Rearranging Spin Electrons by Axial-Ligand-Induced Orbital Splitting to Regulate Enzymatic Activity of Single-Atom Nanozyme with Destructive d−π Conjugation

Most of the nanozymes have been obtained based on trial and error, for which the application is usually compromised by enzymatic activity regulation due to a vague catalytic mechanism. Herein, a hollow axial Mo–Pt single-atom nanozyme (H-MoN₅@PtN₄/C) is constructed by a two-tier template capture strategy. The axial ligand can induce Mo 4d orbital splitting, leading to a rearrangement of spin electrons (↑ ↑ → ↑↓) to regulate enzymatic activity. This creates catalase-like activity and enhances oxidase-like activity to catalyze cascade enzymatic reactions (H₂O₂ → O₂ → O₂^•–), which can overcome tumor hypoxia and accumulate cytotoxic superoxide radicals (O₂^•–). Significantly, H-MoN₅@PtN₄/C displays destructive d−π conjugation between the metal and substrate to attenuate the restriction of orbitals and electrons. This markedly improves enzymatic performance (catalase-like and oxidase-like activity) of a Mo single atom and peroxidase-like properties of a Pt single atom. Furthermore, the H-MoN₅@PtN₄/C can deplete overexpressed glutathione (GSH) through a redox reaction, which can avoid consumption of ROS (O₂^•– and ^•OH). As a result, H-MoN₅@PtN₄/C can overcome limitations of a complex tumor microenvironment (TME) for tumor-specific therapy based on TME-activated catalytic activity.