Dynamic protein hydrogel with supramolecularly enveloped kartogenin promotes cartilage regeneration through mitochondrial activation

Limited self-renewal potency of cartilage impedes the repair and regeneration at the site of damage. Investigating small-molecule compounds to boost chondrogenesis has yielded the dawn. However, the durability and targeting of current drug delivery and the adaptive integration for cartilage defects are not addressed. Herein, we fabricated a dynamic hydrogel based on the coordination between metal ions and collagen and then supramolecularly enveloped with a chondro-inductive factor kartogenin (KGN) via cyclodextrin (CD). The self-recovery and injectability of dynamic hydrogel enabled minimally invasive and precise treatment of cartilage injury assisted by continuous KGN administration. The hydrogel could significantly promote the expression of cartilage matrix components (type II collagen and aggrecan) in articular chondrocytes without affecting cell proliferation or migration in vitro. Mechanistically, the protective effects depended on enhancing chondrocyte mitochondrial function and intracellular antioxidant properties. In situ hydrogel injection strengthened cartilage regenerative potential and facilitated the reconstruction of subchondral bone following full-thickness defects in vivo. This study revealed that the dynamic chondrogenic hydrogel could benefit cartilage repair via mitochondrial reinforcement, acting as a novel therapeutic strategy for refractory cartilage damage.