Dual Active Centers Linked by a Reversible Electron Station as a Multifunctional Nanozyme to Induce Synergetically Enhanced Cascade Catalysis for Tumor-Specific Therapy

Abstract

Nanozymes have shown great promise in reactive oxygen species (ROS)-mediated tumor therapy with mitigated side effects but are normally limited by the complex tumor microenvironment (TME). Herein, to overcome the adverse effects of TME, such as tumor hypoxia and high endogenous glutathione (GSH), an aptamer-functionalized Pd@MoO_3–x nano-hydrangea (A-Pd@MoO_3–x NH) is constructed for high-efficiency cancer therapy. Utilizing the irregular shape characteristics of nano Pd, the A-Pd@MoO_3–x NH nanozyme simultaneously exposes catalase-like Pd(111) and oxidase-like Pd(100) surface facets as dual active centers. This can catalyze cascade enzymatic reactions to overcome the negative effects of tumor hypoxia caused by the accumulation of cytotoxic superoxide (O₂^•–) radicals in TME without any external stimuli. In addition, the nanozyme can effectively degrade the overexpressed glutathione (GSH) through the redox reaction to avoid nontherapeutic consumption of O₂^•– radicals. More significantly, as a reversible electron station, MoO_3–x can extract electrons from H₂O₂ decomposing on Pd(111) or GSH degradation and transfer them back to Pd(100) through oxygen bridges or few Mo–Pd bonds. This can synergistically enhance enzyme-like activities of dual active centers and the GSH-degrading ability to enrich O₂^•– radicals. In this way, the A-Pd@MoO_3–x NH nanozyme can selectively and remarkably kill tumor cells while keeping the normal cell line unharmed.