Ultrasound-Driven Interfacial Electron Modulation Reprograms Mitochondrial Metabolism for Glioblastoma Therapy

Glioblastoma (GBM) remains difficult to treat because the restrictive blood-brain barrier (BBB), the hypoxic tumor microenvironments, and mitochondrial electron transport chain (ETC)-driven metabolic adaptability jointly limit therapeutic delivery and efficacy. Selective disruption of mitochondrial metabolism in GBM is challenging because ETC function is also essential for normal brain cells, and many therapeutic agents show limited BBB penetration or reduced activity under oxygen-limited conditions. Here, we report Ni/LDH@M, an ultrasound-responsive biomimetic Schottky nanoplatform assembled from nickel nanosheets and layered double hydroxide (LDH) nanosheets and cloaked with GL261 glioma cell membranes to enable homotypic recognition and accumulation in orthotopic glioma. Upon ultrasound irradiation, Ni/LDH@M drives carbon monoxide (CO) generation through interfacial electron modulation, and the generated CO inhibits mitochondrial cytochrome c oxidase, disrupts ETC electron transfer, and induces mitochondria-dependent apoptosis and immunogenic cell death (ICD). In mice bearing orthotopic GL261 gliomas, ultrasound-activated Ni/LDH@M suppressed tumor progression and prolonged survival, showing that controlled CO generation can reprogram tumor-cell mitochondrial metabolism for GBM therapy.