cGAS-mediated immunogenicity impairs the stability and safety of LNP-encapsulated DNA in vivo

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.

Abstract from PubMed Central (PMID 42936214, PMC13696765). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.