Atomic-level regulation of the coordination structure in single-atom Fe nanozymes for tumor catalytic therapy

Single-atom nanozymes (SAzymes) exhibit efficient and stable catalytic performance due to their tunable electronic configurations and optimized atomic utilization. However, designing SAzymes with well-defined coordination environments and clarifying their structure–activity relationships for tumor therapy pose significant challenges. This study introduces FeN₄–Pyrrolic single-atom nanozymes (FeN₄–Pyrrolic SAzymes), developed by precisely modulating the first-shell coordination environment. Through X-ray absorption fine structure analyses and density functional theory calculations, the well-defined active centers of FeN₄–Pyrrolic SAzymes are shown to possess higher energy levels in the d_xz, d_yz, and d_z² orbitals than those of FeN₄–Pyridinic SAzymes, resulting in stronger interactions with reaction intermediates and enhanced intrinsic activity along the peroxidase (POD)-like reaction pathway. Both in vitro and in vivo experiments demonstrate that, after endocytosis by tumor cells, FeN₄–Pyrrolic SAzymes promote reactive oxygen species (ROS) accumulation through their exceptional POD-like activity, leading to oxidative damage and subsequent apoptosis. Additionally, their glutathione oxidase-like activity indirectly elevates lipid peroxidation levels, thereby facilitating ferroptosis. By modulating multiple cell death pathways, FeN₄–Pyrrolic SAzymes synergistically suppress tumor growth. This study provides novel insights into the fine regulation of coordination environments to improve the anti-tumor performance of nanozymes.