Nanoparticle-mediated co-delivery of resveratrol and Mg2+ in an injectable hydrogel for multi-targeted repair of osteoporotic bone defects

For osteoporotic bone defects—characterized by excessive reactive oxygen species (ROS) and impaired regenerative capacity—we developed a multifunctional OCS-MSN@Res/Mg 2+ system: Scaffold fabrication: Sodium alginate (SA), silk fibroin (SF), and carboxymethyl chitosan (CMCS) were cross-linked via Schiff base (−C N–) and methacrylate (MA) groups to construct the OCS scaffold. Nanoparticle loading: Resveratrol (Res) was complexed with Mg 2+ , coated onto mesoporous silica nanoparticles (MSN) to form MSN@Res/Mg2 + , and subsequently embedded within the OCS matrix. In vivo efficacy: Following minimally invasive UV-cured in situ injection, the system exerts synergistic therapeutic effects: Efficiently scavenges ROS and activates the Nrf2 signaling pathway, enhancing antioxidant defense and promoting osteoblast proliferation; Modulates the inflammatory microenvironment and stimulates angiogenesis; Significantly accelerates bone regeneration in femoral defects of osteoporotic rats. • The novel scaffold enables efficient targeted drug release in bone tissue. • The scaffold enhances the antioxidant capacity by activating the Nrf2/HO-1 pathway. • The scaffold regulates the immune microenvironment. • This study provides a strategy to promote bone defect regeneration in osteoporosis. Osteoporotic bone defects pose significant challenges for repair due to the excessive accumulation of reactive oxygen species (ROS) and an imbalance in bone regeneration. In this study, we developed a multifunctional delivery system named OCS-MSN@Res/Mg 2+ , which integrates mesoporous silica nanoparticles (MSN) with a sodium alginate/oxidized carboxymethyl chitosan/silk fibroin composite scaffold (OCS). By forming a complex of Resveratrol (Res) with magnesium ions (Mg 2+ ) and subsequently coating it onto MSN particles, followed by embedding them into the OCS scaffold, the system achieves a coordinated controlled release of antioxidants and osteogenic metabolic promoters. In vitro experiments demonstrated that the system can efficiently scavenge ROS, activate the Nrf2/HO-1 pathway to enhance antioxidant defense mechanisms, regulate macrophage polarization toward an anti-inflammatory phenotype, promote osteogenic differentiation of Osteogenic cells (MC3T3-E1), and stimulate angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, in vivo studies confirmed that this system significantly accelerates femoral defect regeneration in osteoporotic rats. Through its multi-effect synergy involving antioxidation, anti-inflammation, and osteogenesis, this innovative system not only optimizes the bone microenvironment but also enhances regenerative capacity. It provides a promising strategy with significant potential for clinical translation in the precise treatment of osteoporotic bone defects.