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

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-N₄-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.