Self‐Reinforced Bimetallic Mito‐Jammer for Ca2+ Overload‐Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization

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. Self‐reinforced bimetallic Mito‐Jammer is rationally designed and synthesized by loading DOX and CaO2 into the hyaluronic acid‐modified metal‐organic framework‐199. By triggering reactive oxygen species storm and Ca2+ overload, the Mito‐Jammer could enhance the tumor‐specific Cu2+ aggregation and induce cascade mitochondrial damage to further arouse tumor‐specific cuproptosis and cuproptosis‐related immunotherapy.