Axial-Ligand-Induced Spin-State Modulation Switching Catalytic Selectivity of Single-Atom Nanozymes for...

Achieving pathway-selective catalysis in single-atom nanozymes (SAzymes) is highly significant yet challenging, especially for heme-like M-N4 structured SAzymes, which demonstrate powerful enzyme-like catalytic efficiency and broad applicability. Inspired by the axial-ligand-regulated local electric fields oriented along the Fe═O axis in natural heme metalloenzymes, which switch selectivity within a shared metal-oxo manifold, we developed FeNSC-O SAzymes featuring axial O coordination stabilized by sulfur doping, achieving a catalase/peroxidase-like (CAT/POD) selectivity up to 7.4 times greater than that of planar oxygen-doped FeNC-O SAzymes. Low-temperature EPR and magnetic susceptibility measurements revealed that axial O coordination shifts the Fe center from the high-spin configuration in FeNC-O to the intermediate-spin state in FeNSC-O. Further DFT analyses demonstrated that the axial O ligand induces strong σ hybridization between Fe 3dz2-O 2pz orbitals and π hybridization between the Fe 3dxz/3dyz-O 2px/2py orbitals. This orbital reconstruction reduces the Fe spin polarization and is accompanied by electron withdrawal from the Fe center, thereby weakening the Fe 3d-O 2p orbital overlap and charge transfer to oxygen-containing intermediates. Consequently, H2O2 adsorption and its dissociative conversion to (*O + H2O) are limited, suppressing the POD-like pathway. Meanwhile, weakened O2 binding facilitates O2 release, thereby enhancing the CAT-like pathway. Together, these effects switch H2O2 activation toward CAT-like disproportionation and enhance CAT/POD selectivity. Furthermore, encapsulating FeNSC-O within asymmetric hollow nanoreactors enabled the construction of H2O2-responsive self-propelled nanomotors capable of active inflammatory-cell penetration and intracellular ROS scavenging, demonstrating their promising potential for targeted therapy and precision medicine.