereof. In certain embodiments, the AIM2 inhibitor is NLPR3 / AIM2- IN-2 or a pro-drug or derivative thereof. The helper molecule may be a TLR9 inhibitor. Toll-like receptor 9 (TLR9) is a receptor that plays a role in recognizing pathogen DNA and differentiating between methylated vertebrate DNA and unmethylated pathogen DNA. Various TLR9 inhibitors are known in the art, and useful herein. See, e.g., Zatsepin et al, Computational Discovery and Experimental Confirmation of TLR9 Receptor Antagonist Leads, J. Chem. Inf. Model.2016, 56, 9, 1835–1846 which is incorporated herein by reference. In one embodiment, the TLR9 inhibitor is one of the following compounds, or a pro- drug or derivative thereof. In certain embodiments, the TLR9 inhibitor is chloroquine, or a derivative or pro- drug thereof. In certain embodiments, the TLR9 inhibitor is chloroquine diphosphosphate or a derivative or pro-drug thereof. In certain embodiments, the TLR9 inhibitor is hydroxychloroquine or a derivative or pro-drug thereof. In certain embodiments, the TLR9 inhibitor is E6446 or a derivative or pro-drug thereof. The helper molecule may be an IFNAR inhibitor. IFNAR1 and IFNAR2 together form the heterodimeric receptor for type I interferons. Inhibitors of IFNAR1 and / or IFNAR2 are known, and useful herein. In certain embodiments, the IFNAR inhibitor is baricitinib or a derivative or pro- drug thereof. In certain embodiments, the IFNAR inhibitor is a JAK / STAT inhibitor. The helper molecule may be an siRNA targeting any of the molecules described above. The person of skill can design useful siRNA, and the sequences of the recited molecules are known in the art. In certain embodiments, the molecule is an siRNA targeting cGAS. In certain embodiments, the molecule is an siRNA targeting STING. In certain embodiments, the molecule is an siRNA targeting AIM2. In certain embodiments, the molecule is an siRNA targeting TLR9. In certain embodiments, the molecule is an siRNA targeting IFNAR. In certain embodiments, the helper molecule may be provided in the from of an mRNA. The mRNA may encode any inhibitor of cGAS, STING, AIM2, TLR9, IFNAR. For example, in certain embodiments, the mRNA encodes any one of the following proteins. Type of virus Protein made Effect HSV-1 VP22, UL411, UL37 cGAS inhibition For examp e, n certa n embod ments, t e mRNA encodes any one o t e o ow ng proteins. Protein made Effect In other embodiments, the mRNA encodes an inhibitor of TBK1, IRF3, NFkB, or the JAK / STAT pathway. For example, the mRNA may encode any of the following proteins: neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to degrade TBK1 to prevent the host from excessive immune response after Viral infection; DDX5 inhibits type I IFN production by promoting degradation of TBK1 and disrupting formation of TBK1 − TRAF3 complex; Suppressor of cytokine signaling 3 (SOCS3) inhibits the IFN-β signaling pathway by promoting proteasomal degradation of TBK1. Overexpression and knockdown experiments indicated that SOCS3 is a negative regulator of IFN regulatory factor 3 (IRF3); Van Gogh–like 2 (VANGL2) acts as an IFN-inducible negative feedback regulator to suppress IFN-I signaling during vesicular stomatitis virus (VSV) infection. Mechanistically, VANGL2 interacted with TBK1 and promoted the selective autophagic degradation of TBK1; RNF19a mediated K48-linked ubiquitination and proteasomal degradation of TBK1; Barrier-to-autointegration factor (BAF). Additional TBK1 Inhibitors include: GSK8612, Amlexanox, MRT67307, MRT67307 hydrochloride, MRT67307 dihydrochloride, BAY-985, (Rac)-BAY-985, TBK1-IN-1, TBK1 / IKKε-IN-1, TBK1 / IKKε- IN-2, TBK1 / IKKε-IN-4, TBK1 / IKKε-IN-5, TBK1 / IKKε-IN-6, GSK319347A, BX795, Idronoxil, Momelotinib, DMX-14, DMX-129, DMX-3433, AZ909, MPC-9528, MRT68601 and MRT68601 hydrochloride. In other embodiments, activation of STING is prevented by avoiding phagocytes. In certain embodiments, a N-acetylgalactosamine (GalNAc)-PEG lipid is incorporated into the LNP. See, e.g., Varun Kumar, et al, Shielding of Lipid Nanoparticles for siRNA Delivery: Impact on Physicochemical Properties, Cytokine Induction, and Efficacy, Molecular Therapy - Nucleic Acids, Volume 3, 2014, e210, ISSN 2162-2531. In certain embodiments, the helper molecule is an excipient selected from tannic acid, punicalagin, vitamin B9, vitamin C, vitamin B12, vitamin D, davunetide, chlorogenic acid, ferulic acid, melatonin, and vitamin K3. In certain embodiments, the helper molecule is annic acid, vitamin B12, davunetide, or chlorogenic acid. The helper molecule may be provided in the same composition as the DNA-LNP. In other embodiments, the helper molecule is provided separately from the DNA-LNP. For example, in certain embodiments, the LNP is formulated with both the DNA cargo and the helper molecule. In other embodiments, the helper molecule is a separate component of the composition that also includes the DNA-LNP. In other embodiments, the helper molecule is conjugated to the DNA-LNP. In other embodiments, the helper molecule is provided as a separate composition to the DNA-LNP, administered prior to, or currently with, the DNA- LNP. Further discussion is provided hereinbelow. DNA Cargo As noted above, the LNP described herein encapsulate a DNA cargo. The DNA cargo comprises an expression cassette that includes open reading frame encoding a protein of interest under control of regulatory sequences that direct expression of the ORF in the target cell. The regulatory sequences can include any of those conventionally used, such as a promoter, appropriate transcription initiation, termination, enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation (polyA) signals; TATA sequences; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); introns; sequences that enhance protein stability, etc. The expression cassette or vector may contain none, one or more of any of the elements described herein. In certain embodiments, the expression cassette further includes viral LTRs or ITRs. The promoter may be selected based on the desired expression of the DNA cargo. In certain embodiments, the promoter is cell-specific, such as for delivery to the target cell. The target cell may, in certain embodiments, include any mammalian cell type, such as neurons, glia, hepatocytes, endothelial cells, epithelial cells, fibroblasts, muscle cells, adipocytes, chondrocytes, osteocytes, keratinocytes, melanocytes, t lymphocytes, b lymphocytes, macrophages, dendritic cells, granulocytes, NK cells, mast cells, hematopoietic stem cells, pancreatic islet cells, spermatocytes, oocytes, thyroid follicular cells, pituitary cells, astrocytes, microglia, Schwann cells, IPSCs, primary neurons, ocular cells, etc. In another embodiment, the promoter is a ubiquitous or constitutive promoter. An example of a suitable promoter is a hybrid chicken β-actin (CBA) promoter with cytomegalovirus (CMV) enhancer elements. In another embodiment, the promoter is the CB7 promoter. Other suitable promoters include the human β-actin promoter, the human elongation factor-1α promoter, the cytomegalovirus (CMV) promoter, the simian virus 40 promoter, and the herpes simplex virus thymidine kinase promoter. See, e.g., Damdindorj et al, (August 2014) A Comparative Analysis of Constitutive Promoters Located in Adeno- Associated Viral Vectors. PLoS ONE 9(8): e106472. Still other suitable promoters include viral promoters, constitutive promoters, regulatable promoters [see, e.g., WO 2011 / 126808 and WO 2013 / 04943]. In another embodiment, the promoter is an inducible promoter. The inducible promoter may be selected from known promoters including the rapamycin / rapalog promoter, the ecdysone promoter, the estrogen-responsive promoter, and the tetracycline- responsive promoter, or heterodimeric repressor switch. The DNA cargo can be any that is desirable to deliver to a target cell. DNA includes those encoding therapeutic proteins, nucleases (e.g., CRISPR-CAS DNA), diagnostic proteins, antibodies, etc. A non-limiting list of applications and DNA cargoes is below. In certain embodiments, the identity of the DNA cargo is not a limitation of this invention. ^ Atherosclerosis • Cargo DNA: IL-10, inhibitors of inflammatory cytokines (IL-6, IL- 1beta), LXR modulators ^ Heart attack: • Cargo DNA: proteins that prevent “in-stent thrombosis” such as antithrombotic proteins (thrombomodulin); proteins that control “re- endothelialization” of the stent (VEGF modulators); proteins that promote regeneration of myocardium (modulators of VEGF, FGF, G- CSF, HDF, SDF, IGF, neuregulin, periostin) ^ Stroke (ischemic): • Cargo DNA: immunomodulators (IL-10), modulators of NGF, BDNF, and other neuronal growth factors ^ Hypertension: • Cargo DNA: modulators of nitric oxide synthase, components of the ACE and neprolysin pathways, etc ^ Sepsis: ^ Cargo DNA: immunomodulators like IL-10 ^ Local expression of peptide antibiotics / antimicrobials, antibodies, anti- inflammatory proteins, etc. ^ Chronic infections: ^ Cargo DNA: Peptide antibiotics include LL37, anti-inflammatory proteins include IL-10, and neutralizing antibodies exist against many bacteria ^ Antibodies during pandemics: One-time delivery of neutralizing antibodies prevents infection for 6 months. ^ Vaccines: mRNA-LNPs are excellent vaccines, but suffer from the cold-chain issue. DNA-LNPs will be much more stable, since RNA is inherently much less stable than DNA. ^ Pain: DNA-LNPs encoding proteins that quiet pain nerves. • Cargo DNA: modulators of various ion channels (eg., TRPV-1, sodium channels, etc), modulators of GABA receptors, modulators of inflammation (IL-10). ^ Wound healing: ^ Cargo DNA: modulators of growth factors such as EGF, FGFs, PDGF, TGF-α, and TGF-β. ^ Burn wound healing: Cargo skin stem cells programmed via DNA-episomes ^ Traumatic brain injury: ^ Cargo DNA: Pro-regenerative proteins (e.g., BDNF, NGF, etc) ^ Broken bones: can take months to heal, but we can speed that up with growth factors and anti-inflammatories. ^ Cargo DNA: BMPs, FGF, IGF, PDGF, TGF-beta, VEGF ^ Chronic toxin accumulation syndromes can be fixed by using DNA-LNPs to express proteins that clear the toxins: • Cargo DNA: Wilson’s disease (we prevent copper accumulation by expressing copper-chelating proteins); hemochromatosis (express iron- chelating proteins); lysosomal storage diseases (lysosomal enzyme activator, lysosomal membrane proteins, or non-lysosomal proteins) ^ Autoimmune: Express the mAbs and other therapeutic proteins that are common for diseases like rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), etc. ^ Cargo DNA: etanercept, antibodies like anti-TNF, IL-4, -IL-5, DNAse for lupus, etc. ^ Deliver to immune cells proteins that prevent their activation. ^ Cargo DNA: IkB and mutations thereof, etc. ^ Diabetes: Cargo DNA: DNA-LNPs encoding for GLP-1 agonists ^ NASH / MASH: ^ Cargo DNA: FGFs, MOTS-c, TGF-beta superfamily members such as GDF15, etc. ^ Inborn errors of metabolism: ^ Cargo DNA: enzymes to combat phenylketonuria, etc ^ Surgical procedures • Surgical wounds: express pro-healing and anti-microbial proteins • Implants (ex: hip replacement, defibrillators): similar to wounds, but also anti-fibrotic proteins will help with neural implants. Cargo DNA: See wound healing above, and antimicrobial proteins. • Transplant: Cargo DNA: Express tolerizing cargo (shRNA against MHC proteins; express PD1, PDL-1, CTLA-4 and other proteins that inhibit T- cell mediated cytolysis), anti-thrombotics (thrombomodulin, etc), pro- healing at the anastomosis (FGF, VEGF, etc.) • Intra-abdominal surgery: deliver DNA-LNPs that secrete proteins that prevent intra-abdominal adhesions. Cargo DNA: tPA, TGFbeta inhibitors such as the TGFbeta decoy receptor or antibody, antibodies targeting VEGF, IL-1, and TNF-alpha. ^ Catheter-based procedures: • Intra-arterial catheters will allow for periodic delivery (every 6 months) to an organ that is hard to target by nanoparticle formulations alone. Usually intra-arterial catheters would be unacceptable for chronic diseases, but q6 months is reasonable for a severe disease. Cargo DNA: same proteins as above for atherosclerosis. ^ Fibrotic diseases: includes IPF (idiopathic pulmonary fibrosis), retroperitoneal fibrosis, etc. Antifibrotic proteins are well known, but have off-target side effects, so local delivery is essential, but requires long-term delivery. Cargo DNA: Antibodies and decoy receptors to inhibit key cytokines and soluble factors: TGFbeta, CTGF, CCN2, PDGF, Oncostatin M, CCL2, CCL3, CXCL12. ^ CAR-T cells (and CAR macrophages, NK cells, etc): • replace the lentiviruses used ex vivo in T cells, as lentivirus can cause cancerous mutations in the T cells • Replace mRNA-LNPs that are used for in vivo production of CAR-T cells. Those mRNA-LNPs need to be dosed daily via IV injection • Cargo DNA: any CAR ^ DNA-vaccines for cancer: • Cargo DNA: Include typical cancer vaccine proteins, including tumor- associated antigens (TAAs) and tumor-specific antigens (TSAs), including antigens such as mesothelin, CEA, PSA, and many more. ^ Chemo-related side effects: ^ Cargo DNA: Chemo-induced esophagitis is treated with a peptide therapeutic, palifermin ^ Anti-cancer antibodies: Both immunotherapies (e.g., anti-PD1) and direct anti- tumor antibodies ^ ADCs (antibody-drug-conjugates) • Cargo DNA: antibodies targeting cancer antigens (e.g., HER2) genetically fused to a toxic protein, such as tetanus or diphtheria toxin, or to a small protein binder such as neutravidin, that binds to biotin that would be covalently conjugated to a toxic small molecule. ^ Regenerative medicine in general: For example, after tissue injury, such as ARDS or IPF, there is a need to deliver growth factors such as Wnts & PDGF, that regulate regeneration of the alveoli. Similar exist for the heart muscle (e.g., VEGF after MI), liver, skin, etc. • Cargo DNA: In lung: Wnt, VEGF; for MI: VEGF, FGF, G-CSF, HDF, SDF, IGF, neuregulin, periostin ^ Alzheimer’s: Numerous genes have been implicated, but we have trouble delivering them to the brain. We can deliver DNA-LNPs via intrathecally (lumbar puncture or intra-cisterna magna) injection every 6 months: • Cargo DNA: antibodies that disrupt beta amyloid plaques such as those already tested clinically; if the DNA-LNPs reach the neurons, cargo DNA can encode shRNA against beta-amyloid and tau, or encode protein variants of presenilin and other products in the beta-amyloid processing pathway. ^ Parkinson’s: • Cargo DNA: antibodies or other proteins that bind and disaggregate α- synuclein aggregation; shRNA to knockdown α-synuclein; antioxidant proteins such as catalase and SOD; anti-inflammatories such as IL-10, IL-1ra. ^ PICS: Post-intensive care syndrome. After ICU admissions, patients have immunoparalysis, a persistent catabolic state, and neuromuscular weakness. All can be addressed by DNA-LNPs ^ Osteoporosis: Less frequent dosing of the current antibodies (e.g., denosumab), and local delivery into the bones at highest risk (e.g., hips). • Cargo DNA: antibodies such as denosumab (or other RANKL antibodies). ^ Chronic low back pain: The problem is local inflammation and pain, and we can deliver via local injections anti-inflammatory proteins and anesthetic proteins. • Cargo DNA: modulators of various ion channels (eg., TRPV-1, sodium channels, etc), modulators of GABA receptors, modulators of inflammation (IL-10). ^ Osteoarthritis: Similar to chronic low back pain, but delivery into joints, this time with pro-regenerative proteins, many of which have been shown preclinically, but have