Modeling and Experimental Insights into the Structure and Dynamics of Lipid Nanoparticles

Liposomes, versatile lipid-based nanoparticles, offer promising potential as drug delivery systems due to their biocompatibility and ability to encapsulate a wide variety of therapeutic agents. However, optimizing their structural stability and encapsulation efficiency is critical for their efficient and controlled use. In this context, this study aims to enhance the stability and drug loading capacity of liposomes through integration of molecular modeling and experimental techniques. Specifically, we investigated the behavior of PC lipid bilayers (DMPC, DOPC, and DSPC) in the presence of PEGylated lipids across varying cholesterol concentrations (0-35%). Our findings reveal that increasing cholesterol levels decrease the area-per-lipid but increase bilayer thickness for DMPC and DOPC lipids in a fluid phase at physiological temperature. In contrast, DSPC lipids, which form gel-like domains, exhibited a similar trend up to 25% cholesterol, after which the properties stabilized. Lipid tail order parameters increased for DMPC and DOPC with rising cholesterol, with DOPC being less ordered due to unsaturated carbon tails, while DSPC showed irregular behavior. Additionally, PEG chain insertion into the bilayer decreased with increasing cholesterol, and their end-to-end distances were reduced, likely due to the enhanced lipid packing and stiffness induced by cholesterol.