Endogenic transferrin-targeted cell membrane-coated biomimetic lipo-complexes for efficient targeting and enhanced antitumor efficacy in orthotopic glioblastoma

Due to the invasive growth of glioblastomas (GBM) and their resistance to conventional chemotherapy, the efficacy of GBM treatment remains limited. Biomimetic BBB-penetrating hybrid nanovehicles, engineered through homologous cell membrane fusion between cancer cells and protein corona (PC)-mediated liposomes coated with cancer cell membranes, have been explored for brain-targeted drug delivery. In this study, T₁₀ peptide-modified cell membrane-coated liposomes were used to construct an <i>in situ</i> transferrin (Tf) PC-mediated lipo-complex carrying a respiratory depressant agent (metformin, MET) and a photosensitizer (Chlorin, Ce6), creating a transferrin- and cancer cell-targeting delivery system (MET/Ce6@Lipo@CM@T₁₀). MET/Ce6@Lipo@CM@T₁₀ possesses a spherical core-shell structure with uniform distribution while maintaining low systemic toxicity. Upon irradiation, MET/Ce6@Lipo@CM@T₁₀ effectively inhibited cell proliferation and induced apoptosis <i>via</i> photodynamic therapy (PDT). Simultaneously, the loaded MET alleviated intracellular hypoxia caused by PDT, thereby enhancing anti-tumor efficacy. The establishment of an <i>in vitro</i> BBB model and 3D tumor spheroid experiments confirmed that MET/Ce6@Lipo@CM@T₁₀ effectively crossed BBB and deeply accumulated within tumor tissues. As a result, in <i>in vivo</i> animal experiments, MET/Ce6@Lipo@CM@T₁₀ significantly inhibited tumor growth, promoted tumor necrosis and apoptosis, and demonstrated systemic safety. In conclusion, MET/Ce6@Lipo@CM@T₁₀ demonstrated enhanced PDT effects on GBM, and will provide new insights and methods for GBM treatment.