Synergistic effects of cerium-containing bioactive glasses and apoptotic extracellular vesicles alleviate bisphosphonate-related osteonecrosis of jaw

Bisphosphonates (BPs) are commonly used to treat skeletal diseases. However, long-term use of BPs can lead to BP-related jaw bone necrosis (BRONJ), particularly in patients undergoing tooth extraction surgery. The treatment of BRONJ remains challenging due to the local inflammatory microenvironment. To address this issue, we developed catechol-conjugated chitosan-based hydrogels incorporating cerium-doped mesoporous bioactive glass nanoparticles (Ce-MBGNs) and apoptotic extracellular vesicles (ApoEVs). The hydrogels containing 1 wt % Ce-MBGNs demonstrated biodegradability and non-cytotoxicity. The incorporation of Ce-MBGNs did not significantly impact gelation and rheological behavior. By leveraging the effects of Ce-MBGNs on regulating macrophage polarization and ApoEVs on mediating macrophage chemotaxis, hydrogels containing 1 wt % Ce-MBGNs and 1 mg/mL ApoEVs were able to recruit inflammatory macrophages and promote their M2 polarization. The in vivo experiments using a Zometa (ZA)-induced mice BRONJ model revealed that the synergistic effects of Ce-MBGNs and ApoEVs enhanced M2 polarization while reducing M1 polarization. This resulted in improved mucosal healing, bone regeneration, and alleviation of osteonecrosis. Overall, our study offers a new strategy for BRONJ therapy by addressing the inflammatory environment. Catechol-conjugated chitosan-based hydrogels containing Ce-MBGNs and ApoEVs have demonstrated impressive potential in the alleviation of BRONJ.