Unraveling the Role of Ionizable Lipid Isomerism in Modulating Lipid Nanoparticles for mRNA Delivery

Mar 2, 2026Journal of the American Chemical Society

How Different Forms of Ionizable Lipids Affect Lipid Nanoparticles for mRNA Delivery

AI simplified

mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Nine isomeric ionizable lipids were synthesized using a four-component reaction.

Differences in the isomeric structure of ionizable lipids affect their interactions with mRNA.
Variations in ionizable lipid distribution within lipid nanoparticles influence their overall performance.
In vivo studies indicate that isomeric ionizable lipids result in different transfection profiles in liver cell types after intravenous delivery.
Muscle-selective mRNA delivery is enhanced by specific isomeric ionizable lipids following intramuscular administration.
Modifications in ionizable lipids can alter the delivery efficiency of lipid nanoparticles targeting the lungs.

AI simplified

Lipid nanoparticles (LNPs) have been demonstrated as effective mRNA delivery systems, with ionizable lipids (ILs) serving as critical determinants of their in vivo delivery efficacy. However, elucidating the structure-activity relationship of ILs remains a formidable challenge, hindering the rational design of next-generation LNPs with improved efficiency and targeting specificity. Here, we present a straightforward and powerful isomerism strategy for the efficient synthesis of 9 isomeric ILs using a four-component Ugi reaction (Ugi-4CR). Molecular dynamics simulations and small-angle neutron scattering investigations revealed that differences in IL isomerism lead to distinct IL-mRNA intermolecular interactions and varied IL distribution patterns within LNPs, ultimately resulting in variations in the apparent pof LNPs. In vivo evaluation demonstrated that isomeric ILs contribute to different transfection profiles across liver cell types following intravenous administration, enhance muscle-selective mRNA delivery after intramuscular administration, and modulate the delivery efficiency of DOTAP-mediated lung-targeted LNPs. The establishment of IL isomerism not only introduces a new molecular design dimension for IL optimization but also lays the foundation for the rational design of ILs for targeted mRNA delivery, thus expanding the potential applications of mRNA therapeutics. K a