Coordination Number‐Tuned FeN x Single‐Atom Nanozymes for Sustained Peroxidase‐Like Catalysis in Tumor Therapy

Peroxidase (POD)‐like catalysis by single‐atom nanozymes (SAEs) under sustained H 2 O 2 exposure requires both rapid substrate activation and durable catalytic turnover, both of which are closely linked to the coordination environment of metal sites. However, how the coordination number governs their balance remains unclear, especially when the interaction strength between SAEs and H 2 O 2 is tuned. Herein, we construct three structurally comparable FeN x ‐SAEs (x = 4, 3, and 2), revealing a volcano‐like relationship between POD‐like activity and H 2 O 2 adsorption strength. The selected FeN 3 ‐SAE exhibits the highest POD‐like activity (1.52 × 10 −6 M s −1 ), which is 1.9‐ and 4.1‐fold greater than those of FeN 2 ‐SAE and FeN 4 ‐SAE, respectively. Moreover, the FeN 3 ‐SAE sustains efficient H 2 O 2 consumption and robust •OH generation during prolonged catalysis, whereas the FeN 4 ‐SAE suffers from inadequate H 2 O 2 activation, and the FeN 2 ‐SAE undergoes rapid kinetic decay. Combined experiments and theoretical calculations attribute this performance to well‐balanced H 2 O 2 adsorption at the FeN 3 site, which facilitates substrate activation, intermediate desorption, and active‐site regeneration. Both cellular and animal experiments reveal that FeN 3 ‐SAE enables continuous H 2 O 2 conversion into cytotoxic •OH, depleting GSH and triggering tumor suppression accompanied by immune activation. This study provides mechanistic insights into sustained POD‐like catalysis from the perspective of coordination number‐regulated adsorption‒turnover balance.