bad PK. • Cargo DNA: Wnt proteins such as Wnt16; cartilage delivery of anti- NFkB therapies (IKB variants such as IKB-super-repressor); anti- cytokine therapy such as local antibodies or decoy receptors of TNF- alpha. • Growth hormone replacement therapy for short stature: ^ Cargo DNA: growth hormone ^ Thyroid diseases: • Cargo DNA: proteins that encode the synthetic enzymes producing T3 & ^ Spinal cord • Spinal cord injury: o Cargo DNA: IL-10; neurotrophic factors such as BDNF • ALS: o Cargo DNA: shRNA against SOD • SMA o Cargo DNA: SMN1, SMN2 ^ Peripheral nervous system: • Regeneration after trauma o Cargo DNA: NGF, BDNF, etc ^ AMD (age-related macular degeneration): less frequent injections of anti-VEGF, and then later, express intracellular proteins that are therapeutic • Cargo DNA: anti-VEGF antibodies ^ Intracochlear injection of proteins that promote regeneration of hair cells • Cargo DNA: Myc, Notch1, Wnt ^ Sinusitis: delivery of anti-microbials and anti-inflammatories • Cargo DNA: IL-10, anti-microbial peptides such as LL37 ^ COPD: Will deliver to airways anti-inflammatories, and to alveoli, pro- regenerative proteins. • Cargo DNA: IL-10, pro-regenerative proteins as above, anti-HER1 to reduce mucus hypersecretion; modulating antibodies or proteins of VEGF, FGF, TGF-β, TNF-α, CXCL1, CXCL8, CCL2, mitogen-activated protein kinase p38, NFkB ^ Asthma: Cargo DNA: dupilumab ^ Pulmonary arterial hypertension: • Cargo DNA: modulators of BMPR2; shRNA against tryptophan hydroxylase-1; modulators of the activin and inhibin family ^ Heart failure: Delivery to the heart is difficult IV, but we can use intra-arterial (IA) catheter delivery every 6 months • Cargo DNA: modulators in the heart of pathways related to: AT-1 receptor, reactive oxygen species, TNF-alpha, NFkB, IL-6, STAT3, LIF, VEGF, and anti-apoptotic pathways ^ Arrhythmias • Cargo DNA: inhibitors of tissue fibrosis (anti-TGF-beta, CTGF, AngII, PDGF), reactive oxygen species (SOD, catalase); expression of connexons and their modulators; modulators of NFAt ^ Alimentary tract: • GERD: inject into LES (lower esophageal sphincter) DNA-LNPs encoding for proteins that regenerate the smooth muscle o Cargo DNA: FGF, PDGF ^ Liver • Cirrhosis: Delivery of anti-fibrotics or pro-regenerative proteins o Cargo DNA: anti-fibrotics as above, such as anti-TGFbeta, and pro-regenerative include HGF, FGF, KGF • Gallstone disease: delivery proteins that prevent gallstone formation ^ Glomerular diseases are a leading cause of kidney failure, and we can deliver DNA-LNPs to the kidney • Cargo DNA: inhibitors of STING including shRNA, inhibitors of APOL1 ^ Muscular dystrophies: • Cargo DNA: dystrophin ^ Muscle regeneration: For sarcopenia of the elderly, post-hospitalization, post injury. Many muscle growth factors are known, and we can do local injections, since muscle is a syncitium. • Cargo DNA: modulators of mTORC1, MEF2, SRF, PGC-1α4, and YAP ^ Male pattern baldness: express growth factors for hair follicles • Cargo DNA: VEGF, shRNA against the DHT receptor ^ Blood thinners for atrial fibrillation or post-pulmonary embolism: • Cargo DNA: proteins that inhibit thrombin or Factor Xa (thrombomodulin, anti-thrombin, etc) Other DNA cargoes include those encoding anti-cancer therapies. Non-limiting examples of anti-cancer molecules include immune checkpoint inhibitors (e.g., CTLA-4 antibodies, PD-1 antibodies, PDL-1 antibodies), cytotoxic agents (e.g., Cly A, FASL, TRAIL, TNF-alpha), immunostimulatory cytokines and co-stimulatory molecules (e.g., OX40, CD28, ICOS, CCL21, IL-2, IL-18, IL-15, IL-12, IFN-gamma, IL-21, TNFs, GM- CSF), antigens and antibodies (e.g., tumor antigens, neoantigens, CtxB-PSA fusion protein, CPV-OmpA fusion protein, NY-ESO-1 tumor antigen, RAF1, antibodies against immune suppressor molecules, anti-VEGF, Anti-CXR4 / CXCL12, anti-GLP1, anti-GLP2, anti- galectinl, anti-galectin3, anti-Tie2, anti-CD47, antibodies against immune checkpoints, antibodies against immunosuppressive cytokines and chemokines), DNA transfer vectors (e.g., endostatin, thrombospondin-1, TRAIL, SMAC, Stat3, Bcl2, FLT3L, GM-CSF, IL-12, AFP, VEGFR2), and enzymes (e.g., E. coli CD, HSV-TK). In one embodiment, the DNA cargo encodes a neutralizing antibody against a viral pathogen. Such anti-viral antibodies may include anti-influenza antibodies directed against one or more of Influenza A, Influenza B, and Influenza C. The 20 type A viruses are the most virulent human pathogens. The serotypes of influenza A which have been associated with pandemics include, H1N1, which caused Spanish Flu in 1918, and Swine Flu in 2009; H2N2, which caused Asian Flu in 1957; H3N2, which caused Hong Kong Flu in 1968; H5N1, which caused Bird Flu in 2004; H7N7; H1N2; H9N2; H7N2; H7N3; and H10N7. Other target pathogenic viruses include, without limitation, arenaviruses (including funin, 25 machupo, and Lassa), filoviruses (including Marburg and Ebola), hantaviruses, picornoviridae (including rhinoviruses, echovirus), coronaviruses, paramyxovirus, morbillivirus, respiratory synctial virus, togavirus, coxsackievirus, JC virus, parvovirus B19, parainfluenza, adenoviruses, reoviruses, variola (Variola major (Smallpox)) and Vaccinia (Cowpox) from the poxvirus family, and varicella-zoster (pseudorabies). Viral hemorrhagic 30 fevers are caused by members of the arenavirus family (Lassa fever) (which family is also associated with Lymphocytic choriomeningitis (LCM)), filovirus (ebola virus), and hantavirus (puremala). The members of picornavirus (a subfamily of rhinoviruses), are associated with the common cold in humans. The coronavirus family, which includes a number of non-human viruses such as infectious bronchitis virus (poultry), porcine transmissible gastroenteric virus (pig), porcine hemagglutinatin encephalomyelitis virus (pig), feline infectious peritonitis virus (cat), feline enteric coronavirus (cat), canine coronavirus (dog). The human respiratory coronaviruses have been putatively associated 5 with the common cold, non-A, B or C hepatitis, and sudden acute respiratory syndrome (SARS). The paramyxovirus family includes parainfluenza Virus Type 1, parainfluenza Virus Type 3, bovine parainfluenza Virus Type 3, rubulavirus (mumps virus, parainfluenza Virus Type 2, parainfluenza virus Type 4, Newcastle disease virus (chickens), rinderpest, morbillivirus, which includes measles and canine distemper, and pneumovirus, which 10 includes respiratory syncytial virus (RSV). The parvovirus family includes feline parvovirus (feline enteritis), feline panleucopeniavirus, canine parvovirus, and porcine parvovirus. The adenovirus family includes viruses (EX, AD7, ARD, O.B.) which cause respiratory disease. Thus, in certain embodiments, an antibody may include an anti-ebola antibody, e.g., 2G4, 4G7, 13C6, an anti-influenza antibody, e.g., FI6, 15 CR8033, and anti-RSV antibody, e.g, palivizumab, motavizumab. A neutralizing antibody construct against a bacterial pathogen may also be selected for use. In one embodiment, the neutralizing antibody construct is directed against the bacteria itself. In another embodiment, the neutralizing antibody construct is directed against a toxin produced by the bacteria. Examples of airborne bacterial pathogens include, e.g., 20 Neisseria meningitidis (meningitis), Klebsiella pneumonia (pneumonia), Pseudomonas aeruginosa (pneumonia), Pseudomonas pseudomallei (pneumonia), Pseudomonas mallei (pneumonia), Acinetobacter (pneumonia), Moraxella catarrhalis, Moraxella lacunata, Alkaligenes, Cardiobacterium, Haemophilus influenzae (flu), Haemophilus parainfluenzae, Bordetella pertussis (whooping cough), Francisella tularensis (pneumonia / fever), 25 Legionella pneumonia (Legionnaires disease), Chlamydia psittaci (pneumonia), Chlamydia pneumoniae (pneumonia), Mycobacterium tuberculosis (tuberculosis (TB)), Mycobacterium kansasii (TB), Mycobacterium avium (pneumonia), Nocardia asteroides (pneumonia), Bacillus anthracis (anthrax), Staphylococcus aureus (pneumonia), Streptococcus pyogenes (scarlet fever), Streptococcus pneumoniae (pneumonia), Corynebacteria diphtheria 30 (diphtheria), Mycoplasma pneumoniae (pneumonia), Bacillius anthracis. Antibodies against infectious diseases caused by parasites or by fungi may be encoded, including, e.g., Aspergillus species, Absidia corymbifera, Rhixpus stolonifer, Mucor plumbeaus, Cryptococcus neoformans, Histoplasm capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Penicillium species, Micropolyspora faeni, Thermoactinomyces vulgaris, Alternaria alternate, Cladosporium species, Helminthosporium, and Stachybotrys species. In another embodiment, the DNA cargo encodes an antibody against pathogenic factors of diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Rheumatoid arthritis (RA), Irritable bowel syndrome (IBS), chronic obstructive pulmonary disease (COPD), cancers, tumors, systemic sclerosis, asthma and other diseases. Such antibodies may be., without limitation, e.g., alpha-synuclein, anti-20 - vascular endothelial growth factor (VEGF) (anti-VEGF), anti-VEGFA, anti-PD-1, antiPDL1, anti-CTLA-4, anti-TNF- alpha, anti-IL-17, anti-IL-23, anti-IL-21, anti-IL-6, anti-IL-6 receptor, anti-IL-5, anti-IL-7, anti-Factor XII, anti-IL-2, anti-HIV, anti-IgE, anti-tumour necrosis factor receptor-1 (TNFR1), anti-notch 2 / 3, anti-notch 1, anti-OX40, anti-erb-b2 receptor tyrosine kinase 3 (ErbB3), anti-ErbB2, anti-beta cell maturation antigen, anti-B 25 lymphocyte stimulator, anti-CD20, anti-HER2, anti-granulocyte macrophage colony- stimulating factor, anti- oncostatin M (OSM), anti-lymphocyte activation gene 3 (LAG3) protein, anti-CCL20, anti- serum amyloid P component (SAP), anti-prolyl hydroxylase inhibitor, anti-CD38, anti- glycoprotein IIb / IIIa, anti-CD52, anti-CD30, anti-IL-1beta, antiepidermal growth factor receptor, anti-CD25, anti-RANK ligand, anti-complement system 30 protein C5, anti- CD11a, anti-CD3 receptor, anti-alpha-4 (α4) integrin, anti-RSV F protein, and anti-integrin α4β7. Still other pathogens and diseases will be apparent to one of skill in the art. Other suitable antibodies may include those useful for treating Alzheimer’s Disease, such as, e.g., anti-beta-amyloid (e.g., crenezumab, solanezumab, aducanumab), anti-betaamyloid fibril, anti-beta-amyloid plaques, anti-tau, and bapineuzamab, among others. In certain embodiments, the DNA cargo encodes a CRISPR-Cas enzyme, e.g., Cas9. The DNA cargo may be in various forms, including a linear or circular structure, and can be either single-stranded or double-stranded. Circular, single-stranded DNA (circDNA or cssDNA) is a specific type where the DNA molecule forms a closed loop. Other useful types include linear double-stranded DNA, which is the most common form found in chromosomes, linear single-stranded DNA, which is less stable than its double-stranded counterpart, and circular double-stranded DNA, which is formed in a closed loop, but it has two strands forming a double helix. Examples include the circular chromosomes of prokaryotes, such as plasmid DNA, and mitochondrial DNA. In certain embodiments, the DNA has been linearized (sometimes referred to herein as linDNA). Other useful DNA structures include closed-ended DNA (CeDNA), circular single-stranded DNA (cssDNA), and heat-denatured DNA (hdDNA). In certain embodiments, the DNA cargo is a cssDNA plasmid that comprises a nuclear localization signal peptide. In another embodiment, the DNA cargo is a cssDNA plasmid that comprises a functional replication protein A (RPA). In another embodiment, the DNA cargo is a linear ssDNA that comprises a nuclear localization signal peptide. In another embodiment, the DNA cargo is a linear ssDNA that comprises a functional replication protein A (RPA). In some embodiments, the nucleic acids described herein have undergone a chemical or biological modification to render them more stable, e.g., nucleic acids containing one or more non-naturally occurring or modified nucleotide. The modified nucleotide analog may be located for example at the 5'-end and / or the 3'-end of the nucleic acid molecule. Representative examples of nucleotide analogs may be selected from sugar- or backbone- modified ribonucleotides. It should be noted, however, that also nucleobase- modified ribonucleotides, i.e. ribonucleotides, containing a non-naturally occurring nucleobase instead of a naturally occurring nucleobase such as uridines or cytidines modified at the 5-position, e.g.5-(2-amino)propyl uridine, 5-bromo uridine; adenosines and guanosines modified at the 8-position, e.g.8-bromo guanosine; deaza nucleotides, e.g.7-deaza- adenosine; 0- and N- alkylated nucleotides, e.g. N6-methyl adenosine are suitable. The 2'-OH- group may be replaced by a group selected from H, OR, R, halo, SH, SR, NH.sub.2, NHR, N.sub.2 or CN, wherein R is C.sub.l-C.sub.6 alkyl, alkenyl or alkynyl and halo is F, Cl, Br or I. Modified nucleotides also include nucleotides conjugated with cholesterol through, e.g., a hydroxy prolinol linkage as described in Krutzfeldt et ak, Nature (Oct.30, 2005), Soutschek et al, Nature 432: 173-178 (2004), and U.S. Patent Publication No.20050107325, which are incorporated herein by reference in their entireties. Modified nucleotides and nucleic acids may also include locked nucleic acids (LNA), as described in U.S. Patent No.20020115080, which is incorporated herein by reference. Additional modified nucleotides and nucleic acids are described in U.S. Patent Publication No.20050182005, which is incorporated herein by reference in its entirety. