cGAS-mediated immunogenicity impairs the stability and safety of LNP-encapsulated DNA in vivo
- 1School of Life Sciences, Laboratory Animal Center, Fudan University, Shanghai 200438, P.R. China
- 2Barball Therapeutics Co. Ltd., Shanghai 201203, P.R. China
- 3Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China
Abstract
DNA-based non-viral gene therapy offers a promising platform for titratable gain-of-function treatments, enabling multi-dosing and sustained efficacy. However, its clinical translation has been constrained by unintended immune activation. We systematically investigated the pathogenesis of DNA drug-induced toxicity in mouse models, with emphasis on the contribution of innate immune responses. Intravenous administration of lipid nanoparticle (LNP)-DNA induces systemic toxicity, characterized by body weight loss, hepatic injury, and cytokine storm. Mechanistically, cyclic GMP-AMP synthase (cGAS) acts as the primary sensor for LNP-delivered DNA, activating two major downstream pathways: type Ⅰ interferon signaling and inflammatory responses. The interferon response contributes partially to overall toxicity and suppresses transgene expression. The suppressive effect on DNA drug stability is mediated by interferon-induced exonuclease three-prime repair exonuclease 1 (TREX1), which actively degrades DNA therapeutics and reduces their bioavailability. In parallel, inflammatory activation constitutes another major source of adverse effects, with TNF-α as a key mediator of liver injury. Importantly, we demonstrated that prophylactic immune modulation with dexamethasone or Janus kinase (JAK) inhibitor alleviates LNP-DNA-induced toxicity. Multi-target agent dexamethasone exhibited a significantly stronger inhibitory effect on adverse effects. Our findings uncover central innate immune mechanisms governing the safety and stability of LNP-DNA formulations and underscore the necessity of immunomodulatory strategies to unlock the potential of DNA-based gene therapy.
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BibTeX
@article{wang2026cgasmediated,
title = {{cGAS-mediated immunogenicity impairs the stability and safety of LNP-encapsulated DNA in vivo}},
author = {Xuelin Wang and Tengyuan Liu and Biao Long and Mingya Li and Ying Yao and Yuqin Fu and Si Xie and Yanfang Gu and Weizhou Yue and Yukun Pan and Xiaohui Wu and Lei Sun},
journal = {Molecular Therapy. Nucleic Acids},
year = {2026},
month = sep,
doi = {10.1016/j.omtn.2026.103118},
url = {https://doi.org/10.1016/j.omtn.2026.103118},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - cGAS-mediated immunogenicity impairs the stability and safety of LNP-encapsulated DNA in vivo
AU - Xuelin Wang
AU - Tengyuan Liu
AU - Biao Long
AU - Mingya Li
AU - Ying Yao
AU - Yuqin Fu
AU - Si Xie
AU - Yanfang Gu
AU - Weizhou Yue
AU - Yukun Pan
AU - Xiaohui Wu
AU - Lei Sun
PY - 2026
DA - 2026/09/29
JO - Molecular Therapy. Nucleic Acids
DO - 10.1016/j.omtn.2026.103118
UR - https://doi.org/10.1016/j.omtn.2026.103118
AB - DNA-based non-viral gene therapy offers a promising platform for titratable gain-of-function treatments, enabling multi-dosing and sustained efficacy. However, its clinical translation has been constrained by unintended immune activation. We systematically investigated the pathogenesis of DNA drug-induced toxicity in mouse models, with emphasis on the contribution of innate immune responses. Intravenous administration of lipid nanoparticle (LNP)-DNA induces systemic toxicity, characterized by body weight loss, hepatic injury, and cytokine storm. Mechanistically, cyclic GMP-AMP synthase (cGAS) acts as the primary sensor for LNP-delivered DNA, activating two major downstream pathways: type Ⅰ interferon signaling and inflammatory responses. The interferon response contributes partially to overall toxicity and suppresses transgene expression. The suppressive effect on DNA drug stability is mediated by interferon-induced exonuclease three-prime repair exonuclease 1 (TREX1), which actively degrades DNA therapeutics and reduces their bioavailability. In parallel, inflammatory activation constitutes another major source of adverse effects, with TNF-α as a key mediator of liver injury. Importantly, we demonstrated that prophylactic immune modulation with dexamethasone or Janus kinase (JAK) inhibitor alleviates LNP-DNA-induced toxicity. Multi-target agent dexamethasone exhibited a significantly stronger inhibitory effect on adverse effects. Our findings uncover central innate immune mechanisms governing the safety and stability of LNP-DNA formulations and underscore the necessity of immunomodulatory strategies to unlock the potential of DNA-based gene therapy.
SN - 2162-2531
ER -