Axial Coordination and Defect Engineering of Copper-Based Single-Atom Nanozymes: Driving Synergistic Disulfidptosis and Pyroptosis for Efficient Prostate Cancer Immunotherapy.

Abstract

Immunotherapy for prostate cancer is severely restricted by the immunosuppressive tumor microenvironment (TME) and the intrinsic antioxidant defense systems of tumor cells. To address these challenges, we develop an efficient copper-based single-atom nanozyme platform (CuN3Cl-BAY@COD) via a facile axial coordination and defect engineering strategy to boost immunotherapy by driving synergistic disulfidptosis and pyroptosis. This dual-engineering strategy effectively regulates the electronic and geometric structures of Cu sites, resulting in significantly improved multienzyme-mimicking activities. Such enhanced multienzyme-mimicking activities endow CuN3Cl-BAY@COD with the robust capacity to disrupt intracellular redox homeostasis and amplify the disulfide stress mediated by BAY-876, inducing efficient tumor cell pyroptosis and disulfidptosis. The loaded cholesterol oxidase degrades cholesterol to inhibit tumor cell invasion while elevating intracellular hydrogen peroxide levels to exacerbate pyroptosis. In summary, by coupling metabolic reprogramming with dual immunogenic cell death, this engineered nanoplatform overcomes TME resistance barriers, providing a robust strategy for prostate cancer immunotherapy.