Simultaneous Modulation of Hypoxia And Metabolism in Glioblastoma for Enhanced Radio‐Immunotherapy

Abstract Glioblastoma (GBM) is the most invasive and lethal primary brain melanoma. The existing treatment modality is unable to achieve thorough elimination of GBM due to the aggressive nature, blood‐brain barrier (BBB), hypoxic environment, and heterogeneous cellular components. Herein, a radio‐immunotherapy regimen based on a versatile nanoplatform (G/APH‐M) is proposed to effectively kill quiescent cancer stem cells (CSCs) and proliferative cancer cells in GBM in a simultaneous manner. Among o ur prepared G/APH‐M, the coating of GL261 cell membrane guarantees the BBB‐penetrable delivery and homologous GBM‐targeting of the hollow Prussian blue loaded with oxidative phosphorylation inhibitor Gboxin and catalase‐mimetic nanozymes. After substantial tumor accumulation, the released Gboxin inhibits mitochondrial oxidative phosphorylation to kill CSCs, while the nanozymes catalyze the production of oxygen to enhance radiotherapy. Consequently, potent immunogenic cell death (ICD) of GBM is induced, which in combination with immune checkpoint inhibitors (αPD‐L1), achieving a potent therapeutic effect with an 80% survival rate in the orthotopic GBM model even at 60 days after the treatment. The synergistic modulation of hypoxia and metabolism based on G/APH‐M greatly intensifies the radio‐immunotherapy of GBM, which would inspire more comprehensive strategies targeting the multiple characteristics of GBM cells for clinical benefits.