Sterol conjugated lipids for improved liposomal stability*

Liposomal nanoparticles are outstanding candidates for vaccine and drug delivery applications. However, the liposomal stability under physiological conditions is a major challenge, and often results in premature drug release. This has been traditionally addressed by incorporating cholesterol which increases membrane stability through its lipid densification effect. But cholesterol tends to rapidly exchange into cell membranes, which compromises liposomal stability. To mitigate this effect, sterol-modified lipids (SMLs) present attractive substitutes for cholesterol. Our experimental results confirm the anticipated structural and mechanical effects of SMLs on lipid membranes. Small-angle X-ray measurements show that SML inclusion increases the bilayer thickness and decreases the area per lipid, indicating tighter molecular packing. These results agree with differential scanning calorimetry studies and surface pressure-area isotherms. Complementary neutron spin-echo (NSE) spectroscopy measurements confirm that the observed structural changes lead to increased membrane bending rigidity and increased liposomal stability. These findings illustrate the structure-property relations underlying improved liposomal designs required for circumventing a current bottleneck in drug delivery.