Multifunctional neuroimmunoregulatory nanoenzyme-enhanced hydrogel promotes bone regeneration by improving bone healing microenvironment

Despite advancements in bone substitute materials for promoting osteogenic activity and angiogenesis, achieving optimal bone regeneration remains challenging due to the complexity of the biological processes involved. An ideal bone healing strategy should integrate multiple biological needs in bone microenvironment, such as innervation, immune regulation, angiogenesis and osteogenesis, and achieve dynamic regulation and promote healing through the interaction of osteocytes, osteogenic factors and biomaterials. In the present study, we investigates a bone regeneration strategy based on bioactive glass (BG)-pretreated extracellular vesicles (EVs) encapsulated within a CeO2-SW033291 (CeO2-SW) hydrogel. BG stimulation enhances EVs stability and functionality, promoting anti-inflammatory and bone regenerative capabilities. CeO2 nanoparticles have antioxidant properties and, when combined with SW033291, can increase PGE2 levels to mediate sensory nerves to control bone homeostasis and promote bone healing. The resulting hydrogel, BEV/CeO2-SW@Gel, demonstrates improved biocompatibility, angiogenesis, osteogenic differentiation, and nerve immune regulation both in vitro and in a rat calvarial defect model. RNA sequencing reveals the hydrogel's potential to activate MAPK signaling, enhancing osteoblast function. These findings suggest BEV/CeO2-SW@Gel as a promising cell-free therapeutic for bone repair. This study provides a promising biomaterial with potential clinical application for the treatment of critical bone defects in the future.