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 in situ 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 via photodynamic therapy (PDT). Simultaneously, the loaded MET alleviated intracellular hypoxia caused by PDT, thereby enhancing anti-tumor efficacy. The establishment of an in vitro 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 in vivo 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.

Transferrin protein corona  /  Cell membrane biomimetic nanoparticles  /  Photodynamic therapy  /  Glioblastoma  /  Blood-brain barrier  /  Brain targeting  /  Hypoxia inhibition relief  /  Immungentic cell death