Atomic‐Level High‐Entropy Nanozymes Enable Remarkable Endogenous Targeted Catalysis and Enhancing Tumor Photothermal Therapy

Abstract Nanozymes hold great potential in protecting human health. However, constructing new and efficient nanozymes is a significant challenge. Developing atomic‐level nanozymes is a promising approach. Despite their potential, atomic‐level high‐entropy nanozymes have not been reported due to thermodynamic instability. Therefore, developing atomic‐level high‐entropy nanozymes are of great significance. What's more, further exploring their biomedical applications can open up new horizons for nanozymology. Here, the atomic‐level high‐entropy nanozyme system capable of remarkable endogenous targeted catalysis and enhancing tumor photothermal therapy is successfully constructed. The system is prepared by reduction‐diffusion and grafting methods. The RuRhPtIrMo sub‐nanometer high‐entropy nanozyme (snHEAzyme) with about 8–10 atoms thickness is first prepared. Then, they are grafted by targeting agent DSPE‐PEG2000‐cRGD and imaging agent Cy7 to obtain the snHEAzyme@DSPE‐PEG2000‐cRGD@Cy7 nanozyme system. The synthesized snHEAzyme@DSPE‐PEG2000‐cRGD@Cy7 system exhibits excellent peroxidase‐like activity and high absorbance in the near‐infrared (NIR) range. Under NIR irradiation, the nanozyme shows efficient photothermal conversion and reactive oxygen species generation effects. In vitro and in vivo experiments demonstrated that the snHEAzyme@DSPE‐PEG2000‐cRGD@Cy7 system can be effectively targeted to penetrate tumor cell membranes and treat tumors. This work offers a new perspective on snHEAzyme fabrication and its biomedical applications.