Nitric oxide-assisted lipid nanoparticles amplify mRNA vaccine responses.

Abstract

mRNA vaccines have made substantial clinical advances, yet their full clinical potential can be further expanded by enhancing cytosolic delivery. Here, we integrate a nitric oxide (NO) generator with lipid nanoparticles (LNPs) to boost mRNA delivery efficiency and mRNA-based vaccine efficacy. SM-102/DEA LNPs, the lead formulation, achieved significantly higher mRNA delivery compared with the FDA approved SM-102 LNPs in both cellular and animal models. The intramuscular administration of SM-102/DEA LNPs encapsulating mRNA encoding SARS-CoV-2 spike protein elicited substantially higher anti-spike IgG levels and robust CD8+ and CD4+ T cell responses compared to SM-102 LNPs. Mechanistic studies revealed that DEA incorporation promotes endosomal escape of mRNA cargos in SM-102/DEA LNPs. These findings establish NO-assisted LNPs as a unique platform for potent mRNA delivery, which provides a new paradigm for overcoming endosomal barriers and improving the efficacy of mRNA vaccines.