Engineering Dimensional Configuration of Single‐Atom S‐Cu‐S Sites as Reversible Electron Station for Enhanced Peroxidase‐Mimicking

Abstract Boosting catalytic activity of single‐atom nanozymes (SAzymes) to substitute natural metalloenzymes remains challenging due to the lack of enzyme‐like secondary building blocks and proper 3D conformation. Herein, a natural amino acid L‐cysteine (L‐Cys)‐triggered auto‐assembly process engineers the spatial positioning of 3D‐biomimetic S‐Cu‐S single‐atom catalytic sites and adjacent L‐Cys on sheet‐like MoS ₂ nanozyme, achieving activated MoCC SAzymes. MoCC achieves a maximum Cu single‐atom loading of 10.11% by suppressing aggregation through L‐Cys coordination. Particularly, MoCC can properly bind and react with the H ₂ O ₂ substrate, mimicking 3D catalytic pockets of natural enzymes. The maximum reaction velocity (4.56×10 ⁻⁷ M s ⁻¹ ), affinity (Michaelis constant, 0.65 mM), and specific activity (SA) (355.59 U mg ⁻¹ ) catalyzed by peroxidase (POD)‐mimicking MoCC are 16.3‐, 17.9‐, and 1.2‐fold higher than natural horseradish peroxidase (HRP). Density functional theory computations reveal that the S‐Cu‐S single‐atom catalytic sites stabilized by L‐Cys bonding function as a reversible electron flow workstation, triggering storage and transfer with MoS ₂ , facilitating swift electron exchange with H ₂ O ₂ , reducing energy barrier for hydroxyl radicals generation. The optimized 3D S‐Cu‐S single‐atom featuring L‐Cys building of MoCC exhibits cascaded catalase‐like activity and sono‐piezocatalysis effect, non‐invasively amplifying the generation of oxygen and singlet oxygen. Consequently, multiple free radicals can selectively eliminate dental bacteria and biofilms.