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments, to enhance diffusion across cell membranes, or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs may be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In some embodiments, the expressible nucleic acid sequence is in the form of DNA. In some embodiments, the expressible nucleic acid is in the form of RNA with a sequence that encodes the polypeptide sequences disclosed herein and, in some embodiments, the expressible nucleic acid sequence is an RNA / DNA hybrid molecule that encodes any one or plurality of polypeptide sequences disclosed herein. Lipid Nanoparticle (LNP) As noted above, the DNA cargo is encapsulated in a lipid nanoparticle (LNP). The term “lipid nanoparticle”, also referred to as LNP, refers to a particle having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which includes one or more lipids (e.g., cationic lipids, non- cationic lipids, and PEG-modified lipids). In some embodiments, such lipid nanoparticles comprise a cationic lipid and one or more excipient selected from neutral lipids, charged lipids, steroids and polymer conjugated lipids (e.g., a pegylated lipid). In some embodiments, the DNA, or a portion thereof, is encapsulated in the lipid portion of the lipid nanoparticle or an aqueous space enveloped by some or all of the lipid portion of the lipid nanoparticle, thereby protecting it from enzymatic degradation or other undesirable effects induced by the mechanisms of the host organism or cells. In some embodiments, the DNA or a portion thereof is associated with the lipid nanoparticles. Preferably, the lipid nanoparticles are formulated to deliver one or more DNA to one or more target cells (e.g., tumor cells). In the context of the present invention, lipid nanoparticles are not restricted to any particular morphology, and should be interpreted as to include any morphology generated when a cationic lipid and optionally one or more further lipids are combined, e.g., in an aqueous environment and / or in the presence of a nucleic acid compound. For example, a liposome, a lipid complex, a lipoplex and the like are within the scope of a lipid nanoparticle. In various embodiments, the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm, and are substantially non-toxic. In certain embodiments, the DNA, when present in the lipid nanoparticles, is resistant in aqueous solution to degradation with a nuclease. As used herein, the mean diameter may be represented by the z-average as determined by dynamic light scattering. An LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which the one or more nucleic acid molecules are encapsulated. The term “lipid” refers to a group of organic compounds that are derivatives of fatty acids (e.g., esters) and are generally characterized by being insoluble in water but soluble in many organic solvents. Lipids are usually divided in at least three classes: (1) “simple lipids” which include fats and oils as well as waxes; (2) “compound lipids” which include phospholipids and glycolipids; and (3) “derived lipids” such as steroids. In one embodiment, the DNA-comprising LNP comprises one or more ionizable cationic lipids as described herein, cholesterol, a helper phospholipid, and a polyethylene glycol-modified lipid. As mentioned, the LNP comprises an ionizable cationic lipid. The cationic lipid is preferably ionizable, i.e., it becomes protonated as the pH is lowered below the pKa of the ionizable group of the lipid, but is progressively more neutral at higher pH values. When positively charged, the lipid is then able to associate with negatively charged nucleic acids. In certain embodiments, the cationic lipid comprises a zwitterionic lipid that assumes a positive charge on pH decrease. The LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which the one or more nucleic acid molecules are encapsulated. In certain embodiments, the LNP may comprise any further cationic or ionizable lipid, i.e., any of a number of lipid species which carry a net positive charge at a selective pH, such as physiological pH. Such lipids include, but are not limited to, N,N-dioleyl-N,N- dimethylammonium chloride (DODAC); N-(2,3-dioleyloxy)propyl)-N,N,N- trimethylammonium chloride (DOTMA); N,N-distearyl-N,N-dimethylammonium bromide (DDAB); N-(2,3dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP); 3- (N—(N′,N′dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(1-(2,3- dioleoyloxy)propyl)N-2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoracetate (DOSPA), dioctadecylamidoglycyl carboxyspermine (DOGS), 1,2-dioleoyl-3- dimethylammonium propane (DODAP), N,N-dimethyl-2,3-dioleoyloxy)propylamine (DODMA), and N-(1,2dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE). Other useful lipids include, without limitation, 98N12-5, C12-200, PLGA, PEG, PEG-DMG, PEGylated lipids, amino alcohol lipids, and KL22. Additionally, a number of commercial preparations of cationic lipids are available which can be used in the present invention. These include, for example, LIPOFECTIN® (commercially available cationic liposomes comprising DOTMA and 1,2-dioleoyl-sn- 3phosphoethanolamine (DOPE), from GIBCO / BRL, Grand Island, N.Y.); LIPOFECTAMINE® (commercially available cationic liposomes comprising N-(1- (2,3dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoroacetate (DOSPA) and (DOPE), from GIBCO / BRL); and TRANSFECTAM® (commercially available cationic lipids comprising dioctadecylamidoglycyl carboxyspermine (DOGS) in ethanol from Promega Corp., Madison, Wis.). The following lipids are cationic and have a positive charge at below physiological pH: DODAP, DODMA, DMDMA, 1,2- dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N- dimethylaminopropane (DLenDMA). In one embodiment, the further cationic lipid is an amino lipid. Suitable amino lipids useful in the invention include those described in WO2012 / 016184, incorporated herein by reference in its entirety. Representative amino lipids include, but are not limited to, 1,2- dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleyoxy- 3morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2- dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy- 3dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-dilinoleoyl-3-trimethylaminopropane chloride salt (DLin- TAP.Cl), 1,2-dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), 3- (N,Ndilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1,2-propanediol (DOAP), 1,2-dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), and 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 4-(dimethylamino)- butanoic acid, (10Z,13Z)-1-(9Z,12Z)-9,12-octadecadien-1-yl-10,13-nonadecadien-1-yl ester (DLin-MC3-DMA), N,N-dimethyl-2,2-di-(9Z,12Z)-9,12-octadecadien-1-yl-1,3-dioxolane-4- ethanamine (DLin-KC2-DMA). See also, e.g., WO2014 / 089486, US 2018 / 0353616A1, and US 8,853,377B2, which are incorporated by reference. In certain embodiments, LNP formulation is performed using routine procedures comprising cholesterol, ionizable lipid, helper lipid, PEG-lipid and polymer forming a lipid bilayer around encapsulated mRNA (Kowalski et al., 2019, Mol. Ther.27(4):710-728). In some embodiments, LNP comprises a cationic lipid (i.e. N-[1-(2,3-dioleoyloxy)propyl]- N,N,N-trimethylammonium chloride (DOTMA), or 1,2-dioleoyl-3-trimethylammonium- propane (DOTAP)) with helper lipid DOPE. In some embodiments, LNP comprises an ionizable lipid Dlin-MC3-DMA ionizable lipids, or diketopiperazine-based ionizable lipids (cKK-E12). In some embodiments, polymer comprises a polyethyleneimine (PEI), or a poly(β-amino)esters (PBAEs). In some embodiments, the LNP comprises C14- 4 / DOPE / Chol / PEG-lipid. See, Rybakova Y., Kowalski P. S., Huang Y., Gonzalez J. T., Heartlein M. W., DeRosa F., et al. (2019). mRNA delivery for therapeutic anti-HER2 antibody expression in vivo. Mol. Ther.27, 1415–1423 which is incorporated by reference. In other embodiments, the LNP comprises L319 / DSPC / Chol / PEG-DMG. See, Thran M., Mukherjee J., Pönisch M., Fiedler K., Thess A., Mui B. L. (2017). mRNA mediates passive vaccination against infectious agents, toxins, and tumors. EMBO Mol. Med.9, 1434–1447 which is incorporated by reference. See also, e.g., WO2014 / 089486, US 2018 / 0353616A1, US2013 / 0037977A1, WO2015 / 074085A1, US9670152B2, and US 8,853,377B2, which are incorporated by reference. Certain LNPs useful herein include those that are described in WO 2021 / 077066 and WO 2021 / 055892, each of which is incorporated herein by reference in its entirety. Useful LNPs include those that show enhanced delivery to tumor cells. LNP formulations may be varied to enhance tumor delivery. For example, the type and ionizable lipid:mRNA ratio, the mRNA:sgRNA ratio, molar ratio of ionizable lipid, phosopholipid, cholesterol, and PEG- lipid, etc. may be varied. In one embodiment, the LNP is one described by Kauffman, K. J.; Dorkin, J. R.; Yang, J. H.; Heartlein, M. W.; DeRosa, F.; Mir, F. F.; Fenton, O. S.; Anderson, D. G., Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano letters 2015, 15 (11), 7300- 7306, which is incorporated herein by reference. In certain embodiments, the LNPs are designed with ionizable lipid: mRNA weight ratios varying between 5:1 to 25:1. In certain embodiments, the ionizable lipid: mRNA weight ratio is 5:1, 10:1, 12.5:1, 15:1, 20:1, or 25:1. In certain embodiments, the mRNA:sgRNA weight ratio is 1:1, 1:2, 2:1, or 1:4. Other LNPs have been described and are useful herein. See, e.g., WO 2016 / 118724, US 10,413,618B2, US 10,723,692B2, and US8754062B2, each of which is incorporated herein by reference. In certain embodiments, the LNP comprises one or more additional lipids which stabilize the formation of particles during their formation. Exemplary neutral lipids include, for example, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane- lcarboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearioyl-2- oleoylphosphatidyethanol amine (SOPE), and 1,2-dielaidoyl-sn-glycero-3- phophoethanolamine (transDOPE). In one embodiment, the neutral lipid is 1,2-distearoyl-sn- glycero-3phosphocholine (DSPC). In some embodiments, the LNPs comprise a neutral lipid selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM. In various embodiments, the molar ratio of the cationic lipid to the neutral lipid ranges from about 2:1 to about 8:1. In various embodiments, the LNPs further comprise a steroid or steroid analogue. In certain embodiments, the steroid or steroid analogue is cholesterol. In some of these embodiments, the molar ratio of the cationic lipid to cholesterol ranges from about 5:1 to 1:1. The term “anionic lipid” refers to any lipid that is negatively charged at physiological pH. These lipids include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, Ndodecanoylphosphatidylethanolamines, N-succinylphosphatidylethanolamines, Nglutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids. In certain embodiments, the LNP comprises glycolipids (e.g., monosialoganglioside GM1). In some embodiments, the LNPs comprise a polymer conjugated lipid. The term “polymer conjugated lipid” refers to a molecule comprising both a lipid portion and a polymer portion. An example of a polymer conjugated lipid is a pegylated lipid. The term “pegylated lipid” refers to a molecule comprising both a lipid portion and a polyethylene glycol portion. Pegylated lipids are known in the art and include 1-(monomethoxy- polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-s-DMG) and the like. In certain embodiments, the LNP comprises an additional, stabilizing-lipid which is a polyethylene glycol-lipid (pegylated lipid). Suitable polyethylene glycollipids include PEG- modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramides (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines, PEG- modified diacylglycerols, PEG-modified dialkylglycerols. Representative polyethylene glycol-lipids include PEG-c-DOMG, PEG-c-DMA, and PEG-s-DMG. In one embodiment, the polyethylene glycol-lipid is N-[(methoxy poly(ethylene glycol)2000)carbamyl]-1,2- dimyristyloxlpropyl-3-amine (PEG-c-DMA). In one embodiment, the polyethylene glycol- lipid is PEG-c-DOMG). In other embodiments, the LNPs comprise a pegylated diacylglycerol (PEG-DAG) such as 1-(monomethoxy-polyethyleneglycol)-2,3- dimyristoylglycerol (PEG-DMG), a pegylated phosphatidylethanoloamine (PEG-PE), a PEG succinate diacylglycerol (PEG-S-DAG) such as 4-O-(2′,3′-di(tetradecanoyloxy)propyl-1-O- (ω-methoxy(polyethoxy)ethyl)butanedioate (PEG-S-DMG), a pegylated ceramide (PEG- cer), or a PEG dialkoxypropylcarbamate such as ω-methoxy(polyethoxy)ethyl-N- (2,3di(tetradeca noxy)propyl)carba mate or 2,3-di(tetradecanoxy)propyl-N-(w- methoxy(polyethoxy)ethyl)carbamate. In various embodiments, the molar ratio of the cationic lipid to the pegylated lipid ranges from about 100:1 to about 25:1. Other exemplary LNPs and their manufacture are described in the art, for example in U.S. Patent Application Publication No. U520120276209, Semple et al., 2010, Nat Biotechnol., 28(2):172-176; Akinc et al., 2010, Mol Ther., 18(7): 1357-1364; Basha et al., 2011, Mol Ther, 19(12): 2186-2200; Leung et al., 2012, J Phys Chem C Nanomater Interfaces, 116(34): 18440-18450; Lee et al., 2012, Int J Cancer., 131(5): E781-90; Belliveau et al., 2012, Mol Ther nucleic Acids, 1: e37; Jayaraman et al., 2012, Angew Chem Int Ed Engl., 51(34): 8529-8533; Mui et al., 2013, Mol Ther Nucleic Acids.2, e139; Maier et al., 2013, Mol Ther., 21(8): 1570-1578; and Tam et al., 2013, Nanomedicine, 9(5): 665-74, each of which are incorporated by reference in their entirety. Methods In one aspect, is provided a DNA-LNP synthesis protocol, termed the Core-then- shell or layer-by-layer protocol. In standard RNA-LNP formation, the RNA is dissolved in an aqueous buffer (usually citrate buffer, pH 4), while the lipids are dissolved in an organic solvent (usually ethanol). The aqueous and organic solvents are then rapidly mixed in a single step, using the “vortex method” (pipetting one solvent phase into another phase while it is being vortexed), microfluidics, confined impingement jet mixing, etc. This method mixing of two phases has been used in all the early DNA-LNP papers as well. Here, we developed a new method, called “core-then-shell.” In this method, we first condense the DNA with a condensing molecule (such as those above), forming condensed “cores.” These are then immediately mixed with the remaining LNP components. This is accomplished via a 3-channel microfluidic mixer as described below for the condensing molecule DOTAP. In other embodiments, the DNA-LNP are formed using an inline dilution cartridge for making LNPs with DOTAP. A mixture of DOTAP and DOPE is diluted in TAE buffer (solution 1), pDNA is also diluted in TAE buffer (solution 2). Mixture of cholesterol, ionizable lipid (e.g., SM102), DMG-PEG and NOA (STING-inhibitory lipid) is diluted with 100% ethanol (solution 3). Solution 1 and 2 are inserted into lipid and DNA channels, respectively, while solution 3 is inserted into the dilution channel (channel labels are those on a standard NanoAssemblr Ignite). In other embodiments, the DNA integrity is protected during LNP synthesis. LNP synthesis was developed for and optimized with RNA delivery in mind. Therefore, many of the conditions used to synthesize LNPs are suboptimal for DNA loading. In particular, DNA is more stable when complexed with specific ions (e.g., Mg2+). Additionally, we have found that particular buffers improve DNA-LNPs ability to express encoded proteins. Particular buffers and solutes might prevent DNA-damage, improve DNA condensation and thus transit through the nucleus, and allow improve opening of DNA in the nucleus. In other embodiments, the DNA-LNP are formed using certain buffers, such as (5mM-300mM, pH = 3-6.5): Magnesium acetate, Tris-acetate-EDTA (TAE) , Tris-buffered Saline(TBS), HEPES, Tris-borate (TB), Tris-borate-EDTA (TBE), Tris-EDTA (TE) buffer In other embodiments, the DNA-LNP are formed using multivalent ions such as Mg2+, Hexaamminecobalt(III) chloride, or Ca2+. Targeting Moiety In certain embodiments, the LNP is associated with a targeting moiety that binds to a target on the surface of the target cell, e.g., a tumor cell. In certain embodiments, the ligand is an antibody or an antigen binding fragment thereof, and the target is an antigen on the surface of the target cell. In other embodiments, the target is a cell surface receptor, and the targeting moiety is its cognate ligand. Ideal targets include those preferentially expressed on tumor cells, including somatostatin receptor (expressed at high level on the surface of MCC cells (Akaike et al., 2019; Akaike et al., 2021; Guida et al., 2020)) and αvβ3 integrin receptor (overexpressed on angiogenic blood vessels in tumors such as MCC (Amaral et al., 2017; Bob et al., 2017; Goutayer et al., 2010; Sofias et al., 2020)), and APOE receptor. In certain embodiments, the targeting moiety binds ICAM. In other embodiments, the targeting moiety binds PECAM. Other targeting moieties include those that bind CD19, CD20, CD22, CD123, CD33, BCMA, or FRβ. Pharmaceutical Compositions In another aspect, a pharmaceutical composition is provided which contains the DNA-LNP described herein and a pharmaceutically acceptable carrier. In certain embodiments, the helper molecule is provided in the same composition as the DNA-LNP. In other embodiments, the helper molecule is provided separately from the DNA-LNP. In certain embodiments, the LNP is formulated with both the DNA cargo and the helper molecule. In other embodiments, the helper