Enhanced Catalytic Therapy by Modulating Substrate Adsorption and Local Electron Density through Coordinatively Unsaturated Cu‐N 2 Single‐Atom Sites on Carbon Dots

ABSTRACT Coordinatively unsaturated single‐atom nanozymes with sufficient H 2 O 2 adsorption and rapid kinetics display excellent peroxidase (POD)‐like activity; however, their rational construction limits their wide application for cancer therapy. Here, we report a ligand chelation‐determined conformation (LCDC) strategy to construct Cu single‐atom nanozymes supported on carbon dots (Cu‐N 2 ‐CDs) that were realized by in situ chelation and carbonization of organic chelating agent and metal cation. Such coordinatively unsaturated Cu‐N 2 ‐CDs expose high‐spin Cu sites that enhance d‐p orbital hybridization to facilitate H 2 O 2 adsorption. Importantly, the coordinatively unsaturated Cu‐N 2 configuration is capable of elevating the electron density at the metal center and narrowing the band gap to accelerate •OH generation reaction kinetics. The Cu‐N 2 ‐CDs outperform their Cu‐N 4 counterparts by achieving a 3.49‐fold stronger H 2 O 2 adsorption and a 3.62‐fold greater maximum reaction rate, leading to the efficient production of toxic •OH from endogenous H 2 O 2 . Consequently, Cu‐N 2 ‐CDs achieve excellent tumor catalytic therapy outcomes both in vitro and in vivo. This work provides fundamental insights for the rational design of high‐performance nanozymes through precise coordination engineering.