Self-Reinforced Bimetallic Mito-Jammer for Ca²⁺ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis...

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO₂) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO₂ and Cu²⁺ in the tumor microenvironment. The exposed CaO₂ further yields hydrogen peroxide (H₂O₂) and Ca²⁺ in a weakly acidic environment to strengthen the Cu²⁺-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca²⁺ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.