Dual-pronged metal ion interference therapy: copper–zinc bimetallic sulfide nanoparticles synergistically disrupt redox homeostasis for enhanced tumor treatment

Metal ion interference therapy (MIIT) employs biocatalytic interference mechanisms, such as Fenton-like reactions and oxidative stress amplification, to disrupt tumor redox homeostasis. Notably, this approach demonstrates excellent therapeutic efficacy and safety. However, biocatalytic efficiency is often hampered by the strong antioxidant system of tumor cells and the catalytic efficiency of metal ions. To address this limitation, in this study, we engineered copper–zinc bimetallic sulfide nanoparticles (CZS NPs) to implement a dual-action therapeutic strategy. The Zn2+ within CZS NPs exploit the enzymatic activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) to amplify tumor oxidative stress, while Cu+ boosts Fenton-like catalytic activity, intensifying oxidative stress damage. These components synergistically drive the NOX/superoxide dismutase (SOD)/peroxidase (POD) nanocascade reaction, achieving the combinatorial activation of three cell death pathways: ferroptosis, cuproptosis, and apoptosis. The synthesized CZS NPs achieve remarkable therapeutic efficacy in tumor cells through a fully optimized MIIT. These findings suggest a potential strategy for MIIT-mediated biocatalytic tumor therapy.