Mitochondrial ‘Attack-and-Trap’ strategy potentiates cGAS-STING signaling to stimulate durable antitumor immunity against glioblastoma

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Glioblastoma (GBM) recurrence, driven by therapeutic resistance and diffuse infiltration, remains a critical clinical challenge, fundamentally sustained by a mitochondrial metabolic addiction. To leverage this, we developed a biomimetic nanoplatform (HM-NPs@CM) camouflaged with cancer cell-mitochondria hybrid membranes. This ensures efficient blood-brain barrier traversal and precise mitochondria-targeted co-delivery of sonosensitizer Ce6 and mitophagy inhibitor Mdivi-1 within orthotopic GBM. Upon ultrasound activation, the nanoplatform executes a synergistic ‘Attack-and-Trap’ strategy: sonodynamic therapy (SDT) launches a targeted oxidative assault, while concurrent pharmacological inhibition of mitophagy traps irreparably damaged mitochondria. This accumulation of damaged mitochondria triggers a lethal pathological cascade, where mitochondrial oxidative stress progresses into severe intracellular oxidative stress, culminating in irreversible lytic cell death and sustained cytosolic mtDNA leakage. The liberated mtDNA robustly activates the cGAS-STING pathway, driving Type I interferon synthesis and transforming tumor cells into immunogenic reservoirs. Subsequently, this severe oxidative stress forces the terminal rupture of the plasma membrane, orchestrating the massive release of pre-synthesized immune effectors and damage-associated molecular patterns (DAMPs). Capitalizing on these signals, combination with anti-PD-L1 blockade potently induces dendritic cell maturation and CD8 + T cell infiltration, significantly suppressing tumor growth. Ultimately, this multimodal strategy establishes durable immunological memory, providing comprehensive protection against tumor rechallenge and post-surgical recurrence.

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