Histidine‐Induced Cu(II) Coordination Distortion in Cu‐MOF: A Groundbreaking Strategy to Revolutionize Nanozyme Catalytic Mechanisms and Break pH Limitations

Abstract Peroxidase‐like (POD‐like) nanozymes have attracted widespread interest for their compelling catalytic capabilities, nevertheless, conventional POD‐like nanozymes typically exhibit infinitesimal activity under neutral and alkaline conditions, severely restricting their applications. Developing nanozymes with high catalytic performance under neutral and alkaline conditions remains formidable yet highly sought‐after challenges. Herein, a dual‐ligand Cu‐MOF nanozyme is introduced with histidine (His)‐induced Cu(II) coordination distortion to innovate the H 2 O 2 ‐decomposition pathway for breaking pH limitations. This nanozyme displays activity across pH ranges of 2.0‐12.0 (with optimal at pH 9.0) and achieves superior catalytic efficiency of 2–3 orders of magnitude higher than the reported nanozymes under alkaline conditions. His coordination promotes the generation of singlet oxygen ( 1 O 2 ) instead of hydroxyl radicals (•OH) typically produced by traditional nanozymes, thereby overcoming the self‐decomposition and low oxidizing activity of H 2 O 2 under alkaline conditions. Theoretical calculations reveal that His‐induced coordination distortion modulates the electron distribution and alters H 2 O 2 binding sites, fundamentally reshaping the reaction mechanism. Leveraging on its exceptional catalytic properties, multifunctional colorimetric sensing platforms are constructed for diverse biomarkers. This study pioneers a transformative strategy based on ligand‐induced metal‐center coordination distortion, offering insight into optimize H 2 O 2 catalytic pathways, surmounting pH limitations, and broadening the functional application of nanozymes.