Engineering Asymmetric and Highly Exposed Fe Single‐Atom Nanozymes for siMMP13 Delivery and Ferroptosis Inhibition in Osteoarthritis Therapy

ABSTRACT Ferroptosis, driven by redox imbalance, plays a critical role in osteoarthritis (OA) progression. Although antioxidant nanozymes hold therapeutic potential, designing highly efficient and targeted systems to inhibit ferroptosis remains challenging. Here, we developed a 2D nitrogen‐doped graphene‐like nanomesh (NGM) loaded with asymmetric and highly exposed Fe single atoms, carried with the cartilage‐targeting WYRGRL peptide and siRNA (siMMP13) to form Fe SAzymes (si‐FeSA/NGM‐W) as ferroptosis inhibitors to alleviate OA. By mixed molten salt and Zn removal, exfoliating Zn‐ZIF into an ultrathin 2D hierarchical porous NGM with topological defects and hierarchical structure, we created a scaffold for anchoring asymmetric and highly exposed Fe single atoms. The abundant Fe‐N 4 ‐Cl coordination active sites then introduce strain and defects, which facilitate electron transfer, enhance radical adsorption, and lower reaction barriers, thereby augmenting multi‐enzyme (SOD/CAT/GPx) activities. This enables the functionalized si‐FeSA/NGM‐W to target cartilage, where it inhibits ferroptosis by downregulating MMP13, upregulating GPX4, restoring mitochondrial function, and modulating inflammation, ultimately achieving targeted OA therapy. Mechanistically, this process involves suppression of the IL‐17 pathway and enhancement of glutathione metabolism. This work presents a targeted nanozyme platform for precise OA therapy via ferroptosis inhibition.