LAUSR

Single‐atom nanozymes (SAzymes) represent a new research frontier in the biomedical fields. The rational design and controllable synthesis of SAzymes with well‐defined electronic and geometric structures are essential for maximizing their enzyme‐like catalytic activity and therapeutic efficacy but remain challenging. Here, a melamine‐mediated pyrolysis activation strategy is reported for the controllable fabrication of iron‐based SAzyme containing five‐coordinated structure (FeN5), identified by transmission electron microscopy imaging and X‐ray absorption fine structure analyses. The FeN5 SAzyme exhibits superior peroxidase‐like activity owing to the optimized coordination structure, and the corresponding catalytic efficiency of Fe‐species in the FeN5 SAzyme is 7.64 and 3.45 × 105 times higher than those in traditional FeN4 SAzyme and Fe3O4 nanozyme, respectively, demonstrated by steady‐state kinetic assay. In addition, the catalytic mechanism is jointly disclosed by experimental results and density functional theory studies. The as‐synthesized FeN5 SAzyme demonstrates significantly enhanced antitumor effect in vitro and in vivo due to the excellent peroxidase‐like activity under tumor microenvironment.