Axial-Ligand-Induced Spin-State Modulation Switching Catalytic Selectivity of Single-Atom Nanozymes for Self-Propelled Nanomotors

Abstract 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.