Biomimetic Nanoreactor‐Driven Synergistic Anti‐Glioblastoma Therapy Through Integrated Bioorthogonal Catalysis and Sonodynamic Activation

ABSTRACT Glioblastoma multiforme (GBM) remains an aggressive, treatment‐refractory central nervous system malignancy, largely due to its invasiveness, vascular heterogeneity, and the blood‐brain barrier (BBB). Conventional therapies suffer from poor specificity and insufficient intratumoral drug delivery. To address these challenges, we developed a tumor microenvironment (TME) and ultrasound (US) responsive biomimetic nanoreactor (CuTPD@M NPs) integrating bioorthogonal catalytic therapy (BCT) and sonodynamic therapy (SDT) for precision‐targeted GBM treatment. The nanoplatform comprises a Cu(II)‐coordinated porphyrinic metal‐organic framework encapsulating azide and alkyne‐functionalized prodrugs, cloaked with homologous GBM cell membranes, which enhances BBB penetration and homotypic tumor targeting. In response to elevated intracellular glutathione levels, Cu(II) is reduced to Cu(I), triggering an azide‐alkyne cycloaddition to generate a combretastatin A‐4 analog in situ, effectively disrupting tumor angiogenesis. Concurrently, US activates the porphyrin‐based sonosensitizer, producing reactive oxygen species that induce mitochondrial dysfunction, glutathione peroxidase 4 downregulation, and ferroptosis. In murine GBM models, CuTPD@M combined with US achieved significant tumor growth inhibition, reduced angiogenic markers, and prolonged median survival. This work suggests a potentially transformative nanotherapeutic approach that leverages TME‐ response to co‐activate BCT and SDT within a biomimetic nanosystem. The CuTPD@M platform demonstrates potential as an advance in precision nanomedicine for the treatment of intracranial malignant tumors.