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

Dec 1, 2025Journal of controlled release : official journal of the Controlled Release Society

A new ionizable lipid improves safety and immune response of mRNA nanoparticle vaccines

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

MOP-1-LNPs achieved a 90% survival rate and near-complete viral clearance in response to an influenza mRNA vaccine challenge.

MOP-1 is a novel ionizable lipid that enhances lipid nanoparticle delivery efficiency and safety.
The MOP-1-LNPs demonstrated high colloidal stability and effective endosomal escape characteristics.
Safety evaluations showed negligible cytotoxicity in vitro and no organ damage in vivo at high doses.
MOP-1-LNPs stimulated strong immune responses, including high levels of neutralizing antibodies and CD8T-cell activation.
The immune response was associated with an optimized cytokine profile, reducing the risk of excessive inflammation.

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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 CD8T-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. +