Silicon Doping-Engineered Asymmetric Coordination and Electronic Structure Modulation for Amplified Single-Atom Nanozyme Catalytic Therapy

Single-atom nanozymes (SANs), which feature tunable electronic structures and optimized atomic utilization efficiency, have garnered significant attention in biomedical applications. Despite substantial advancements, the catalytic performance of SANs remains suboptimal compared with that of natural enzymes, largely due to their symmetric coordination environments and electronic structures. Herein, we successfully engineer an asymmetrically coordinated Fe-based SAN with Si doping, termed Fe-SiN 3 /SAN, which demonstrates superior catalytic performance compared with its symmetric counterpart, Fe-N 4 /SAN. The low electronegativity of Si induces slight elongation of the Fe-N bonds in Fe-SiN 3 /SAN, optimizing the adsorption and desorption of oxygen intermediates and thereby significantly enhancing catalytic activity. Density functional theory (DFT) calculations reveal that asymmetric coordination in Fe-SiN 3 /SAN enhances structural electron activation, shifting the d-band center of Fe closer to the Fermi level. This shift facilitates the adsorption and activation of hydrogen peroxide and glutathione. Importantly, Bader charge analysis based on DFT calculations reveals that Fe-SiN 3 /SAN exhibits a lower charge during the desorption of rate-determining intermediates (*OH and *GS) compared with Fe-N 4 /SAN, confirming its superior reactive oxygen species generation capability. Experimental results further confirm that Fe-SiN 3 /SAN effectively induces irreversible tumor ferroptosis by promoting lipid peroxidation accumulation and inactivating glutathione peroxidase 4. We engineered a Si-doped asymmetric Fe-based single-atom nanozyme (Fe-SiN 3 /SAN) that exhibited superior enzymatic activity compared to symmetric Fe-N 4 /SAN. The low electronegativity of Si elongates the Fe-N bonds, optimizing oxygen intermediate adsorption/desorption. Density functional theory calculations revealed that asymmetric coordination facilitated the activation of hydrogen peroxide and glutathione, thus confirming its enhanced catalytic activity.