Molecular dynamics deciphers drug-dependent stability in therapeutic liposomes.

Liposomal stability is critical for effective drug delivery, yet its dependence on drug-membrane interactions remains incompletely understood. Here, we employ atomic-scale molecular dynamics simulations to investigate the structural stability of a commercial liposome (composed of DMPC/DMPG phospholipids) when loaded with two therapeutic agents: amphotericin B (an antifungal) and 5-fluorouracil (5-FU, an anticancer drug). Our simulations reveal that amphotericin B maintains liposomal integrity, with minimal perturbations to membrane thickness, lipid order, and surface area. In contrast, 5-FU induces significant destabilization, including reduced membrane thickness, expanded lipid spacing, and disordered acyl chain packing-corroborated by alterations in deuterium order parameters, mass density profiles, and charge distributions. These findings demonstrate that while the liposome is an optimal carrier for amphotericin B, its composition requires modification for some anticancer drug delivery. The study provides mechanistic insights into drug-dependent liposomal stability, offering a framework for the rational design of tailored nanocarriers.