Rational Head-Group Engineering of Ionizable Lipids for High-Performance mRNA Delivery

Lipid nanoparticles (LNPs) have emerged as a leading delivery platform for nucleic acids, particularly for mRNA vaccines and gene therapy. Among their constituent lipids, ionizable lipids play a central role in determining delivery efficiency, endosomal escape, protein expression, and the immunogenicity of mRNA vaccines. Here, we present a rational head-group engineering strategy to optimize ionizable lipids for mRNA vaccine delivery. Precisely engineered head groups may serve as molecular recognition elements capable of modulating interactions with mRNA nucleobases as well as downstream innate immune receptors, including Toll-like receptors (TLRs). A series of ionizable lipids bearing structurally diverse heterocyclic head groups was synthesized and formulated into LNPs.

Systematic investigation revealed structure-dependent effects on in vivo protein expression and vaccine immunogenicity, establishing head-group engineering as an effective design strategy for next-generation ionizable lipids.