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.