Liposomal nanoparticles serve as biocompatible shuttles for drug delivery applications, including the delivery of mRNA vaccines. Liposomes have low toxicity, and the relative ease of their functionalization enables target-specific delivery. However, a major challenge in these applications is premature drug release due to the instability of liposomes under physiological conditions. Therefore, the development of stable, long-circulating liposomes is necessary for efficient liposomal drug delivery. Traditionally, stabilizing molecules such as cholesterol, have been added to liposomal formulations to improve circulation times. However, despite cholesterol’s known effects in enhancing the membrane rigidity, incorporating more cholesterol in liposomes does not resolve this issue. That is due to cholesterol’s tendency to rapidly exchange into cell membranes and phase separate at elevated concentrations, resulting in liposomal degradation prior to reaching the target. Instead, sterol-modified lipids (SMLs), formed via the conjugation of sterols with lipid acyl chain(s), offer an attractive solution to this problem. These lipids provide the needed stability without risking sterol exchange with lipoproteins and biomembranes. Our experimental results confirm that substituting cholesterol with SML in select lipid membranes increases the liposomal stability. Small-angle X-ray (SAXS) measurements show that the inclusion of SMLs increases bilayer thickness and decreases the area per lipid, indicative of tighter lipid packing. These results support conclusions from differential scanning calorimetry (DSC) studies and surface-pressure/area isotherms. Complementary neutron spin-echo (NSE) spectroscopy studies on SML-containing liposomes show increased stiffness relative to liposomes prepared with identical free-cholesterol content. These observations confirm that the structural changes leading to enhanced membrane stabilization also increase membrane bending rigidity. Our findings illustrate the close dependence of liposomal stability on molecular packing motifs, offering a molecular perspective for enhanced designs of liposomal drug-carriers.

Sterol conjugated lipids results in improved liposomal stability

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.