molecule is a separate component of the composition that also includes the DNA-LNP. In other embodiments, the helper molecule is conjugated to the DNA-LNP. In certain embodiments, the composition is formulated for in vivo delivery. As used herein, “carrier” includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions. The phrase “pharmaceutically-acceptable” refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a host. In one embodiment, a composition includes a final formulation suitable for delivery to a subject, e.g., is an aqueous liquid suspension buffered to a physiologically compatible pH and salt concentration. Optionally, one or more surfactants are present in the formulation. In another embodiment, the composition may be transported as a concentrate which is diluted for administration to a subject. In other embodiments, the composition may be lyophilized and reconstituted at the time of administration. Methods and agents well known in the art for making formulations are described, for example, in “Remington's Pharmaceutical Sciences,” Mack Publishing Company, Easton, Pa. Formulations may, for example, contain excipients, carriers, stabilizers, or diluents such as sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes, preservatives (such as octadecyldimethylbenzyl, ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol), low molecular weight polypeptides, proteins such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, and lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, and dextrins, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). A suitable surfactant, or combination of surfactants, may be selected from among non-ionic surfactants that are nontoxic. In one embodiment, a difunctional block copolymer surfactant terminating in primary hydroxyl groups is selected, e.g., such as Pluronic® F68 [BASF], also known as Poloxamer 188, which has a neutral pH, has an average molecular weight of 8400. Other surfactants and other Poloxamers may be selected, i.e., nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol. In one embodiment, the formulation contains a poloxamer. These copolymers are commonly named with the letter “P” (for poloxamer) followed by three digits: the first two digits x 100 give the approximate molecular mass of the polyoxypropylene core, and the last digit x 10 gives the percentage polyoxyethylene content. In one embodiment Poloxamer 188 is selected. The surfactant may be present in an amount up to about 0.0005 % to about 0.001% of the suspension. These above compositions may be administered in a variety of volumes of carrier, excipient or buffer formulation, ranging from about 25 to about 1000 microliters, or higher volumes, including all numbers within the range, depending on the size of the area to be treated, the viral titer used, the route of administration, and the desired effect of the method. Any suitable route of administration may be selected. Accordingly, pharmaceutical compositions may be formulated for any appropriate route of administration, for example, in the form of liquid solutions or suspensions (as, for example, for intratumoral administration, intravenous administration, for oral administration, etc.). Alternatively, pharmaceutical compositions may be in solid form (e.g., in the form of tablets or capsules, for example for oral administration). In some embodiments, pharmaceutical compositions may be in the form of powders, drops, aerosols, etc. Methods The compositions provided herein are useful for delivery of a DNA cargo to a subject in need thereof. Treatment of various conditions are provided, by selection of the DNA suitable for said condition. Provided herein, in one aspect, is a method of delivering a DNA cargo to a subject. In one embodiment, method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising an inhibitor of the cGAS- STING pathway and the DNA cargo. In another embodiment, method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR and the DNA cargo. In one embodiment, the method of treatment includes administering to the subject an effective amount of the DNA-LNP composition described herein, wherein the method includes administering a helper molecule. As noted herein, the helper molecule can be administered as part of, or separate from, the DNA-LNP composition. In certain embodiments of the methods described herein, DNA-LNPs are formulated with a “helper molecule”. In other embodiments, the “helper molecule” is delivered separately, e.g., in separate nanoparticles or as free drugs, some time before the DNA-LNPs. Exemplary methods include one day prior to the DNA-LNP injection, siRNAs targeting cGAS, STING, AIM2, and / or TLR9 are administered to the subject. In another example, an RNA-LNP comprising an mRNA encoding a cGAS, STING, AIM2, TLR9, or IFNAR inhibitor is delivered 1 hour before DNA-LNPs. Diseases treatable using the DNA-LNP compositions described herein include, but are not limited to, the following: Atherosclerosis, Heart attack, Stroke (ischemic), Hypertension, Sepsis, bacterial infection, viral infection, Pain, Wound healing, Traumatic brain injury, broken bones, Wilson’s disease (we prevent copper accumulation by expressing copper-chelating proteins); hemochromatosis (express iron-chelating proteins); lysosomal storage diseases (lysosomal enzyme activator, lysosomal membrane proteins, or non- lysosomal proteins), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), lupus, diabetes, NASH / MASH, PKU, citrullinemia, surgical wounds, IPF (idiopathic pulmonary fibrosis), retroperitoneal fibrosis, cancer, chemo-related side effects, Alzheimer’s disease, Parkinson’s disease, Post-intensive care syndrome, osteoporosis, osteopenia, chronic pain, osteoarthritis, Thyroid diseases, spinal cord injury, ALS, SMA, peripheral nerve trauma, hearing loss, Sinusitis, COPD, asthma, Pulmonary arterial hypertension, Heart failure, Arrhythmias, GERD, cirrhosis of the liver, gallstone disease, Glomerular diseases, Muscular dystrophies, Male pattern baldness, atrial fibrillation or post-pulmonary embolism. Other exemplary diseases or disorders that can be treated include, but are not limited to, hepatitis A, hepatitis B, hepatitis C, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, liver cancer, bile duct cancer, liver adenoma, transthyretin (TTR), proprotein convertase subtilisin / kexin type 9 (PCSK9)-based diseases or disorders, or any combination thereof. Further disorders include glycogen storage disease or deficiency type 1A (GSD1), PEPCK deficiency, CDKL5 deficiency, galactosemia, phenylketonuria (PKU), Primary Hyperoxaluria Type 1, Maple syrup urine disease, tyrosinemia type 1, methylmalonic acidemia, medium chain acetyl CoA deficiency, ornithine transcarbamylase deficiency, citrullinemia; lecithin-cholesterol acyltransferase (LCAT) deficiency, amethylmalonic acidemia (MMA), Niemann-Pick disease, propionic academia (PA); familial hypercholesterolemia (FH), dementia, Lipoprotein Lipase Deficiency, Crigler-Najjar disease, severe combined immunodeficiency disease, Gout and Lesch-Nyan syndrome, biotimidase deficiency, Fabry disease, GM1 gangliosidosis, Gaucher disease type 2 and 3, Zellweger syndrome, metachromatic leukodystrophy, Krabbe disease, Pompe disease, Nieman Pick disease type A, Argininosuccinic Aciduria, adult onset type II citrullinemia, urea cycle disorders; Farber lipogranulomatosis, aspartyl-glucosaminuria, fucosidosis, alpha- mannosidosis, acute intermittent porphyria (AIP), alpha-1 antitrypsin deficiency (emphysema), anemia due to thalassemia or to renal failure, ischemic diseases, occluded blood vessels as seen in, for example, atherosclerosis, thrombosis, or embolisms, Parkinson's disease, congestive heart failure, muscular dystrophies, and diabetes. The DNA-LNP compositions may be administered locally or systemically, as needed to treat the specific condition desired. Acceptable routes of administration include, but are not limited to, direct delivery to a desired organ (e.g., the liver (optionally via the hepatic artery), lung, heart, eye, kidney,), oral, inhalation, intranasal, intrathecal, intratracheal, intraarterial, intraocular, intravenous, intramuscular, subcutaneous, intradermal, ICM, and other parental routes of administration. Routes of administration may be combined, if desired. In certain embodiments, the composition is administered intratumorally. In certain embodiments, the method further includes administration of an additional therapeutic agent. In certain embodiments, the LNP composition and additional agent are delivered essentially simultaneously via the same route. In other embodiments, the LNP composition is delivered first. In other embodiments, the LNP composition is delivered subsequent to the additional agent(s). In another aspect, the compositions provided herein are useful for delivery of a DNA cargo to a target cell, in vitro or ex vivo. The method includes contacting the cell with a DNA compaction / condensation molecule, an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR, and the DNA cargo, and optionally, a transfection reagent. In other embodiments, the method includes contacting the cell with a DNase inhibitor, an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR, and the DNA cargo, and optionally, a transfection reagent. Transfection reagents are known in the art and include Lipofectamine, polyethylenimine (PEI), calcium phosphate, etc. Desirable target cells include those useful for medical research or therapeutic purposes. Such cells include primary cells, such as neurons, T cells, B cells, IPSC and cell lines, such as HeLa Cells, HEK 293 Cells, Jurkat Cells, MDCK Cells, HepG2 Cells, MCF-7 Cells, PC-12 Cells, SH-SY5Y Cells, CHO Cells, and NIH / 3T3 Cells. In another embodiment is included a composition comprising a DNA-LNP, a DNase inhibitor, an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR, and a transfection reagent. In yet another embodiment is included a composition comprising a DNA-LNP, a DNA compaction / condensation agent, an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR, and a transfection reagent. Specific embodiments: 1. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response. 2. The composition of embodiment 1, wherein the helper molecule is an inhibitor of cGAS-STING pathway, optionally cGAS, STING, AIM2, TLR9, TBK1, or IFNAR. 3. The composition of embodiment 2, wherein the inhibitor is a nitrated fatty acid or prodrug thereof, optionally nitro-oleic acid, nitro-conjugated linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, or 4-octyl itaconate. 4. The composition of embodiment 1, wherein the helper molecule is an inhibitor of the cGAS-STING pathway, optionally a cGAS inhibitor or a STING inhibitor. 5. The composition of embodiment 4, wherein the cGAS inhibitor is PF-06928215, RU.365, RU.521, G150, compound S3, hydroxychloroquine, quinacrine, X6, suramin, ODN A151, or CU-76. 6. The composition of embodiment 2, wherein the inhibitor is an AIM2 siRNA, sulfonic calixarene, Shikonin, NLPR3 / AIM2-IN-3, JC2-11, or NLPR3 / AIM2-IN-2. 7. The composition of embodiment 4, wherein the STING inhibitor is Astin C, C-176, C178, C170, C171, H151, NO2-cLA, NO2-OA, BPK-21, BPK-25, or a STING siRNA. 8. The composition of embodiment 1, comprising i) a molecule capable of complexing or condensing DNA. 9. The composition of any one of embodiments 1 to 8, wherein the molecule capable of complexing or condensing DNA is a cationic lipid. 10. The composition of embodiment 9, wherein the cationic lipid is DOTAP, DOSPA, or spermine / spermidine-conjugated lipid. 11. The composition of any one of embodiments 1 to 8, wherein the molecule capable of complexing or condensing DNA is a polyamine. 12. The composition of embodiment 9, wherein the polyamine is spermine or spermadine. 13. The composition of any one of embodiments 1 to 8, wherein the molecule capable of complexing or condensing DNA is a cationic protein or peptide. 14. The composition of embodiment 9, wherein the cationic protein or peptide is a histone, protamine, Brdt (sperm protein), polyamine, HU protein, HMGB protein, DNA polymerase, surface-modified bovine serum albumin (BSA), spermidine, PKKKRKV (NLS), PKKKRKVEDPYC (NLS), TAT (GRKKRRQRRRPQ), or a TAT-NLS conjugate. 15. The composition of any one of embodiments 1 to 8, wherein the molecule capable of complexing or condensing DNA is an ionizable lipid, optionally an ionizable lipid that is positively charged at pH 6 - 7.4. 16. The composition of embodiment 9, wherein the ionizable lipid is 98N-12 or 306- N16B. 17. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and a DNase inhibitor. 18. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, a DNase inhibitor, and an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR. 19. The composition of embodiment 17 or 18, wherein the DNase inhibitor is a DNase I, DNase II, or DNaseIII peptide inhibitor or an siRNA that degrades DNase I, DNase II, or DNaseIII. 20. The composition of any one of embodiments 1 to 19, wherein the molecule to aid in nuclear localization of DNA is a nuclear localization signal (NLS) peptide. 21. The composition of embodiment 20, wherein the NLS further comprises an oligo. 22. The composition of any one of embodiments 1 to 19, wherein the molecule to aid in nuclear localization of DNA is a cell penetrating peptide or Replication Protein A (RPA). 23. The composition of embodiment 20 or 21, wherein the peptide is coupled to a plasmid that encodes the DNA cargo. 24. The composition of embodiment 13, wherein the coupling is via covalent or non- covalent binding. 25. The composition of any one of embodiments 1 to 19, wherein the molecule to aid in nuclear localization of DNA is a DNA-binding domain (DBD) mimicking peptide. 26. The composition of embodiment 25, wherein the DBD-mimicking peptide is fused with a nuclear localization signal peptide. 27. The composition of embodiment 25 or 26, wherein the DBD-mimicking peptide mimics helix-turn-helix (HTH), zinc finger, leucine zipper, or basic region leucine zipper (bZIP). 28. The composition of any one of embodiments 1 to 17, wherein the DNA cargo is in the form of a DNA nanostructure. 29. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, a DNA-binding domain (DBD) mimicking peptide, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the DNA cargo is in the form of a DNA nanostructure. 30. The composition of any one of embodiments 1 to 29, wherein the DNA cargo is comprised in a plasmid that comprises one or more tandem repeats of the SV40 DNA targeting sequence (DTS). 31. The composition of any one of embodiments 1 to 30, wherein the LNP comprises a short-chain aminolipid. 32. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the LNP comprises an aminolipid. 33. The composition of embodiment 31 or 32, wherein the aminolipid is N-dodecyl-N- (3-methoxypropoyl)dodecan-1-amine (AL-A12). 34. The composition of any one of embodiments 1 to 33, wherein the LNP further comprises a fusion protein comprising dCas9-importin. 35. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and a fusion protein comprising dCas9-importin, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR. 36. The composition of any one of embodiments 1 to 35, further comprising an excipient, optionally tannic acid, vitamin B12, davunetide, or chlorogenic acid. 37. The composition according to any one of embodiments 1 to 36, further comprising a ligand conjugated to the LNP. 38. The composition according to embodiment 37, wherein the ligand binds a receptor or a target on the surface of a cell. 39. The composition according to embodiment 37 or 38, wherein the ligand is an antibody or antigen binding fragment thereof. 