Engineering Asymmetric and Highly Exposed Fe Single‐Atom Nanozymes for siMMP13 Delivery and Ferroptosis Inhibition in Osteoarthritis Therapy
Abstract
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.
Article Details
Authors (16)
Ji Luo
Feiying Yin
Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Collaborative Innovation Centre of Regenerative Medicine and Medical Bioresource Development and Application Co‐Constructed by the Province and Ministry Guangxi Key Laboratory of Regenerative Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
Yuan Liang
Yuting Ye
Shihui Xiao
Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Collaborative Innovation Centre of Regenerative Medicine and Medical Bioresource Development and Application Co‐Constructed by the Province and Ministry Guangxi Key Laboratory of Regenerative Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
Jianfeng Guo
Jianhui Xiang
Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Collaborative Innovation Centre of Regenerative Medicine and Medical Bioresource Development and Application Co‐Constructed by the Province and Ministry Guangxi Key Laboratory of Regenerative Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
Guanhua Li
Xin Yang
Jiejia Deng
Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Collaborative Innovation Centre of Regenerative Medicine and Medical Bioresource Development and Application Co‐Constructed by the Province and Ministry Guangxi Key Laboratory of Regenerative Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
Junxu Yang
Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Collaborative Innovation Centre of Regenerative Medicine and Medical Bioresource Development and Application Co‐Constructed by the Province and Ministry Guangxi Key Laboratory of Regenerative Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
Zhengtian Li
Jinmin Zhao
Li Zheng
Dizal Pharmaceutical, Shanghai
Kelong Fan
Jingping Zhong
Guangxi Engineering Center in Biomedical Material for Tissue and Organ Regeneration Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Coconstructed By the Province and Ministry Guangxi Key Laboratory of Regenerative Medicine The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi P. R. China