Decoupling reactogenicity from efficacy enables safer mRNA vaccines, AAV gene delivery, and in vivo base editing.

Nucleic-acid therapeutics, including mRNA vaccines, genome editors, and viral vectors, are constrained by acute innate reactogenicity that limits dosing flexibility, tissue targeting, and safety. Here we identify a conserved early innate inflammatory program, peaking approximately six hours after administration, that governs reactogenicity across mRNA formulated lipid nanoparticle (LNP), adenoviral vectors and AAV9. Using pharmacological and biochemical probes, we show that this program is driven predominantly by nucleic-acid cargo sensing, rather than lipid components, and is mechanistically separable from antigen expression, adaptive immune priming, and in vivo genome-editing efficacy. Selective modulation of this early cytokine burst achieved here using endosomal nucleic-acid sensing suppressors markedly reduces reactogenicity in multiple mouse models while preserving humoral and cellular immunity to mRNA vaccines, maintaining transgene expression, protecting blood-brain barrier integrity during stereotactic AAV9 delivery, and mitigating LNP-associated hepatotoxicity and thrombocytopenia. These findings define a unifying innate-sensing architecture for nucleic-acid therapeutics and establish that reactogenicity is not required for effective vaccination or gene delivery, enabling a broadly applicable strategy to widen the safety window of mRNA medicines, viral vectors, and in vivo genome editing.