An Attack and Defense Strategy for Osteoarthritis Repair: Constructing a Trace Element Modulated Hydrogel to Mitigate Ferroptosis and Promote Cartilage Matrix Reconstruction
Wenhui Hu, Fei Kang, Yuheng Li, Yixiang Xu, Xiaoming Li, Jing Zhang, Jie Liao, Jingjin Dai, Xiaoshan Gong, Jian‐Mei Li, Xuan Yao, Shiwu Dong
Abstract
Osteoarthritic cartilage tissue displays a characteristic imbalance in trace element metabolism closely associated with the production of oxidative stress. This study revealed the pivotal role of iron-overload-triggered and selenoprotein-catalyzed lipid peroxidation in osteoarthritis pathogenesis. Based on this discovery, we innovatively pioneered the integration of Fe 2+ -capturing (attack) nanocatalysts and selenium-enriched (defense) polypeptides (selenomethionine [SeMet]) into a hydrogel platform. Polyvinylpyrrolidone-assembled magnesium hexacyanoferrate (MgHCF) nanoparticles enabled efficient Fe 2+ chelation to counteract ferroptosis. SeMet utilization by the selenoprotein glutathione peroxidase 4 is required to prevent hydroperoxide-induced ferroptosis. Furthermore, a dynamically cross-linked network was constructed from oxidized hyaluronic acid (OHA) and hyaluronic acid–adipic acid dihydrazide (HA-ADH), enhanced by grafting SeMet onto the OHA chain and encapsulating MgHCF into the polymeric matrix. MgHCF@OHA/HA-ADH/SeMet hydrogels exhibited injectable, self-healing, and sustainable drug release capabilities. The platform promoted the anti-lipid peroxidation process and restored the mitochondrial homeostasis of chondrocytes under inflammatory stimulation via the phosphoinositide 3-kinase/Akt/forkhead box O1 pathway. In vivo investigations showed its anti-inflammatory activity, ferroptosis-inhibiting capacity, and ability to reverse cartilage degeneration. This work establishes a therapeutic paradigm based on trace element synergy, providing a translatable disease-modifying candidate.