Senapati, SujataBertolini, Thais B.Minnier, Michael A.Yazicioglu, Mustafa N.Markusic, David M.Zhang, RuiWicks, JoanNahvi, AliHerzog, Roland W.Walsh, Matthew C.Cejas, Pedro J.Armour, Sean M.2025-05-202025-05-202025-03-05Senapati S, Bertolini TB, Minnier MA, et al. Inhibition of IFNAR-JAK signaling enhances tolerability and transgene expression of systemic non-viral DNA delivery. Mol Ther Nucleic Acids. 2025;36(2):102502. Published 2025 Mar 5. doi:10.1016/j.omtn.2025.102502https://hdl.handle.net/1805/48249Lipid nanoparticles (LNPs) have demonstrated significant therapeutic value for non-viral delivery of mRNA and siRNA. While there is considerable interest in utilizing LNPs for delivering DNA (DNA-LNPs) to address a broad range of genetic disorders, acute inflammatory responses pose significant safety concerns and limit transgene expression below therapeutically relevant levels. However, the mechanisms and immune signaling pathways underlying DNA-LNP-triggered inflammatory responses are not well characterized. Through the use of gene-targeted mouse models, we have identified cGAS-STING and interferon-α/β receptor (IFNAR) pathways as major mediators of acute inflammation triggered by systemic delivery of DNA-LNPs. cGAS-STING activation induces expression of numerous JAK-STAT-activating cytokines, and we show that treatment of mice with the JAK inhibitors ruxolitinib or baricitinib significantly improves tolerability to systemically delivered DNA-LNPs. Furthermore, specific inhibition of IFNAR signaling enhances both DNA-LNP tolerability and transgene expression. Utilization of JAK inhibitors or IFNAR blockade represent promising strategies for enhancing the safety and efficacy of non-viral DNA delivery for gene therapy.en-USAttribution 4.0 InternationalDelivery strategiesDNA sensorInflammasomeNanoparticleGene therapyArticle