Biomimetic Nanodelivery System Based on Polyester-Lipid-Cell Membrane for the Sustained Release and Targeted Chemotherapy

Liposomal chemotherapy often suffers from structural instability and premature drug leakage in the bloodstream, leading to systemic toxicity and reduced tumor accumulation. Herein, we developed a robust biomimetic nanodelivery system (PDLC) designed to stabilize the lipid bilayer via a rigid polymer core. The PDLC was synthesized based on the strong molecular affinity between poly(L-lactic acid) and phospholipid monomer to form a molecular interlock that prevents premature drug leakage. The system comprises a DOX-loaded PLLA core, a lipid stabilization layer, and a 4T1 tumor cell membrane coating for homotypic targeting. PDLC effectively suppressed the initial burst release (<10% at 24 h) while exhibiting pH-responsive release in acidic tumor microenvironments. Facilitated by cell membrane-mediated endocytosis, PDLC showed enhanced uptake in 4T1 cells. In vivo imaging confirmed superior tumor homing capabilities, translating to a potent 80.1% tumor inhibition rate without the cardiotoxicity typical of free DOX. By mechanistically reinforcing lipid stability through polymer-lipid interactions, this study offers a compelling biomimetic strategy to maximize the therapeutic index of chemotherapeutic agents.