Glutarimide-derived ionizable lipid enables mRNA lipid nanoparticle vaccines with enhanced safety and immunogenicity

While lipid nanoparticle (LNP)-mRNA vaccines have shown remarkable clinical success, their broader application remains limited by relatively low stability, dose-dependent toxicity, and suboptimal immune activation efficiency. Here, we describe an innovative glutarimide-derived ionizable lipid, MOP-1, that enables an LNP with high delivery efficiency and a favorable safety profile. MOP-1-LNPs exhibited optimal physicochemical properties, including high colloidal stability and favorable acid dissociation characteristics for efficient endosomal escape. Comprehensive safety evaluations revealed that MOP-1-LNPs maintained exceptional biocompatibility, with negligible in vitro cytotoxicity and no evidence of organ damage in vivo even at high doses. When evaluated as an influenza mRNA vaccine platform, MOP-1-LNPs induced robust humoral and cellular immune responses, including high neutralizing antibody production and CD8⁺ T-cell activation. These immunogenic properties translated to excellent protection against a lethal viral challenge, with a 90 % survival rate and near-complete viral clearance. Notably, this potent immune response was achieved while maintaining an optimized cytokine profile that avoids excessive inflammatory responses associated with current LNP platforms. These findings indicate that MOP-1-LNPs could become a transformative mRNA delivery system that successfully addresses key challenges in delivery efficiency, stability, and safety. The unique properties of this platform may enable broader applications in prophylactic and therapeutic vaccine development.