Coordination-Driven Self-Assembly Strategy-Activated Cu Single-Atom Nanozymes for Catalytic Tumor-Specific Therapy

Abstract

How to optimize the enzyme-like catalytic activity of nanozymes to improve their applicability has become a great challenge. Herein, we present an l-cysteine (l-Cys) coordination-driven self-assembly strategy to activate polyvinylpyrrolidone (PVP)-modified Cu single-atom nanozymes MoO_<i>x</i>-Cu-Cys (denoted as MCCP SAzymes) aiming at catalytic tumor-specific therapy. The Cu single atom content of MCCP can be rationally modulated to 10.10 wt %, which activates the catalase (CAT)-like activity of MoO_<i>x</i> nanoparticles to catalyze the decomposition of H₂O₂ in acidic microenvironments to increase O₂ production. Excitingly, the maximized CAT-like catalytic efficiency of MCCP is 138-fold higher than that of typical MnO₂ nanozymes and exhibits 14.3-fold higher affinity than natural catalase, as demonstrated by steady-state kinetics. We verify that the well-defined l-Cys-Cu···O active sites optimize CAT-like activity to match the active sites of natural catalase through an l-Cys bridge-accelerated electron transfer from Cys-Cu to MoO_<i>x</i> disclosed by density functional theory calculations. Simultaneously, the high loading Cu single atoms in MCCP also enable generation of •OH via a Fenton-like reaction. Moreover, under X-ray irradiation, MCCP converts O₂ to ¹O₂ for cascading radiodynamic therapy, thereby facilitating the multiple reactive oxygen species (ROS) for radiosensitization to achieve substantial antitumor.