Entropy‐Encoded Electronic Reconstruction in High‐Entropy Nanozymes Enables Cofactor‐Free Monooxygenase‐Like Catalysis

ABSTRACT Flavin‐dependent monooxygenases (FMOs) catalyze redox reactions central to antibiotic degradation and metabolic detoxification, yet replicating their intricate cofactor‐dependent electron transfer in synthetic systems has remained elusive. Here, we report an electronic modulation strategy that enables cofactor‐free FMO‐like catalysis within a high‐entropy alloy nanozyme (HEAzyme‐Cu 1.5 ). We induce localized electron cloud enrichment that shifts Cu 3 d orbitals toward the Fermi level, establishing a self‐sustained redox channel without flavin cofactors. This atomic‐scale entropy‐driven alignment bridges the functional gap between natural cofactor‐dependent enzymes and artificial catalysts, demonstrating for the first time that complex redox cascades traditionally confined to biological systems can be reconstructed purely by materials design. This entropy‐driven electronic reconfiguration enables near‐zero barrier O 2 activation and rapid hydroxylation with a kinetic constant. Integrating this multifunctional HEAzyme into a portable hydrogel sensor platform achieves real‐time antibiotic detection down to 11–25 nM and > 90% degradation within 20 min in complex water samples. This work establishes a universal design principle for programmable enzyme mimetics, where atomic‐scale entropy, electronic‐state alignment, and multimetal cooperation converge to emulate and transcend biological catalysis. Such entropy‐encoded redox systems offer a transformative route toward intelligent bioinspired materials for environmental remediation, green synthesis, and metabolic engineering.