40. The composition of any one of embodiments 37 to 39, wherein the ligand binds ICAM or PECAM. 41. A method of delivering a DNA cargo to a subject, the method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response. 42. The method according to embodiment 41, wherein the composition comprises the composition according to any one of embodiments 1 to 40. 43. The method according to any one of embodiments 41 or 42, wherein the composition is formulated for in vivo delivery. 44. The method according to embodiment 43, wherein the composition is formulated for intravenous, intraarterial, ICM, or inhaled delivery. 45. A method of treating a subject in need thereof, the method comprising administering to the subject an effective amount of a composition according to any one of embodiments 1 to 40. 46. A method of treating idiopathic pulmonary fibrosis (IPF) a subject, the method comprising administering to the subject an effective amount of the composition according to any one of embodiments 1 to 40, wherein the DNA cargo comprises an ORF encoding an anti-fibrotic agent, optionally an antibody to TGFalpha, TGFbeta, VEGF, FGF, CTGF, CCN2, PDGF, Oncostatin M, CCL2, CCL3, or CXCL12. 47. A kit comprising a medicament comprising a composition according to any one of embodiments 1 to 40 and a pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament for treating or delaying IPF in an individual. 48. A method of delivering a DNA cargo to a cell, the method comprising contacting the cell with a composition comprising a lipid nanoparticle (LNP) comprising an inhibitor of the cGAS-STING pathway, a molecule capable of condensing DNA, and the DNA cargo. 49. The method according to embodiment 48, wherein the composition comprises the composition according to any one of embodiments 1 to 40. 50. The method according to embodiment 48 or 49, wherein the composition is formulated for in vitro delivery. 51. The method according to any one of embodiments 48 to 50, wherein the cell is a mammalian cell, optionally an IPSC, immune cell, or primary neuron. 52. The composition or method of any preceding embodiment, wherein the DNA cargo is a polynucleotide comprising a promoter and a coding sequence for a gene product of interest. 53. The composition or method of embodiment 52, wherein the promoter is a tissue- specific promoter. 54. The composition or method of embodiment 52, wherein the promoter is a regulatable promoter. 55. The composition or method of any one of embodiments 52 to 54, wherein the polynucleotide further comprises LTRs or ITRs. 56. A treatment regimen for a subject in need thereof, comprising: i) delivering to the subject an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR; ii) subsequently delivering to the subject a lipid nanoparticle (LNP) comprising a DNA cargo and a molecule capable of condensing DNA. a molecule capable of complexing or condensing DNA and / or a molecule to aid in nuclear localization of DNA. 57. The treatment regimen of embodiment 56, wherein the inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR is comprised in an LNP. 58. The treatment regimen of embodiment 56 or 57, wherein the inhibitor is an siRNA, mRNA, small molecule drug, peptide, antibody fragment, or aptamer. 59. A method of delivering a DNA cargo to a subject, the method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising the DNA cargo and a molecule capable of complexing or condensing DNA. 60. A method of delivering a DNA cargo to a subject, the method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising the DNA cargo and a DNase inhibitor. EXAMPLES Example 1: Materials and methods Materials Ionizable lipids (D-Lin-MC3-DMA, ALC-0315, and SM-102), ALC-0159, and nitro- oleic acid (NOA) were purchased from Echelon Biosciences (Cat# N-1282, N-1102, N-1020, L-0112, respectively). Docosahexaenoic acid (DHA) was purchased from MedChemExpress (Cat# HY-B2167). Eicosapentaenoic acid (EPA) and nitro-linoleic acid (NLA) were purchased from Cayman Chemical (Cat# 90110, 30160, respectively).18:0 PC (DSPC, 1,2- distearoyl-sn-glycero-3-phosphocholine) and DMG-PEG 2000 (1,2-dimyristoyl-rac-glycero- 3-methoxypolyethylene glycol-2000) were purchased from Avanti Polar Lipids (Cat# 850365, 880151, respectively). Plasmid DNA was purchased from Aldevron (<0.1 EU / µl endotoxin level, Cat# 5078-5).5moU-containing firefly luciferase mRNA was purchased from TriLink BioTechnologies (Cat# L-7202). Animals All animal experiments strictly adhered to the guidelines established in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD). Approval for all animal procedures was obtained from the University of Pennsylvania Institutional Animal Care and Use Committee. Naïve C57BL / 6, naïve BALB / c, and STING- knockout BALB / c mice, aged 6–8 weeks and weighing 23-25 g, were procured from The Jackson Laboratory, Bar Harbor, ME, for the study. The mice were housed in a controlled environment maintained at temperatures between 22–26 °C, with a 12 / 12-hour light / dark cycle, and provided with access to food and water. For survival curve studies, mice were monitored and weighed daily. Any mice with visual cues of extreme distress or weight loss >20% were euthanized and removed from study. All intravenous injections were done retro-orbitally by injecting into the retro-bulbar sinus. LNP Formulation LNPs were formulated using microfluidics (NanoAssemblr Ignite, Precision Nanosystems). Lipids were dissolved in ethanol and mixed with aqueous buffer (50 mM citrate buffer, pH 4) containing either 5moU modified mRNA or pDNA, at a total flow rate of 6 mL / min, a flow rate ratio of 1-to-3, and total lipid to nucleic acid ratio of 40 to 1 (w / w). LNPs were dialyzed against 1× PBS in a 10 kDa molecular weight cut-off cassette for 2 h, stored at 4 °C, and used within 2 days. For drug loaded LNPs, anti-inflammatory lipids were added as a 5thcomponent at a drug-to-total lipid ratio of 0.2 (mole-to-mole) for all studies unless otherwise indicated. All LNPs made used FDA-approved formulations with the following molar ratios (D-Lin-MC3-DMA LNPs: 50% D-Lin-MC3-DMA, 38.5% cholesterol, 10% DSPC, 1.5% DMG-PEG 2000; SM-102 LNPs: 50% SM-102, 38.5% cholesterol, 10% DSPC, 1.5% DMG- PEG 2000; ALC-0315 LNPs: 46.3% ALC-0315, 42.7% cholesterol, 9.4% DSPC, 1.6% ALC-0159). All studies used ALC-0315 LNP formulation unless otherwise indicated. LNP Characterization Measurements of hydrodynamic nanoparticle size and polydispersity index was conducted through dynamic light scattering (DLS) using a Zetasizer Pro ZS (Malvern Panalytical). The encapsulation efficiencies and concentrations of LNP mRNA or pDNA were determined using a Quant-iT RiboGreen RNA assay or Quant-iT PicoGreen dsDNA assay, respectively (Invitrogen). Anti-inflammatory lipid (AIL) drug loading in LNP was determined using ultra-performance liquid chromatography (UPLC, UV / Vis) after purifying unloaded AIL using size exclusion column (Zeba Spin Desalting Columns). Cell Culture RAW264.7 mouse macrophages were purchased from ATCC and cultured in Dulbecco’s modified Eagle’s medium (DMEM) with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin / streptomycin (PS). All cells were incubated with 5% CO2 at 37°C. For cell viability and luciferase assays, cells were seeded at a density of 1E5 cells / well in a 96 (clear bottom for cell viability assay and white bottom for luciferase assay) well plate using 100 uL 24h prior to LNP treatment. cck8 assay was performed according to manufacturer’s instructions to measure cell viability % (Abcam). “Luciferase Assay Systems” protocol was used to measure expression capacity of either mRNA or pDNA LNPs (Promega). For cytokine studies, cells were seeded at a density of 3E5 cells / well in a 24 clear bottom well plate using 300 uL 24h prior to LNP treatment.4-hours post LNP treatment, supernatant was collected, spun down at 10,000 g for 10 min to remove any debris and stored at -80°C. For immunofluorescence imaging studies, cells were seeded at a density of 1.2E5 cells / well in 8-well µ-Slide chambers. p-STING and p-TBK1 imaging and quantification Cells were treated with LNPs for 4-hours. Then, they were fixed in 4% fresh paraformaldehyde for 15 min. Permeability was then performed with 0.05% saponin buffer (J63209.AK, Invitrogen) for 10 min. Then, samples were incubated with 10% normal goat serum (50062Z, Life Technologies Corp.) for 1 h. After PBS washing, cells were treated with 1:150 primary antibodies (anti p-STING, 62912S, Cell Signaling Technology Inc.; anti p-TBK1, 5483S, Cell Signaling Technology Inc.) at 4°C overnight. Cells were washed with PBS to remove unbound antibodies. Next, cells were incubated with 1:750 secondary antibodies (Alexa Fluor 488-conjugated goat anti-rabbit antibody, A11008, Invitrogen) at 37 ℃ for 1.5 h. Cell nuclei were labeled using DAPI. Images were acquired by LSM980 microscopy (Zeiss) and mean fluorescent intensity was measured by Image J. iPSC-derived Alveolar type 2 epithelial cell transfection Alveolar type 2 epithelial cells derived from human induced pluripotent stem cells (iAT2s) were maintained in 3D growth factor reduced (GFR)-Matrigel culture as previously described24,25. Plating iAT2s on 2D transwell inserts (6.5mm; Falcon) was performed as previously described26. In brief, transwell inserts were coated with diluted hESC-Qualified Matrigel (Corning) as instructed by the manufacturer. A single-cell suspension of iAT2s from 3D culture was obtained by dissociating Matrigel droplets for 30 minutes with 2 mg / mL Dispase (Gibco) followed by 15 minutes of 0.05% trypsin-EDTA (Gibco) at 37 °C. iAT2s were plated on pre-coated transwell inserts at a density of 500,000 live cells / cm2in 500 μL of CK+DCI+Y (3 μM CHIR99021, 10 ng / mL KGF, 50 nM dexamethasone, 0.1 mM cAMP, 0.1 mM IBMX, 10 μM Rho-associated kinase inhibitor (Y) [MilliporeSigma, Y- 27632]), with 500 μL of CK+DCI+Y added to the basolateral compartment.48-hours after plating, iAT2s were refreshed with 500uL CK+DCI in both the apical and basolateral compartments prior to LNP administration and transfection. Various conditions of LNPs containing eGFP pDNA were administered dropwise onto 2D cultures of iAT2s. Lipofectamine 2000 (Thermo) transfection of eGFP Nanoplasmid was performed according to the manufacturer's protocol. iAT2s were imaged for tdTomato retention and GFP expression using an Eclipse Ti2 Series inverted microscope (Nikon) and 24-, 48-, and 120-hours post-treatment. At 120 hours, iAT2s were isolated from transwell inserts with Accutase (StemCell) and washed in FACS Buffer (0.1% BSA, 2mM EDTA, in PBS pH 7.4) for flow cytometry analysis. iAT2 tdTomato retention and GFP expression was assessed by flow cytometry using a CytoFlex SRT (Beckman) and analyzed using FlowJo v10.10 software. In Vivo Plasma Collection Mice treated with LNPs were sacrificed by terminal blood collection via inferior vena cava. Opening of the major body cavity and subsequent thoracotomy was performed as a secondary measure of sacrifice. Blood was spun down at 1000 g for 10 mins (room temperature), plasma supernatant was collected and stored at -80°C. In Vitro and In Vivo Cytokine Measurements Cytokine measurements were carried out on plasma (2x diluted in 1x PBS) or cell culture supernatant (undiluted) with a LegendPlex 13-plex Mouse Inflammation Panel (Biolegend) according to the manufacturer’s instructions. In Vivo Imaging System (IVIS) At the time of imaging, mice were intraperitoneally injected with 100 uL of 30 mg / mL D-luciferin sodium salt (Regis Technologies Inc, 103404-75-7) under 3% isoflurane- induced anesthesia, then placed in an IVIS Spectrum machine (PerkinElmer) belly up and imaged for whole body chemiluminescence every 0.2 minutes with automatically determined exposure time for 10-12 images, until the signal reached the peak intensity. Statistics All results are expressed as mean ± SEM unless specified otherwise. Statistical analyses were performed using GraphPad Prism 8 (GraphPad Software) * denotes p<0.05, ** denotes p<0.01, *** denotes p<0.001, **** denotes p<0.0001. Example 2: Unlike nucleoside-modified and purified mRNA-LNPs, pDNA-LNPs induce serious inflammatory responses in wild type mice. To systematically probe toxicities, we used BioNTech / Pfizer’s FDA-approved COVID-19 mRNA vaccine LNP formulation, containing the ionizable lipid ALC-0315, formulated with either mRNA or plasmid DNA (pDNA) To remove carrier toxicity as a variable, both mRNA- and pDNA-LNPs were formulated using the same 40-to-1 total lipid to nucleic acid (w / w) ratio. When IV injecting a commonly used therapeutic dose6of 1 mg / kg (~25 µg per mouse) into naïve C57BL / 6 mice, we observed 100% mortality within 2 days for mice that received pDNA-LNPs, compared to 0% for ones that received mRNA-LNP (FIG.1A). Furthermore, we noticed extreme lethargy and lack of movement of mice ~4-hours after pDNA-LNP administration, using an artificial intelligence (AI) motion-tracking device that we previously validated for detecting infusion reactions7(FIG.1B). Thus, LNPs delivering pDNA at a 1 mg / kg dose, but not nucleoside-modified mRNA at the same dose, induce an acute reaction that leads to death within 2 days. To study the mechanisms underlying pDNA-LNP-induced toxicities, we reduced the pDNA-LNP dose 5-fold (to 5 µg per mouse), ensuring survival and enabling assessment of signaling pathways. Even one day after the administration of 5 µg pDNA-LNP, the mice lost >10% of their body weight, taking ~5 days to return to baseline levels (FIG.1C). Furthermore, to assess systemic toxicities, we collected plasma 4-hours after pDNA-LNP injection and observed a drastic increase in the levels of various pro-inflammatory cytokines (FIG.1D). Specifically, we found a ~1400x increase in IFN-β and ~1000x in IL-6 when compared to the levels measured in the mRNA-LNP group (FIG.1E, 1F). Thus, LNPs loaded with pDNA, but not with nucleoside-modified mRNA, induce a massive cytokine response, including IFN-β. Notably, IFN-β is a type 1 interferon that is traditionally known as an antiviral cytokine, hinting that the immune system likely identifies pDNA-LNP administration as a viral infection8. To ensure pDNA-LNP toxicity was independent of LNP formulation, we formulated pDNA-LNPs using 2 other FDA-approved LNP formulations (D-Lin-MC3-DMA and SM- 102 ionizable lipids). Regardless of LNP formulation, we observe acute toxicities in vivo (FIG.1G). Moreover, we observed these toxicities regardless of plasmid size (FIG.2). We next interrogated the kinetics of the inflammatory responses, as the mice returned to a normal visual and behavioral phenotype 24-hours after pDNA-LNP administration. In agreement with our visual assessment, we observed a decrease in most pro-inflammatory cytokines in the plasma 24-hours after the 5 µg pDNA-LNP dose, with the majority of cytokines – specifically IFN-β and IL-6 – back to baseline (FIG.1H). Furthermore, we ensured inflammation does not reappear at later time points by measuring plasma cytokines 5 days after pDNA-LNP administration (FIG.3). Since this response seems to be acute, we investigated the role of macrophages that we previously showed are key in mediating LNP-related toxicities and is known to sensitively detect DNA-viruses9,10. To assess general pDNA-LNP toxicity in vitro, we dosed the macrophage-derived cell line RAW264.7 with various concentrations, for various treatment