Spin-State Engineering of Asymmetric Fe-PN3 Single-Atom Nanozyme Enables Redox Microenvironment Reprogramming in...

Nanozymes, which mimic the catalytic activities of natural enzymes, have been investigated as therapeutic agents for treating reactive oxygen species (ROS)-related diseases. Despite progress having been made in nanozyme engineering, their diverse nanostructures and poor atom utilization efficiency severely limit further applications. Symmetric Fe-N4 coordination in iron-based single-atom nanozymes (SANs) confers intrinsic ROS scavenging activity; however, excessive adsorption of oxygen intermediates restricts catalytic turnover. Here, we describe a spin-state engineering strategy to address this limitation through asymmetric coordination design. Phosphorus incorporation transforms the symmetric Fe-N4 motif into an Fe-PN3 configuration, inducing a transition of Fe 3d orbitals from a low-spin to a high-spin state. Density functional theory calculations indicate that this spin modulation raises the count of unpaired electrons and moves the d-band center nearer the Fermi level, which in turn tunes the binding energies of oxygen intermediates and speeds up the catalytic cycle. Consequently, the Fe-PN3 nanozyme exhibits substantially enhanced ROS detoxification efficiency compared with its Fe-N4 counterpart. In a glucocorticoid-induced osteonecrosis model, the spin-engineered nanozyme modulates the pathological redox microenvironment, restores impaired autophagic flux, and preserves tissue integrity. Single-cell RNA sequencing further indicates coordinated modulation of oxidative stress-responsive and autophagy-related pathways. Collectively, this work supports asymmetric coordination-induced spin-state regulation as a strategy for designing high-performance iron-based single-atom nanozymes with translational potential in ROS-driven degenerative diseases.