Biointerface‐Customized Nanomodulators Induce Mitochondria‐Specific Dysfunction to Reprogram Tumor Immunity

Tumor mitochondria regulate cancer progression and immune evasion. However, current therapeutic strategies lack the subcellular precision required to selectively induce immune-beneficial mitochondrial dysfunction without causing systemic toxicity. Here, we report a biointerface-customized nanomodulator (C/C-HP@M2M-TPP), developed through a biointerface-engineered strategy (BES), that integrates sequential targeting and controlled activation to induce mitochondria-specific dysfunction and reprogram tumor immunity. Through a customized biointerface coating, the nanomodulators achieve preferential tumor accumulation and mitochondria-directed subcellular localization. Co-delivered calcium ion donors and efflux inhibitors cooperatively induce mitochondrial ion interference and dysfunction, which is further amplified by photothermal activation. This localized mitochondrial interference promotes immunogenic cell death and robust antitumor immune activation, resulting in potent tumor regression in mice. Integrated single-cell transcriptomic and proteomic analyses further identify mitochondrial disruption as a key mechanistic driver of tumor immune reprogramming. This work establishes biointerface-customized nanomodulation as a subcellular immunomodulatory therapeutic strategy in vivo.