A multifunctional neuromodulation platform utilizing Schwann cell-derived exosomes orchestrates bone microenvironment via immunomodulation, angiogenesis and osteogenesis.

Recent evidence highlights multifaceted biological needs to recapitulate the bone microenvironment for bone regeneration. Neurotization has great potential for realizing multi-system modulations in bone tissue engineering (BTE). However, a neural strategy involving all the key bone repair steps temporally has not yet been reported. In this study, we reported the neural tissue engineering hydrogel-encapsulated Schwann cell-derived exosomes (SC Exo). This sustained-release SC Exo system prominently enhanced bone regeneration by promoting innervation, immunoregulation, vascularization, and osteogenesis in vivo. Moreover, the in vitro results further confirmed that this system significantly induced M2 polarization of macrophages, tube formation of HUVECs, and BMSCs osteogenic differentiation. Furthermore, BMSCs osteogenesis was promoted by upregulating the TGF-β1/SMAD2/3 signaling pathway. In summary, a novel cell-free and easily prepared SC Exo neural engineering was successfully developed to promote bone regeneration by orchestrating the entire bone healing microenvironment, which may provide a new strategy for tissue engineering and clinical treatment of bone defects.