times, and measured cell viability (FIG.4). At a concentration of 1000 ng / mL for both mRNA- and pDNA-LNPs, we found a significant decrease in cell viability over time, with ~90% cell death 48-hours after pDNA-LNP compared to <50% post mRNA-LNP (FIG.1I). The decreasing trend in cell viability for mRNA group is likely due to carrier-mediated inflammation and cell confluency issues at later time points. Moreover, similarly to the in vivo cytokine results, we observed a significant increase (~10x) in IFN-β levels in the cell supernatant for pDNA- LNPs compared to empty- and mRNA-LNP controls 4-hours after 1000 ng / mL LNP treatment (FIG.1J). Lastly, we performed a dose response study of pDNA-LNPs which showed exponential increase in IFN-β. Prior to investigating the mechanisms that mediate pDNA-LNP-induced adverse events, we inquired if the route of administration led to varying toxicities. We administered mRNA- and pDNA-LNPs intratracheally (to the lungs) at a dose of 5 µg. We evaluated inflammation specific to the lungs by examining protein and leukocyte levels in the bronchoalveolar lavage (BAL) fluid, which indicates capillary leakage and leukocyte penetration into the alveoli (air sacs). In mice that received mRNA-LNPs, we observed an increase in total protein and leukocyte count in the BAL, which we have previously thoroughly characterized as carrier-related inflammation10,11, meaning it is due to the LNPs themselves, not their cargo nucleic acids. Importantly, we noticed even higher levels of protein and leukocyte in BAL in mice that received pDNA-LNPs compared to mRNA-LNPs, highlighting pDNA cargo-related toxicity (FIG.5). In summary, we show that pDNA-LNPs elicit significant morbidity and even mortality in a dose-dependent manner, when IV-injected at commonly used therapeutic doses. Example 3: STING activation drives pDNA-LNP-induced toxicity Amongst the many known DNA-sensing pathways, cGAS-STING was reported to induce acute toxicities and significantly upregulate type 1 interferons4,5,12–14, as measured in the studies described above. Interestingly, cGAS activation can occur not only from viral DNA, but any cytosolic DNA. Thus, it serves as a versatile sensor that can also be activated by bacterial DNA, DNA from dying cells, and even self-mitochondrial DNA that is released into the cytosol during cell stress leading to downstream activation of STING, which upregulates type 1 IFNs and pro-inflammatory cytokines (FIG.6A). As such, we investigated if pDNA-LNPs activate this pathway. To assess the role of the cGAS-STING pathway in pDNA-LNP-elicited adverse events, we IV injected pDNA-LNP in wild type and STING-knock out (KO) mice and collected plasma 4-hours later. Note, we used BALB / c mice instead of C57BL / 6 animals as the only STING-KO mice that were commercially available were of the BALB / c strain. After 5 µg IV injection of pDNA-LNPs, we observed significantly lower levels of various pro-inflammatory cytokines in STING-KO mice compared to wild type mice, indicating STING activation as a primary driver of pDNA-LNP inflammation (FIG.6B). Importantly, the two major cytokines IFN-β and IL-6 were down to baseline levels in STING-KO mice injected with pDNA-LNPs. Furthermore, the overall level of inflammation appeared to be lower in the BALB / c strain compared to C57BL / 6 (~2x lower IFN-β), though both are much above the baseline and the mRNA-LNP control (FIG.6C). Furthermore, we found the mortality rate to be 20% for the 1 mg / kg of pDNA-LNP dose, compared to 100% mortality in C57BL / 6 mice at 1 mg / kg (~25 µg) dose (FIG.6D). Notably, the BALB / c mice that survived still experienced significant weight loss (FIG.7) In addition, using confocal microscopy, we confirmed STING activation in macrophages treated with pDNA - using lipofectamine or LNP - by staining for activated phospho-STING (pSTING) (FIG.6E). Note, we do not see STING activation in the lipofectamine-only control, indicating it is a pDNA-specific activation rather than carrier- based activation (FIG.6F). Example 4: Developing a platform technology: co-loading of endogenous anti-inflammatory lipids with STING inhibitory activity into standard pDNA-LNP formulations We next looked into inhibitors of the STING pathway that we can potentially co-load into standard pDNA-LNP to ameliorate its acute toxicities. We first investigated potential anti-inflammatory lipids (AILs) as they are highly lipophilic and have greater chance of loading into standard pDNA-LNPs compared to small molecule drugs. We also prioritized fast-acting drugs as opposed to siRNAs, since pDNA-LNP inflammation is acute-but- transient, as shown previously in FIG.1H. Interestingly, many unsaturated fatty acids - such as Docosahexaenoic acid (DHA), Eicosapentaenoic acid (EPA), Linoleic acid (LA), and Oleic acid (OA) - have been found to be nitrated after a virus infection as a negative feedback loop to dampen excessive inflammation17,18(FIG.8A). These nitrated fatty acids (NFAs) act as electrophiles with the ability to modify various proteins on specific exposed cysteines, leading to inhibition of NF- κB and activation of Nrf2 (which controls an array of antioxidant response element– dependent genes). Most importantly, NFAs are potent inhibitors of STING palmitoylation and signaling18. We loaded DHA and EPA - lipids shown to be nitrated in the cell17- and already nitrated versions of LA and OA (NLA and NOA, respectively) by adding these AILs as a fifth component into standard LNP formulation at a drug-to-total lipid ratio of 0.2 mole-to- mole (FIG.8B). Using dynamic light scattering, we confirmed LNP size and polydispersity are unaffected by the addition of this fifth component (FIG.8C). Furthermore, all AILs showed encapsulation efficiency of >80% without negatively affecting pDNA loading (FIG. 8D). To initially assess the safety profile of AIL-loaded pDNA-LNPs (+AIL-pDNA- LNPs), we treated RAW264.7 cells with a 1000 ng / mL dose and quantified IFN-β levels in the cell supernatant 4-hours post treatment. All AILs significantly reduced IFN-β indicating the protective effects of AIL-pDNA-LNPs compared to standard pDNA-LNPs (FIG.8E). Furthermore, AILs that were nitrated prior to LNP formation (NLA and NOA) performed better in reducing IFN-β (back to baseline levels) compared to LNPs loaded with non- nitrated AILs (DHA and EPA) that are known to be nitrated within the cell after viral infection. We proceeded to use NOA for rest of the studies as it was the more effective in vitro compared to DHA and EPA and more cost-effective than NLA. Moreover, we did not observe a decrease in cell viability of NOA-pDNA-LNPs (FIG.9) 4-hours after administrating at 1000 ng / mL dose. Example 5: NOA-pDNA-LNPs show superior safety profiles in vitro and in vivo To confirm the reduction in IFN-β production of macrophages treated with NOA- pDNA-LNPs is due to STING inhibition, we performed confocal imaging, staining for activated phospho-STING (pSTING). At a dose of 1000 ng / mL, there was no measurable STING activation in macrophages treated with NOA-pDNA-LNPs compared to ones treated with standard pDNA-LNPs 4-hours post treatment (FIG.10A, 10B). We also could not detect TANK-binding Kinase 1 (TBK1), a downstream marker of STING activation, in cells that received NOA-pDNA-LNPs compared to pDNA-LNPs (FIG.10C, 10D). Furthermore, due to the reduction of pro-inflammatory cytokines, NOA-pDNA- LNPs maintained higher cell viability over time compared to standard pDNA-LNPs indicating protective effects of NOA in vitro (FIG.10E). To demonstrate that incorporation of NOA into pDNA-LNPs is associated with an improved safety profile, we added NOA to three different LNPs formulated with the same components found in the FDA-approved LNPs (D-Lin-MC3-DMA, SM-102, and ALC-0315). Regardless of the LNP composition, addition of NOA leads to significant reduction in IFN-β secretion in cell supernatant 4-hours post 1000 ng / mL dose in macrophages (FIG.10F, 10G, 10H). Notably, the total levels of IFN-β vary with each ionizable lipid used (SM-102 > ALC-0315 > D-Lin-MC3-DMA) which also correlated with the transgene expression (FIG.11). Next, we investigated the safety profile of NOA-pDNA-LNPs in C57BL / 6 mice. To assess the effect on acute response to pDNA, we IV-injected 5 µg of standard pDNA-LNP or NOA-pDNA-LNP in mice and collected plasma for cytokine analysis 4-hours post injection. We observed a significantly less levels of various pro-inflammatory cytokines (IFN-β, IL-1α, IFN-γ, TNF-α, MCP-1, IL-1β, and IL-6) (FIG.10I). Specifically, IFN-β and IL-6 were reduced ~4x and ~8x, respectively (FIG.10J, 10K). By performing a dose-response study, we identified NOA to total lipid ratio (mole-to-mole) of 0.2-0.8 for NOA-pDNA-LNPs as the optimal formulation parameter for the most reduction on plasma cytokines (FIG.12). We attempted to further reduce the inflammatory response by loading A151, an oligonucleotide that was previously shown to inhibit other DNA-sensors, AIM2 and TLR919. We observed some efficacy in vitro but did not see any additive or synergistic effects in vivo when co-loaded into NOA-pDNA-LNPs further indicating cGAS-STING signaling is the primary driver of pDNA-LNP toxicity in mice (FIG.13). Most importantly, NOA-pDNA-LNPs completely prevent mortality in C57BL / 6 mice compared to standard pDNA-LNPs at the 1 mg / kg dose (FIG.10L). However, the inflammatory response is not completely ablated as mice experience weight loss (FIG.14), indicating further improvements are required prior to clinical translation. Example 6: NOA-pDNA-LNPs show prolonged transgene expression in vivo We next investigated the functional capacity of LNPs to ensure that the addition of NOA does not hinder transgene expression. The duration of luciferase expression within the whole body of BALB / c mice was monitored following IV injection of either 25 µg of pDNA-LNPs or NOA-pDNA-LNPs using IVIS imaging (FIG.15A). Importantly, pDNA- LNP and NOA-pDNA-LNP show similar levels of protein expression confirming that addition of NOA provides better safety profiles without hindering transgene expression in vivo for at least 1 month (FIG.15B). Of note, two mice that received 25 µg of pDNA-LNPs died within 2 days. Furthermore, mRNA-LNP protein expression is back to baseline within 8 days (FIG. 16), while NOA-pDNA-LNP expression is significantly greater than baseline and mRNA- LNP control at 15 days after dose (FIG.15C). Example 7: Small lipid screen significantly boosts transgene expression of +NOA-pDNA- LNPs As a proof of concept, we next investigated if we could improve NOA-pDNA-LNPs’ total pDNA expression capacity. Besides pDNA-induced inflammation, there are additional challenges in pDNA-LNP delivery such as poor nuclear translocation which is required for pDNA transcription and pDNA degradation due to endosomal and cytosolic DNases21–23. As such, many studies optimizing LNP formulation for mRNA delivery may not translate to improving pDNA delivery. Thus, we first performed a small Design of Experiments (DoE) screen to find optimal formulation parameters for NOA-pDNA-LNP transfection. Using JMP software, we designed a full factorial DoE by varying 3 parameters: amount of ionizable lipid (30-50 mole % using ALC-0315), total lipid to pDNA ratio (20:1 to 40:1, w / w), and the type of helper lipid (DSPC, DOPE, DOTAP, 18:0 PG). All formulations contained NOA to total lipid mole ratio of 0.2 and used a luciferase reporter plasmid. A total of 48 DoE LNP formulations were tested in RAW264.7 cells at a dose of 1000 ng / mL for 24-hours prior to measuring luciferase expression. DoE results show the importance of LNP formulation parameters for transgene expression capacity (FIG.17A). LNPs formulated with DOPE or 18:0 PG as the helper lipid had lower transgene expression compared to LNPs made with DSPC or DOTAP. Importantly, optimized LNPs with DSPC or DOTAP as the helper lipid leads to a ~3.5x and ~23x increase in pDNA transgene expression in vitro, respectively (FIG.17B). DSPC optimized NOA-pDNA-LNPs were made using 30% ALC-0315, 54.5% cholesterol, 15% DSPC, 0.5% ALC-0519, and 0.2 D / L of NOA. DOTAP optimized +NOA-pDNA-LNP were made using 40% ALC-0315, 46.4% cholesterol, 12.1% DOTAP, 1.5% ALC-0519, and 0.2 D / L of NOA. We speculate that DOTAP optimized NOA-pDNA-LNPs help condense and protect pDNA, but further studies are required to elucidate the specific mechanisms. To validate and generalize the DOTAP optimized NOA-pDNA-LNP formulation, we treated difficult-to-transfect cells, human induced-pluripotent-stem-cell-derived alveolar epithelial type II-like cells (iAT2s) and measured eGFP transgene expression over time using microscopy. Note, mCherry (red) signal confirms iAT2 phenotype. Representative images show improved transfection efficiencies of DOTAP optimized NOA-pDNA-LNPs compared to the gold standard, Lipofectamine (FIG.17C). After 120-hours, iAT2s were isolated and flow cytometry was performed showing similar (but trending higher) % eGFP positivity to Lipofectamine (FIG.17C). Importantly, we show that NOA-pDNA-LNP formulation can be further optimized to significantly improve transgene expression in vitro. Example 8: Discussion Despite the success of nucleoside-modified mRNA-LNP therapeutics, the short half- life of mRNA expression remains one of the biggest challenges limiting its application in the treatment of chronic diseases. In contrast, pDNA delivery shows great promise, with prolonged gene expression (months) and tunable promoters providing cell-specificity and temporal control. However, here we show the acute toxicities associated with pDNA delivery via LNPs, triggering a high level of morbidity and even mortality (depending on the administered pDNA-LNP dose) in wild type BALB / c and C57BL / 6 mice. Through use of immunofluorescence staining in vitro and genetic knockout mice in vivo, we identify STING activation as a primary driver of pDNA-LNP-elicited adverse events. The acute response to pDNA-LNPs is highlighted by the rapid onset of lethargy and lack of movement in mice within hours of administration, culminating in 100% mortality within 48-hours at 1 mg / kg dose. Furthermore, we show the toxicities caused by pDNA-LNP across various LNP formulations, various plasmids, and the mouse strains. To increase the safety profile of pDNA-LNPs, we introduce a novel platform technology: co-loading of endogenous anti-inflammatory lipids with STING inhibitory activity into standard pDNA-LNP formulations. We show that various AILs can be loaded into standard pDNA-LNPs without negatively affecting pDNA loading or particle stability. Specifically, we demonstrate the efficacy of nitro-oleic acid in mitigating pDNA-induced inflammation both in vitro and in vivo. By incorporating NOA into pDNA-LNPs, we achieve a significant reduction in pro-inflammatory cytokine levels and adverse events, without compromising transgene expression efficiency. Moreover, NOA-pDNA-LNPs express transgene for at least 1 month compared to ~8 days for mRNA-LNPs. We also show that NOA-pDNA-LNP formulation can be optimized for improved expression in vitro by performing a Design of Experiments (DoE) screen, revealing critical LNP formulation parameters on pDNA expression capacity. Optimized NOA-pDNA-LNPs with DOTAP as the helper lipid exhibit superior transfection efficiency compared to standard +NOA-pDNA-LNPs (~23x increase) in RAW264.7 and similar efficiencies to the gold-standard, Lipofectamine, even in difficult-to-transfect cells, human induced-pluripotent-stem-cell-derived type II alveolar epithelial