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.