Microglial Membrane‐Coated Biomimetic Nanoplatform for Enhanced Blood–Brain Barrier Penetration and Targeted Photodynamic Therapy in Orthotopic Glioblastoma

Glioblastoma multiforme (GBM) continues to pose a significant challenge in the field of neuro-oncology primarily because of the limited penetration of therapeutics across the blood-brain barrier (BBB) and the presence of immunosuppressive tumor microenvironments. To address these challenges, a HD-PEG_2K@BM biomimetic nanoplatform (hereinafter referred to as HD-P@BM) is developed that cloaks the near-infrared II photosensitizer HD-PEG_2K (HD-P) inside microglial membranes to enable enhanced BBB penetration and tumor-targeted delivery. In this study, it is found that the microglia-derived membranes enhanced the uptake of nanoparticles by both the glioma cells and tumor-associated microglia. Furthermore, irradiation with 808 nm laser induced a photodynamic effect that caused mitochondrial dysfunction and elicited immunogenic cell death. Notably, HD-P@BM reprogrammed the immunosuppressive microglia to pro-inflammatory M1 phenotypes, which promoted cytotoxic T-cell infiltration and remodeled the tumor immune landscape. In orthotopic GBM models, HD-P@BM significantly suppressed tumor growth, prolonged survival, and mitigated systemic toxicity. This multifunctional strategy synergized biomimetic delivery, photodynamic therapy (PDT), and immunotherapy is a promising therapeutic approach for GBM. Thus, this study establishes a multifunctional nanotherapeutic strategy that combines enhanced BBB penetration, precise tumor targeting, and synergistic PDT, showing high potential for effective clinical GBM treatment.