Enhancing Catalytic Activity of a Nickel Single Atom Enzyme by Polynary Heteroatom Doping for Ferroptosis-Based Tumor Therapy.

Abstract

As a rising generation of nanozymes, single atom enzymes show significant promise for cancer therapy, due to their maximum atom utilization efficiency and well-defined electronic structures. However, it remains a tremendous challenge to precisely produce a heteroatom-doped single atom enzyme with an expected coordination environment. Herein, we develop an anion exchange strategy for precisely controlled production of an edge-rich sulfur (S)- and nitrogen (N)-decorated nickel single atom enzyme (S-N/Ni PSAE). In particular, sulfurized S-N/Ni PSAE exhibits stronger peroxidase-like and glutathione oxidase-like activities than the nitrogen-monodoped nickel single atom enzyme, which is attributed to the vacancies and defective sites of sulfurized nitrogen atoms. Moreover, both <i>in vitro</i> and <i>in vivo</i> results demonstrate that, compared with nitrogen-monodoped N/Ni PSAE, sulfurized S-N/Ni PSAE more effectively triggers ferroptosis of tumor cells via inactivating glutathione peroxidase 4 and inducing lipid peroxidation. This study highlights the enhanced catalytic efficacy of a polynary heteroatom-doped single atom enzyme for ferroptosis-based cancer therapy.