Enhancing radiation-resistance and peroxidase-like activity of single-atom copper nanozyme via local coordination manipulation

The inactivation of natural enzymes by radiation poses a great challenge to their applications for radiotherapy. Single-atom nanozymes (SAzymes) with high structural stability under such extreme conditions become a promising candidate for replacing natural enzymes to shrink tumors. Here, we report a CuN₃-centered SAzyme (CuN₃-SAzyme) that exhibits higher peroxidase-like catalytic activity than a CuN₄-centered counterpart, by locally regulating the coordination environment of single copper sites. Density functional theory calculations reveal that the CuN₃ active moiety confers optimal H₂O₂ adsorption and dissociation properties, thus contributing to high enzymatic activity of CuN₃-SAzyme. The introduction of X-ray can improve the kinetics of the decomposition of H₂O₂ by CuN₃-SAzyme. Moreover, CuN₃-SAzyme is very stable after a total radiation dose of 500 Gy, without significant changes in its geometrical structure or coordination environment, and simultaneously still retains comparable peroxidase-like activity relative to natural enzymes. Finally, this developed CuN₃-SAzyme with remarkable radioresistance can be used as an external field-improved therapeutics for enhancing radio-enzymatic therapy in vitro and in vivo. Overall, this study provides a paradigm for developing SAzymes with improved enzymatic activity through local coordination manipulation and high radioresistance over natural enzymes, for example, as sensitizers for cancer therapy.