Closed-loop iron chelate recycling via molecularly imprinted hydrogels suppresses ferroptosis

Ferroptosis, an iron-dependent form of oxidative cell death, has emerged as a key driver of osteoarthritis, yet therapeutic strategies remain limited by the inability to safely eliminate iron–chelate complexes after treatment. Their local accumulation can lead to secondary iron release, oxidative stress, and sustained tissue damage. This study presents a hydrogel-based system that enables selective recognition and removal of these complexes through engineered molecular “memory” sites. By encoding the structural features of iron–chelate complexes into the hydrogel network, this system captures and clears them after cellular export, thereby preventing their re-entry and uncontrolled degradation. This approach markedly improves the efficiency and specificity of complex removal compared to non-imprinted materials. In cell and animal models, it restores iron balance, suppresses ferroptosis, and protects cartilage integrity. These findings establish a closed-loop strategy for regulating iron homeostasis and highlight a generalizable materials-based framework for treating iron-driven degenerative diseases. Iron overload can drive cartilage damage in osteoarthritis. Here, authors develop molecularly imprinted hydrogel microspheres that capture iron-chelate complexes, alleviating ferroptosis, inflammation and cartilage degeneration.