β‐Diketone Functionalized Microspheres Chelate Reactive Iron via Metal Coordination for Cartilage Repair

Excessive intracellular iron accumulation can induce mitochondrial dysfunction, leading to chondrocyte ferroptosis, a key contributor to cartilage damage in osteoarthritis (OA). Here, micelle-microfluidic hydrogel microspheres, featuring keto-enol-thiol bridged nano-sized secondary structures that disintegrate within the intracellular peroxidative environment to reveal β-diketone groups with metal chelation capabilities, are utilized for the in situ removal of reactive iron, thereby facilitating cartilage repair through the restoration of mitochondrial homeostasis. The relevant experiments demonstrate that the microspheres reduce iron influx by downregulating transferrin receptor (TfR1) expression and decrease mitochondrial iron uptake by upregulating mitochondrial outer membrane iron-sulfur cluster protein (CISD1), thus restoring intracellular mitochondrial iron homeostasis. Furthermore, the antioxidant properties of the ketone-thioether segments synergistically mitigate chondrocyte phospholipid peroxidation via Nrf2/SLC7A11/GPX4 axis, inhibiting ferroptosis and slowing OA progression. In summary, this system that in situ sustainably chelates reactive iron via metal coordination exhibits great potential in the minimally invasive treatment of OA and other ferroptosis-mediated diseases.