Dual mitochondrial-targeting nanoplatform integrating cuproptosis and pyroptosis for robust antitumor immune...

Cuproptosis and pyroptosis have emerged as highly promising strategies for cancer immunotherapy by boosting tumor immunogenicity and reversing the immunosuppressive tumor microenvironment. However, the precise and synergistic activation of these two cell-death pathways remains a major challenge due to insufficient tumor specificity and inefficient mitochondrial targeting. Herein, we engineered a dual mitochondria-targeting nanoplatform (ESCu/CyNH₂) via Cu²⁺-mediated coordination assembly of elesclomol (ES) and hemicyanine (CyNH₂), enabling programmable co-induction of cuproptosis and pyroptosis for amplified cancer immunotherapy. Upon intracellular GSH activation, ESCu/CyNH₂ rapidly disassembled to release Cu²⁺, ES, and CyNH₂. ES-mediated mitochondrial delivery of Cu²⁺ induced DLAT aggregation and severe mitochondrial dysfunction, thereby triggering cuproptosis, while CyNH₂ concurrently disrupted mitochondrial membrane integrity and activated the cytochrome c/caspase-3/GSDME signaling cascade to initiate pyroptosis. This mitochondria-centered dual-death amplification not only provoked potent immunogenic cell death (ICD) but also elicited robust systemic antitumor immune responses and remarkable tumor suppression. Collectively, this work establishes a mitochondria-targeted dual-death nanotherapeutic paradigm for precise spatiotemporal co-activation of cuproptosis and pyroptosis, offering new opportunities for next-generation cancer immunotherapy.