cells (iAT2s). Mechanistically, this increase in expression warrants further investigation, though we speculate it is likely due to improved protection and or condensation of pDNA. In conclusion, our study highlights the need to address the adverse events associated with the administration of pDNA-LNPs and presents a transformative approach to enhance the safety and efficacy of non-viral pDNA delivery. Co-loading pDNA-LNPs with bioactive molecules, such as NOA, will enable pDNA-LNPs to attain a useful position in the genetic medicine toolbox, working alongside the other clinically validated tools of mRNA-LNPs, siRNA, CRISPR, and adeno-associated viruses. Example 9: Standard LNPs loaded with DNA do not achieve high expression and are toxic (FIG.18). “Standard LNPs" with DNA (+ / - NOA) are compared, in vitro and in vivo. Comparisons include mRNA and Lipofectamine. Readouts include expression of luciferase and GFP (indicating % of cells that are transfected), cell death, and IFN-beta. Example 10: Mix plasmids with DNA-condensing proteins or molecules and co- load them into LNPs DNA-condensing proteins are proteins in cells that help with the assembly of DNA into tight structures. DNA-condensing proteins are mixed with DNA, during which they will pack DNA into a more condensed structure. Then this protein-DNA complex is co-loaded into LNPs. DNA-condensing proteins and molecules with special properties of condensation include: histones, protamines, Brdt, polyamines, HU protein, HMGB proteins, DNA polymerases, surface-modified bovine serum albumin (BSA), and spermidine. DNA-condensing proteins effectively facilitate the compaction of the plasmid into a condensed structure, thereby mitigating its susceptibility to DNAse degradation. This compaction enhances its resilience during residence within the endosomal and cytoplasmic compartments. Moreover, DNA-condensing proteins are a known cargo of transportation. For example, histone can act as an adaptor for binding several nuclear transport receptors such as importin β / α and transportin, thereby benefiting DNA nuclear localization. Thus, the DNA-condensing proteins bound with plasmid will site-specifically bind to the plasmid DNA and shuttle it into the nucleus. Example 11: Conjugate / Bind functional peptides such as nuclear localization signal (NLS) and cell penetrating peptides (CPP) on plasmids The plasmid sequence contains specific sites amenable to modification, enabling the incorporation of desired functional proteins and peptides through site-directed processing. The following strategies couple functional peptides and plasmids: i) Conjugate functional peptides to nucleic acid analogs such as bridged nucleic acid (BNA) or peptide nucleic acid (PNA), anneal them to DNA by forming a triple helix with double-stranded DNA; ii) Conjugate functional SV40 NLS (PKKKRKV) to nucleic acid analogs and hybridize them to plasmids; iii) Noncovalently mix functional peptides including NLS (such as PKKKRKRKVED) and CCP (such as TAT peptide: GRKKRRQRRRPQ) with DNA, co- load into LNPs. All of these may be co-loaded into LNPs, or the DNA-binding complex may be formed before LNP synthesis and then added into the LNP synthesis reaction. Example 12: Fuse DNA-binding domain (DBD) mimicking peptide motifs with nuclear localization signals (NLS), mix with DNA, and then co-loaded into LNPs DNA-binding proteins (DBP) are proteins which have high affinity towards DNA due to their DNA-binding domains (DBDs). There are several specific structural motifs facilitating the non-sequence-specific interactions between DBP and DNA, such as helix- turn-helix (HTH), zinc finger, leucine zipper, and basic region leucine zipper (bZIP). We can take advantage of this structure-oriented binding and fuse DBD-mimicking peptide motifs with NLS. Then we mix this fused peptide with DNA and co-load them into LNPs. One example of this fused peptide is bZIP-mimicking (KUA)3-(LU)4. This fused peptide can be mixed with DNA and get co-loaded into LNPs. The structural DBD-mimicking motifs and NLS sequences can both be varied. Example 13: Modify plasmid to nucleus-tropic secondary structures DNA secondary structures are artificially designed structures that do not exist in nature. Previous investigations have demonstrated their notable efficacy in cellular and nuclear uptake, coupled with minimal immune reactivity. Leveraging this understanding, through the manipulation of plasmid processing to form specialized secondary structures such as origami, we anticipate enhanced stability and transfection efficiency of the plasmid. For example, we can first load the plasmid into a tetrahedral DNA nanostructure (TDN), as a protected external layer, then load the entire plasmid-TDN complex into LNPs, thereby helping plasmid to better enter the nucleus. Example 14: Modify plasmid’s own sequence With advancements in plasmid manufacturing methodologies, we can now directly integrate three tandem repeats of the DNA Targeting sequence (DTS) from SV40 into plasmid’s own sequence, allowing plasmids getting shuttled to the nucleus via binding to the NLS sequences in transcription factors. dCAS9+sgRNA sequences can also integrate into the plasmid and play the same role. We can directly load this special plasmid into the LNP without any other helper. Example 15: mRNAs co-delivered with the cargo DNA to aid DNA transport into the nucleus An “assistant” mRNA can be easily co-loaded into the same LNP as the cargo DNA, or delivered via separate LNPs sometime before (e.g., 1 hour is clinically convenient and allows time for translation of the mRNA). The assistant mRNAs can encode the following fusion protein: dCas9 fused to importin (alpha or beta). dCas9 is a catalytically-dead version of the most commonly used protein used in CRISPR. The dCas9 here will bind to a short DNA sequence on the cargo DNA plasmid, via an sgRNA (single guide RNA) that is complementary to the that short DNA sequence, and the sgRNA would be co-loaded into the same LNP. The dCas9 is fused to importin, which is a protein that imports diverse cytosolic molecules into the nucleus. Thus, the dCas9-importin + sgRNA complex will site- specifically bind to the plasmid DNA and shuttle it into the nucleus. Many variations of the above assistant mRNA exist. dCas9 + sgRNA can be replaced by other DNA-binding proteins, including the site-specific ones (other Cas proteins, TALENs, transcription factors). Importin can be replaced by transportin, other beta- karyopherins, or by nothing at all in the case of a DNA-binding protein that has its own nuclear localization sequence (NLS). Example 16: Add cationic lipids (such as DOTAP) and / or short-chain aminolipids in LNPs DOTAP, as a cationic lipid, has a positively charged head group. This feature allows it to interact electrostatically with the negatively charged phosphate groups of DNA. This electrostatic interaction can help DNA condensation, protect DNA from enzymatic degradation during the delivery process, and thereby increase transfection efficiency. However, one of the major challenges of the cationic lipids is their toxicity, in terms of their interaction with negatively charged cell membranes, induction of inflammatory responses, and non-specific interactions with cellular components. To ameliorate the toxicity of DOTAP, we use short-chain aminolipids such as N- dodecyl-N-(3-methoxypropoyl)dodecan-1-amine (AL-A12). Aminolipids are synthetic lipids containing amine groups, which have been found to decrease toxicity in lipoplex systems. The amine groups can possess a “proton sponge” effect and increase buffering capacity, thereby being able to buffer the pH within endosomes. We have the hypothesis that by buffering the pH, aminolipids prevent endosomes from being too acidic while leading to the swelling and rupture of endosomes. In this way, aminolipids may facilitate a more efficient escape of DNA into cytoplasm without the need for extreme acidity which will cause cell damage or death. Moreover, faster endosomal escape of DNA may protect DNA from DNAse II, allowing sequential nuclear transport without DNA nicks and fragmentation. Example 17: Buffer optimization to improve expression (FIG.19). This demonstrates importance of Mg2+, pH, and buffer ions (TAE, etc), in vitro and in vivo. Toxicity measures are also shown. Example 18: Linear DNA delivered by LNPs is less inflammatory than pDNA in vitro Plasmid DNA (pDNA) was linearized (linDNA) using restriction enzyme digestion. FIG.25A. LNPs loaded with either pDNA or linDNA were generated (FIG.25B) and tested in vitro with RAW264.7 macrophages. Results show that linDNA-LNPs had both improved cell viability FIG.25D and gene expression (FIG.25E) over pDNA-LNPs. Further, linDNA- LNPs had undetectable levels of STING in raw cells. FIG.25F. Example 19: Adding a GalNAc peg lipid reduces pDNA-LNP inflammation Phagocytes play a key role in pDNA-LNP-induced inflammation in vivo. FIG.26. We aimed to indirectly avoid phagocytes to reduce pDNA-LNP toxicity. We tested the following: pDNA-LNP (SM-102), NOA-pDNA-LNP, GalNAc-pDNA-LNP, NOA / GalNAc- pDNA-LNP (combo-pDNA-LNP), and pDNA-LNP (4A3-Sc8). Adding a GalNAc peg lipid (with or without NOA) reduced pDNA-LNP inflammation. FIG.27 We then sought to determine whether altering mol % of GalNAc-PEG lipid affected the LNP formulation. We found that higher mol% GalNAc-PEG-lipid leads to low pDNA encapsulation and smaller particle size. FIG.28. Example 20: Certain excipients improve pDNA transfection with LNPs We tested various excipients to see if they improved pDNA transfection with LNPs. Tannic acid, punicalagin, vitamin B9, vitamin C, vitamin B12, vitamin D, davunetide, chlorogenic acid, ferulic acid, melatonin, and vitamin K3 were tested. Tannic acid, vitamin B12, davunetide, and chlorogenic acid improved transfection of RAW264.7 cells. FIG.31. Example 21: Histone subcomponents are effective DNA condensing agents We tested histone subcomponents H2A and H3 to see if they were effective in condensing DNA. We loaded H2A- and H3-condensed plasmids into LNP and observed cell viability and expression of transfected RAW264.7 cells. While there was no cell death observed with either preparation, loading H2A-condensed plasmids into LNP resulted in expression at least comparable to lipofectamine. FIG.30. Example 22: Modification of cssDNA plasmid with NLS peptide or RPA A cssDNA plasmid was modified with an NLS peptide-oligo. A cssDNA complement strand was functionalized by click chemistry and linked to an NLS peptide. A cssDNA plasmid was modified with the NLS peptide-oligo (FIG.32). HeLa and RAW cells were transfected with the modified plasmid and transgene expression, and inflammatory cytokines were measured. Modification with NLS peptide-oligo improved transgene expression (FIG.33). A cssDNA plasmid was modified with a functional replication protein A (RPA). HeLa and RAW cells were transfected with the modified plasmid and transgene expression was measured. Modification with RPA improved transgene expression (FIG.34). Example 23: TCF1 Improves Expression TCF1 is a transcription factor active in T cells. We added the protein TCF1 protein into LNPs, and it improved DNA-LNPs’ expression (FIG.35). Example 24: TREX1-degrading molecules can improve expression We loaded DNA-LNPs with either 48C or 86C TREX1 degraders. We treated RAW cell and Hela cell with LNPs loaded with TREX1 degraders, and measured expression. TREX1 degrading molecules improved expression. FIG.36. References 1. Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release 217, 345–351 (2015). 2. Zhang, W. et al. The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice. Vaccines (Basel) 11, 1580 (2023). 3. Herweijer, H. et al. Time course of gene expression after plasmid DNA gene transfer to the liver. The Journal of Gene Medicine 3, 280–291 (2001). 4. Yu, L. & Liu, P. Cytosolic DNA sensing by cGAS: regulation, function, and human diseases. Sig Transduct Target Ther 6, 1–15 (2021). 5. Chauvin, S. D., Stinson, W. A., Platt, D. J., Poddar, S. & Miner, J. J. Regulation of cGAS and STING signaling during inflammation and infection. J Biol Chem 299, 104866 (2023). 6. Laczkó, D. et al. A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice. Immunity 53, 724-732.e7 (2020). 7. Chase, L. S., Zaleski, M. H., Morrell, L. J. & Brenner, J. S. Automated measurement of distance-walked as a “sixth vital sign” for detecting infusion reactions during preclinical testing. International Journal of Pharmaceutics 645, 123369 (2023). 8. Type I interferons in infectious disease - PMC. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC7162685 / . 9. Parhiz, H. et al. Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE). Journal of Controlled Release 344, 50–61 (2022). 10. Omo-Lamai, S. et al. Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects. bioRxiv 2024.04.16.589801 (2024) doi:10.1101 / 2024.04.16.589801. 11. Omo-Lamai, S. et al. Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions. bioRxiv (2023) doi:10.1101 / 2023.07.21.550080. 12. Cheng, Z. et al. The interactions between cGAS-STING pathway and pathogens. Sig Transduct Target Ther 5, 1–15 (2020). 13. Domizio, J. D. et al. The cGAS–STING pathway drives type I IFN immunopathology in COVID-19. Nature 603, 145–151 (2022). 14. Wang, D., Zhao, H., Shen, Y. & Chen, Q. A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions. Frontiers in Immunology 13, (2022). 15. Zhu, Y. et al. Multi-step screening of DNA / lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression. Nat Commun 13, 4282 (2022). 16. Zhu, Y. et al. Optimization of lipid nanoparticles for gene editing of the liver via intraduodenal delivery. Biomaterials 308, 122559 (2024). 17. Melo, T., Montero-Bullón, J.-F., Domingues, P. & Domingues, M. R. Discovery of bioactive nitrated lipids and nitro-lipid-protein adducts using mass spectrometry-based approaches. Redox Biol 23, 101106 (2019). 18. Hansen, A. L. et al. Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling. Proc Natl Acad Sci U S A 115, E7768–E7775 (2018). 19. Kaminski, J. J. et al. Synthetic Oligodeoxynucleotides (ODN) Containing Suppressive TTAGGG Motifs Inhibit AIM2 Inflammasome Activation. J Immunol 191, 10.4049 / jimmunol.1300530 (2013). 20. Chatterjee, S., Kon, E., Sharma, P. & Peer, D. Endosomal escape: A bottleneck for LNP- mediated therapeutics. Proceedings of the National Academy of Sciences 121, e2307800120 (2024). 21. Bai, H., Lester, G. M. S., Petishnok, L. C. & Dean, D. A. Cytoplasmic transport and nuclear import of plasmid DNA. Biosci Rep 37, BSR20160616 (2017). 22. Zanta, M. A., Belguise-Valladier, P. & Behr, J. P. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. Proc Natl Acad Sci U S A 96, 91–96 (1999). 23. Sperinde, J. J., Choi, S. J. & Szoka, F. C. Phage display selection of a peptide DNase II inhibitor that enhances gene delivery. J Gene Med 3, 101–108 (2001). 24. Jacob, A. et al. Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21, 472-488.e10 (2017). 25. Jacob, A. et al. Derivation of self-renewing lung alveolar epithelial type II cells from human pluripotent stem cells. Nat Protoc 14, 3303–3332 (2019). 26. Abo, K. M. et al. Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell–derived alveolar epithelium. JCI Insight 7, e155589. All documents cited in this specification are incorporated herein by reference. US Provisional Patent Application Nos.63 / 637,731, 63 / 653,164, and 63 / 653,163 are incorporated herein by reference in their entireties. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response.

