Mitochondria-Targeted Dual-Ion Perturbator Amplifies Cuproptosis for Enhanced Melanoma Immunotherapy and Accelerated...

Melanoma recurrence and full-thickness skin defects severely impair patient recovery and quality of life. There is an urgent need for therapeutic platforms that not only eliminate residual melanoma cells but also accelerate wound healing. Cuproptosis has emerged as a promising anticancer strategy. However, a significant challenge remains in overcoming the adaptive defenses of cancer cells and sensitizing them to cuproptosis. Herein, we explore a mitochondrial-targeted Ca/Cu dual-ion chaos inducer (Mito-chaos) by integrating a mitochondria-targeted curcumin derivative (MitoCur) into a calcium- and copper-co-doped Prussian blue nanoplatform. Mito-chaos exhibits excellent mitochondrial targeting, multienzyme-mimicking catalytic activity, and strong NIR-II photothermal properties. Mito-chaos can precisely deliver Cu²⁺ and Ca²⁺ ions into mitochondria, disrupting mitochondrial ion homeostasis, inducing calcium overload, and consequently amplifying cuproptosis. Combined with mild NIR-II photothermal treatment, Mito-chaos achieves effective melanoma suppression accompanied by robust antitumor immune activation. Beyond tumor eradication, Mito-chaos significantly enhances skin vascularization and collagen deposition, accelerating postoperative wound healing and reducing wound closure time. This mitochondria-targeted therapeutic platform not only effectively eliminates residual melanoma cells but also promotes tissue regeneration, providing an integrated and effective strategy for melanoma postoperative management. Our study presents a promising paradigm for precisely amplifying subcellular organelle dysfunction to boost cancer cuproptosis therapy and tissue repair.