Bio-functional immunomodulatory europium-doped hydroxyapatite nanorods for osteochondral repair via CDH5-RAS-RAF-MEK-ERK-CSF1 axis

Osteoarthritis (OA) remains an unsolved clinical problem characterized by cartilage degradation and subchondral bone remodeling. Most studies have focused on cartilage lesions, while rare effective strategies have been developed to reconstruct osteochondral defects simultaneously. Moreover, cartilage regeneration under inflammatory conditions is even more limited. M1/M2 macrophage imbalance has been demonstrated to be a crucial player in the inflammatory microenvironment. Accordingly, immunoregulation during OA progression may be a promising method to create a favorable microenvironment for the efficient repair of cartilage and subchondral bone lesions. Herein, we developed new europium (Eu)-doped hydroxyapatite (HAp) nanorods that could simultaneously mediate the differentiation of chondrocytes and BMSCs to facilitate both cartilage and subchondral bone regeneration. Innate immunity participates in Eu-HAp-mediated tissue regeneration, and a comprehensive CDH5-RAS-RAF-MEK-ERK-CSF1 axis is critical in the crosstalk between biomaterials, immune cells, and effector cells. The GelMA/Eu-HAp nanocomposite hydrogel system is first successfully fabricated, and the treatment outcome in an osteochondral defect model is confirmed. Overall, our findings uncover the positive regulation of Eu-HAp nanorods in cartilage-related lesions by inhibiting inflammation and creating a regenerative microenvironment. This study may inspire the concept of developing next-generation nanomaterials with ion-doping properties and provide novel insight for treating compound defects in inflammatory diseases.