An Attack and Defense Strategy for Osteoarthritis Repair: Constructing a Trace Element Modulated Hydrogel to Mitigate...

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 Fe²⁺-capturing (attack) nanocatalysts and selenium-enriched (defense) polypeptides (selenomethionine [SeMet]) into a hydrogel platform. Polyvinylpyrrolidone-assembled magnesium hexacyanoferrate (MgHCF) nanoparticles enabled efficient Fe²⁺ 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.