High‐Throughput Screening and General Synthesis Strategy of Single‐Atom Nanozymes for Oral Squamous Cell Carcinoma Therapy

Abstract Single‐atom nanozymes (SAzymes), with their superior enzyme‐like catalytic activity, have emerged as promising candidates for oncology therapeutics. The well‐defined structures of SAzymes make them well predictable by experiences and theoretical calculation. However, the effects of metal center species and coordination environments on enzyme‐like activity are variable, and screening catalytic activity by artificial experiments is challenging. High‐throughput screening can rapidly select the activity center structures of SAzymes with optimal enzyme‐like activity, thus their better application in tumor therapy is highly desirable. Herein, a “high‐throughput screening‐SAzymes structures” system is established for efficient oncology drug preparation by density functional theory for oxidase‐like processes and screened the differences brought about by different metals and coordination environments. Through this screening process, SAzymes with transition metals (Mn, Fe, Co, Ni) as active centers are synthesized and then tested the multi‐enzyme activities. It is found that the SAzyme with Co as the active metal center exhibited the best oxidase‐like activity, and the system further showed good anti‐oral squamous cell carcinoma properties both in vitro and in vivo. This study opens up a new avenue for the rational design of SAzymes in oral cancer therapy by combining computational screening and experimental validation.