2. The composition of claim 1, wherein the helper molecule is an inhibitor of cGAS- STING pathway, optionally cGAS, STING, AIM2, TLR9, TBK1, or IFNAR.

3. The composition of claim 2, wherein the inhibitor is a nitrated fatty acid or prodrug thereof, optionally nitro-oleic acid, nitro-conjugated linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, or 4-octyl itaconate.

4. The composition of claim 1, wherein the helper molecule is an inhibitor of the cGAS-STING pathway, optionally a cGAS inhibitor or a STING inhibitor.

5. The composition of claim 4, wherein the cGAS inhibitor is PF-06928215, RU.365, RU.521, G150, compound S3, hydroxychloroquine, quinacrine, X6, suramin, ODN A151, or CU-76.

6. The composition of claim 2, wherein the inhibitor is an AIM2 siRNA, sulfonic calixarene, Shikonin, NLPR3 / AIM2-IN-3, JC2-11, or NLPR3 / AIM2-IN-2.

7. The composition of claim 4, wherein the STING inhibitor is Astin C, C-176, C178, C170, C171, H151, NO2-cLA, NO2-OA, BPK-21, BPK-25, or a STING siRNA.

8. The composition of claim 1, comprising i) a molecule capable of complexing or condensing DNA.

9. The composition of any one of claims 1 to 8, wherein the molecule capable of complexing or condensing DNA is a cationic lipid.

10. The composition of claim 9, wherein the cationic lipid is DOTAP, DOSPA, or spermine / spermidine-conjugated lipid.

11. The composition of any one of claims 1 to 8, wherein the molecule capable of complexing or condensing DNA is a polyamine.

12. The composition of claim 9, wherein the polyamine is spermine or spermadine.

13. The composition of any one of claims 1 to 8, wherein the molecule capable of complexing or condensing DNA is a cationic protein or peptide.

14. The composition of claim 9, wherein the cationic protein or peptide is a histone, protamine, Brdt (sperm protein), polyamine, HU protein, HMGB protein, DNA polymerase, surface-modified bovine serum albumin (BSA), spermidine, PKKKRKV (NLS), PKKKRKVEDPYC (NLS), TAT (GRKKRRQRRRPQ), or a TAT-NLS conjugate.

15. The composition of any one of claims 1 to 8, wherein the molecule capable of complexing or condensing DNA is an ionizable lipid, optionally an ionizable lipid that is positively charged at pH 6 - 7.

4.

16. The composition of claim 9, wherein the ionizable lipid is 98N-12 or 306-N16B.

17. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and a DNase inhibitor.

18. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, a DNase inhibitor, and an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR.

19. The composition of claim 17 or 18, wherein the DNase inhibitor is a DNase I, DNase II, or DNaseIII peptide inhibitor or an siRNA that degrades DNase I, DNase II, or DNaseIII.

20. The composition of any one of claims 1 to 19, wherein the molecule to aid in nuclear localization of DNA is a nuclear localization signal (NLS) peptide.

21. The composition of claim 20, wherein the NLS further comprises an oligo.

22. The composition of any one of claims 1 to 19, wherein the molecule to aid in nuclear localization of DNA is a cell penetrating peptide or Replication Protein A (RPA).

23. The composition of claim 20 or 21, wherein the peptide is coupled to a plasmid that encodes the DNA cargo.

24. The composition of claim 13, wherein the coupling is via covalent or non-covalent binding.

25. The composition of any one of claims 1 to 19, wherein the molecule to aid in nuclear localization of DNA is a DNA-binding domain (DBD) mimicking peptide.

26. The composition of claim 25, wherein the DBD-mimicking peptide is fused with a nuclear localization signal peptide.

27. The composition of claim 25 or 26, wherein the DBD-mimicking peptide mimics helix-turn-helix (HTH), zinc finger, leucine zipper, or basic region leucine zipper (bZIP).

28. The composition of any one of claims 1 to 17, wherein the DNA cargo is in the form of a DNA nanostructure.

29. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, a DNA-binding domain (DBD) mimicking peptide, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the DNA cargo is in the form of a DNA nanostructure.

30. The composition of any one of claims 1 to 29, wherein the DNA cargo is comprised in a plasmid that comprises one or more tandem repeats of the SV40 DNA targeting sequence (DTS).

31. The composition of any one of claims 1 to 30, wherein the LNP comprises a short- chain aminolipid.

32. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR, wherein the LNP comprises an aminolipid.

33. The composition of claim 31 or 32, wherein the aminolipid is N-dodecyl-N-(3- methoxypropoyl)dodecan-1-amine (AL-A12).

34. The composition of any one of claims 1 to 33, wherein the LNP further comprises a fusion protein comprising dCas9-importin.

35. A composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and a fusion protein comprising dCas9-importin, and an inhibitor of cGAS, STING, AIM2, TLR9, TBK1, or IFNAR.

36. The composition of any one of claims 1 to 35, further comprising an excipient, optionally tannic acid, vitamin B12, davunetide, or chlorogenic acid.

37. The composition according to any one of claims 1 to 36, further comprising a ligand conjugated to the LNP.

38. The composition according to claim 37, wherein the ligand binds a receptor or a target on the surface of a cell.

39. The composition according to claim 37 or 38, wherein the ligand is an antibody or antigen binding fragment thereof.

40. The composition of any one of claims 37 to 39, wherein the ligand binds ICAM or PECAM.

41. A method of delivering a DNA cargo to a subject, the method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising a DNA cargo and one or more of: i) a molecule capable of complexing or condensing DNA; ii) a molecule to aid in nuclear localization of DNA; and / or iii) a helper molecule that attenuates the inflammatory response.

42. The method according to claim 41, wherein the composition comprises the composition according to any one of claims 1 to 40.

43. The method according to any one of claims 41 or 42, wherein the composition is formulated for in vivo delivery.

44. The method according to claim 43, wherein the composition is formulated for intravenous, intraarterial, ICM, or inhaled delivery.

45. A method of treating a subject in need thereof, the method comprising administering to the subject an effective amount of a composition according to any one of claims 1 to 40.

46. A method of treating idiopathic pulmonary fibrosis (IPF) a subject, the method comprising administering to the subject an effective amount of the composition according to any one of claims 1 to 40, wherein the DNA cargo comprises an ORF encoding an anti- fibrotic agent, optionally an antibody to TGFalpha, TGFbeta, VEGF, FGF, CTGF, CCN2, PDGF, Oncostatin M, CCL2, CCL3, or CXCL12.

47. A kit comprising a medicament comprising a composition according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament for treating or delaying IPF in an individual.

48. A method of delivering a DNA cargo to a cell, the method comprising contacting the cell with a composition comprising a lipid nanoparticle (LNP) comprising an inhibitor of the cGAS-STING pathway, a molecule capable of condensing DNA, and the DNA cargo.

49. The method according to claim 48, wherein the composition comprises the composition according to any one of claims 1 to 40.

50. The method according to claim 48 or 49, wherein the composition is formulated for in vitro delivery.

51. The method according to any one of claims 48 to 50, wherein the cell is a mammalian cell, optionally an IPSC, immune cell, or primary neuron.

52. The composition or method of any preceding claim, wherein the DNA cargo is a polynucleotide comprising a promoter and a coding sequence for a gene product of interest.

53. The composition or method of claim 52, wherein the promoter is a tissue-specific promoter.

54. The composition or method of claim 52, wherein the promoter is a regulatable promoter.

55. The composition or method of any one of claims 52 to 54, wherein the polynucleotide further comprises LTRs or ITRs.

56. A treatment regimen for a subject in need thereof, comprising: i) delivering to the subject an inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR; ii) subsequently delivering to the subject a lipid nanoparticle (LNP) comprising a DNA cargo and a molecule capable of condensing DNA.

57. The treatment regimen of claim 56, wherein the inhibitor of cGAS, STING, AIM2, TLR9, or IFNAR is comprised in an LNP.

58. The treatment regimen of claim 56 or 57, wherein the inhibitor is an siRNA, mRNA, small molecule drug, peptide, antibody fragment, or aptamer.

59. A method of delivering a DNA cargo to a subject, the method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising the DNA cargo and a molecule capable of complexing or condensing DNA.

60. A method of delivering a DNA cargo to a subject, the method comprising administering to the subject an effective amount of a composition comprising a lipid nanoparticle (LNP) comprising the DNA cargo and a DNase inhibitor.

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