Lipid nanoparticles (LNPs) are a versatile delivery mechanism designed for therapeutics and nucleic acids. Encapsulation of nucleic acid with ionizable lipids and phospholipids is essential for maintain nanoparticle stability and ensuring efficient intracellular cargo delivery. The physiochemical properties of LNPs, dictated by lipid composition greatly influence particle size, internal phase structure, and delivery efficiency. However, the molecular determinants governing lipid nanoparticle assembly is hindered by their dynamic and heterogeneous nature, which restricts the use of conventional high-resolution structural approaches. In this study, we applied extensive atomistic molecular dynamics simulations to probe how varying the ionizable lipids can control the atomistic structure of the LNP. By combining structural metrics of particle organization, measurements of nucleic acid-lipid interactions, and analyses of phase behavior, we show differences in lamellar organization impacted nucleic acid shielding, particle stability, and compaction based on lipid composition. Our findings provide mechanistic insights into lipid assembly at the atomic scale, which advances our understanding of nanoparticle formation. These investigations establish a framework for enhancing stability and delivery efficiency of LNPs, with broad implications for vaccine development and clinical translation.
Wang et al. (Sun,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: