BPS2026 – Engineering structural complexity in lipid nanoparticles to enhance their fusogenicity

Lipid nanoparticles (LNPs) are the most successful delivery carriers of biologics to cells and tissues. Expanding LNP-based therapies hinges on efficient cell entry and delivery, a process often hindered by endosomal entrapment. It is well known that depending on molecular properties, lipids self-assemble into different nanostructures. LNPs can recapitulate some of these mesophases dispersed in solution, but how structure imparts interaction with cells and endosomal escape remains unclear. We demonstrate that combining lipid composition with nanostructure synergistically impacts the ability of LNPs to escape endosomes via enhanced fusogenicity. Specifically, LNPs prescribed with bicontinuous cubic and inverse hexagonal internal structures facilitate the topological transition of LNP-endosome fusion-pore formation. In this talk, we show our recent advances in experimental and theoretical approaches that enable the quantification and prediction of lipid fusogenicity. We show that not only spontaneous curvature but also Gaussian modulus plays a critical role in regulating LNP fusogenicity.