Engineering Metal‐Pocket Cooperativity in Single‐Atom COF Nanozymes for Selective Cascade Catalysis

Abstract

ABSTRACT Nanozymes have emerged as robust and scalable alternatives to natural enzymes, offering high catalytic activity and structural stability. However, reproducing the exquisite selectivity of enzymatic catalysis, particularly their ability to operate with high precision in complex reaction systems, remains a central challenge. Herein, inspired by the heme–pocket architecture and cooperative regulation in cytochrome P450, we report a nanozyme multilevel programming strategy based on a single‐atom covalent organic framework (COF) platform constructed from heme‐like metal–porphyrin nodes and linkers bearing chiral amino‐acid residues, enabling selective editing of metal catalytic centers and enzyme‐mimetic pockets to control catalytic activity, chemoselectivity, and stereochemical outcomes. As a proof of concept, we employ a biomimetic chiral cascade that couples methanol dehydrogenase‐like alcohol oxidation with a chymopapain‑inspired asymmetric aldol reaction to probe and optimize metal–pocket cooperativity within the nanozyme. The programmed MnPor‐Pro‐based nanozyme delivers high product yields, excellent chemo‐ and stereoselectivity, and outstanding recyclability in the cascade reactions, indicating the effectiveness of this strategy. This work provides a rational design insight for engineering highly selective nanozymes capable of addressing complex, multistep transformations, significantly bridging the gap between artificial and natural enzymatic systems.