Spatiotemporal delivery of exosomes and alendronate orchestrates osteoblastic and osteoclastic activity for osteoporotic bone regeneration.

The treatment of bone defects in osteoporotic (OP) patients remain a significant clinical challenge. The most important and challenging task is to promote sufficient bone formation in the early stage and effectively inhibit bone resorption all period of bone healing. Unfortunately, the efficacy of current strategies falls short of meeting this requirement. In this study, we developed a dual-delivery system that allows spatiotemporal release of bone marrow stem cell-derived exosomes (BMSC-Exo) and alendronate (Aln) by core-shell nanofiber to match the spatiotemporal dynamics of bone healing and effectively treat OP bone defects. Core-shell polycaprolactone/polyvinyl alcohol (P/PVA) nanofibers were fabricated through coaxial electrospinning, incorporating Aln within the core layer and BMSC-Exo functionalized onto the surface of nanofiber via chemical modification with polyethyleneimine (PEI). Physicochemical characterization confirmed the successful fabrication of PEI@P/PVA-Aln nanofibers, which exhibited excellent mechanical strength (22.77 MPa), hydrophilicity (9.66°), and enabled the spatiotemporal release of BMSC-Exo and Aln. In vitro experiments showed that Exo-PEI@P/PVA-Aln scaffold effectively promoted osteogenic differentiation by miR-486 in the BMSC-Exo through regulation of the PTEN/AKT signaling axis and significantly reduced osteoclastic differentiation. Under a rat OP cranial defect model, the Exo-PEI@P/PVA-Aln scaffold demonstrated substantially enhanced bone repair efficiency after 4 and 10 weeks. To conclude, our results showed that the dual delivery of BMSC-Exo and Aln with spatiotemporal release orchestrates osteoblastic and osteoclastic activity, providing a potential strategy to facilitate the regeneration of OP bone defects.