Insights into Composition-Induced Structural Shifts in Lipid Nanoparticles

Abstract Lipid nanoparticles (LNPs) are a leading platform for nucleic acid delivery, yet current formulations typically suffer from rapid in vivo clearance and limited extrahepatic delivery. Recent experiments demonstrate that increasing the helper lipid content (e.g., to 40% 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]) can significantly improve mRNA stability, prolong circulation, and enhance transfection efficiency. In this study, we used coarse-grained molecular dynamics simulations to provide mechanistic insight into the structural changes driving these improvements. Our simulations confirm that an elevated helper lipid content fundamentally alters the internal morphology of the LNP. Consistent with experimental observations, at high DSPC levels, the core transitions from a compact, disordered, predominantly lipid state to an extended structure with distinct lamellar-like elements encompassing lipid-rich and water-rich regions. This structural reorganization can be used to rationalize the enhanced stability and delivery properties reported in the experiments. These findings provide a molecular-level understanding of the composition-morphology relationship and suggest that coarse-grained modeling can inform the design of novel LNP formulations.