Biomimetic Nanoparticles With Overexpressed Adhesion Proteins for Targeted Delivery of Gambogic Acid in Hepatocellular Carcinoma

Cancer cell membrane coating offers a promising strategy for targeted drug delivery, yet its homotypic targeting mechanism and optimization remain insufficiently understood. This study identifies epithelial cell adhesion molecule (EpCAM), rather than Galectin-3, as the pivotal mediator of homologous uptake in hepatocellular carcinoma. Through genetic engineering, HepG2 cells overexpressing EpCAM are generated, and their membranes are used to coat gambogic acid-loaded PLGA nanoparticles. Cellular uptake assays reveal that EpCAM-enriched membranes significantly enhance nanoparticle internalization by homologous cancer cells via clathrin-mediated endocytosis, a process dependent on both clathrin heavy chain and light chain. In vivo biodistribution studies demonstrate that the EpCAM-engineered biomimetic platform markedly improves tumoral drug accumulation and retention, leading to potent antitumor efficacy through BAX/BCL-2-mediated apoptosis without inducing significant systemic toxicity. Mechanistically, this enhanced targeting is attributed to multivalent EpCAM-EpCAM interactions and the preservation of native membrane functionalities, including immune evasion and prolonged circulation. By elucidating the molecular machinery driving membrane-mediated homotypic recognition, this work establishes a rational basis for engineering cell membranes with overexpressed adhesion proteins, thereby enabling a novel and translatable strategy for precision chemotherapy delivery in hepatocellular carcinoma and potentially other epithelial tumors.