已传文件：photo/1772413442.png
Ferroptosis is driven by redox imbalance and plays a key role in the progression of osteoarthritis (OA). Although antioxidant nanozymes have therapeutic potential, designing an efficient and targeted ferroptosis inhibition system remains challenging. We developed a two-dimensional nitrogen-doped graphene-like nanosheet (NGM), loaded with asymmetrical and highly exposed iron single atoms, and carrying cartilage-targeting WYRGRL peptides and siRNA (siMMP13), forming an ironzyme (si-FeSA/NGM-W) as a ferroptosis inhibitor to alleviate osteoarthritis. By using mixed molten salts and zinc removal, Zn-ZIF was exfoliated into an ultrathin two-dimensional hierarchical porous NGM structure with topological defects and hierarchical structure, creating a scaffold for anchoring asymmetrical and highly exposed iron single atoms.The abundant Fe‐N4‐Cl coordinated active sites introduce strain and defects, promoting electron transfer, enhancing free radical adsorption, and lowering reaction barriers, thereby enhancing multi-enzyme (SOD/CAT/GPx) activity. This enables the functionalized si-FeSA/NGM-W to target cartilage, inhibiting ferroptosis by downregulating MMP13, upregulating GPX4, restoring mitochondrial function, and modulating inflammation, ultimately achieving targeted osteoarthritis therapy. Mechanistically, this process involves inhibiting the IL-17 pathway and enhancing glutathione metabolism. This work proposes a targeted nanoenzyme platform for precise OA treatment via ferroptosis inhibition.
Summary
The progression of osteoarthritis is closely related to ferroptosis within chondrocytes—accumulation of reactive oxygen species, depletion of glutathione, and inactivation of GPX4, ultimately leading to mitochondrial collapse and matrix degradation. A team from Guangxi Medical University and the Institute of Biophysics, Chinese Academy of Sciences, published a study in Advanced Materials. They used a mixed molten salt exfoliation strategy to convert a Zn-ZIF precursor into an ultrathin two-dimensional nitrogen-doped graphene nanonet, anchored asymmetrically coordinated Fe-N4-Cl single-atom sites on it, and then conjugated a cartilage-targeting peptide WYGRGL and MMP13 siRNA, constructing a multifunctional nanozyme named si-FeSA/NGM-W.
The brilliance of this structural design lies in the fact that the two-dimensional porous nanonetwork highly exposes single iron atoms, and the asymmetric coordination of Fe-N4-Cl induces lattice strain and defect enrichment, accelerating electron transfer and lowering reaction barriers. DFT calculations show that the d-band center of Fe shifts upward, enhancing hybridization with oxygen intermediates, which synergistically improves the activities of the three enzymes SOD, CAT, and GPx — enabling the conversion of superoxide anions into hydrogen peroxide, decomposition of hydrogen peroxide into water, and removal of hydroxyl radicals, effectively equipping chondrocytes with a complete antioxidant system. In vitro experiments show that 8 μg/mL of si-FeSA/NGM-W eliminates 64.5% of H₂O₂-induced reactive oxygen species, restores 91.7% of mitochondrial membrane potential, markedly suppresses the expression of IL-1β and MMP13, and boosts GPX4. Transcriptome sequencing reveals that this is due to inhibition of the IL-17 pathway and activation of glutathione metabolism.
Reference News:
DOI: 10.1002/adma.202520951
