Platycodon grandiflorus-Derived Nanovesicles Sensitize Gastric Cancer to T Cell Killing via Ferroptosis-Driven Membrane Mechanical Remodeling.

Plant-derived nanovesicles have emerged as promising natural nanotherapeutics for cancer treatment, yet whether they can overcome the intrinsic resistance of tumor cells to cytotoxic T-cell-mediated killing remains largely unexplored. Here, we show that lipid-enriched Platycodon grandiflorus-derived nanovesicles (PGNs) sensitize gastric cancer to immune attack through ferroptosis-driven plasma membrane mechanical remodeling. Mechanistically, PGNs reprogram tumor lipid composition by coordinately suppressing the SLC7A11-GPX4 antioxidant axis while delivering polyunsaturated fatty acids, particularly Gamma-linolenic acid, thereby promoting glutathione depletion, lipid peroxidation, and ferroptosis. Transcriptomic analyses further revealed coordinated attenuation of malignant epithelial programs together with remodeling of membrane-associated and glutathione metabolic pathways following PGN treatment. Fluorescence lifetime imaging microscopy and atomic force microscopy revealed concomitant increases in plasma membrane tension and cellular stiffness during ferroptosis, facilitating perforin pore formation and enhancing the susceptibility of gastric cancer cells to cytotoxic T-cell-mediated killing. Collectively, these findings establish a mechanistic link between ferroptosis-driven membrane mechanical remodeling and tumor immune susceptibility, highlighting plant-derived lipid nanovesicles as a promising natural strategy for enhancing antitumor immunity.