Spatially targeted triple amplification of oxidative stress for enhanced tumor therapy via effective modulation of metal ion valence states

Inducing oxidative stress through metal ions activated biocatalysis is a fundamental mechanism of metal ion-interference therapy (MIIT). However, the actual catalytic efficiency of MIIT is often limited by the random valence states of metal ions and scattered space. Herein, copper-iron bimetallic sulfide nanoparticles coated with bovine serum albumin (CFS NPs) are synthesized through metal ion valence modulation strategy. Significant amounts of Cu⁺ and Fe²⁺ were released by CFS NPs, which is crucial for catalyzing Fenton-like reaction. The presence of Fe³⁺ further boosts Fe²⁺ availability and protects against hydroxyl radical (•OH) elimination via glutathione (GSH) consumption, amplifying the mitochondrial oxidative stress to induce apoptotic cell death. This oxidative stress damage is manifested in Cu⁺ targeting the mitochondrial tricarboxylic acid (TCA) cycle, further causing proteotoxic stress and cuproptosis. The production of lipid peroxidation (LPO) and the inactivation of glutathione peroxidase 4 (GPX4) expression are also affected by the amplified oxidative stress to achieve efficient ferroptosis. As a result, the synergistic apoptosis/cuproptosis/ferroptosis multimodal therapy almost completely inhibits tumor growth in vivo. It is believing that CFS NPs provide feasible implications for multiple combination therapy of tumors with the rational regulation of metal ion valence state and precise spatial control to effectively improve the level of oxidative stress. STATEMENT OF SIGNIFICANCE: : Metal ion-interference therapy induces oxidative stress in tumor cells via metal ion-activated biocatalysis, influencing reactive oxygen species (ROS) levels, proteotoxic stress, and lipid peroxidation accumulation. However, the actual catalytic efficiency of metal ion-interference therapy is often limited by the random valence state of these metal ions and scattered space. Herein, we constructed variable valence copper-iron bimetallic sulfides nanoparticles (CFS NPs) through metal ion valence modulation strategy to overcome the key factors that constrain efficiency with the combination of triple oxidative stress spatially treatment for apoptosis/cuproptosis/ferroptosis therapy. The reduced acidity and GSH concentration within normal cells lead to a much low cytotoxicity to normal cells, and therefore higher biocompatibility and biosafety for bio-medical applications.