Injectable photo-crosslinkable GelMA hydrogel incorporating quercetin@Zif-8 nanocarriers for osteoimmunomodulation and bone regeneration

Injectable Que@ZIF-8/Gel hydrogel offers structural support and sustained quercetin release. • The hydrogel demonstrates pro-osteogenic, pro-angiogenic, antioxidant, and immunomodulatory effects. • It enables effective bone regeneration in rat calvarial defects, showing clinical promise. Effective bone regeneration demands biomaterials that provide mechanical support and actively orchestrate osteogenesis, angiogenesis, and immune modulation. Here, we engineered an injectable, photo-crosslinkable hydrogel by integrating quercetin-loaded Zif-8 nanoparticles within a GelMA matrix (Que@Zif-8/Gel). This composite exhibited tunable mechanics, sustained drug release, and favorable physicochemical properties. In vitro, Que@Zif-8/Gel supported BMSC adhesion, proliferation, and osteogenic differentiation without cytotoxic or hemolytic effects. It also enhanced endothelial migration and tube formation, attenuated LPS-induced oxidative stress, and directed macrophages toward a reparative M2 phenotype characterized by elevated IL-10 and reduced TNF-α. In a rat calvarial defect model, Que@Zif-8/Gel treatment promoted substantial new bone formation, improved mineral density and trabecular structure, and upregulated osteogenic markers including COL-1 and OPN. In summary, these findings establish Que@Zif-8/Gel as a multifunctional platform that integrates structural reinforcement with angiogenic, antioxidant, and immunoregulatory activities, offering strong translational potential for vascularized bone regeneration.