Nature nanotechnologyNov 7, 2025

Breakdown-Friendly Ionizable Lipids for Strong Influenza mRNA Vaccines

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A degradable ionizable lipid, AMG1541, may make influenza mRNA vaccines more potent while reducing liver expression after intramuscular injection.

Evidence

This formulation and platform experiment compared AMG1541 LNP-mRNA vaccines with SM-102 for H3 influenza antigen responses, in vivo clearance, tissue expression, antigen-presenting-cell delivery, and structure-activity relationships.

Caveat

The abstract reports vaccine-model and delivery endpoints rather than human clinical protection or safety outcomes.

Simplified

The next generation of mRNA vaccines must address several limitations, including enhancing vaccine potency and reducing toxicity. Here we develop a class of degradable, cyclic amino ionizable lipids via sequential combinatorial chemistry and rational design. Lipid nanoparticles (LNPs) formulated with the top-performing ionizable lipid, AMG1541, elicited similar protective neutralization antibody titres against an H3 influenza antigen when compared with the FDA-approved ionizable lipid SM-102 at a 100-fold lower dose, with enhanced clearance in vivo. AMG1541 mRNA LNPs substantially reduced expression in the liver following intramuscular injection, mitigating the associated toxicity. We also observed improved mRNA delivery to antigen-presenting cells at the injection site and the draining lymph node, leading to stronger germinal centre reactions. Structure-activity relationship studies suggest that cyclic headgroups and β-amino alcohols facilitate interactions with the mRNA backbone and enhance endosomal escape. The formulations developed here significantly enhance the potency of mRNA vaccines, and our structural insights may guide the development of next-generation vaccine delivery systems.