Functional extracellular vesicles enable injectable hydrogels with stable osteogenic properties for minimally invasive bone defect repair

The clinical use of bone morphogenetic protein 2 (BMP2) is limited by supraphysiological dosing requirements, which can cause adverse effects such as heterotopic ossification and radiculitis. To address this, we developed a cell-free delivery system using BMP2-enriched extracellular vesicles (BMP2-EVs) derived from mesenchymal stem cells engineered via adenoviral transduction. The BMP2-EVs were thoroughly characterized and combined with an injectable collagen hydrogel for sustained release. In vitro, BMP2-EVs significantly enhanced osteogenic differentiation and mineralized nodule formation in MSCs, while the hydrogel showed high biocompatibility (> 92% cell viability) and prolonged BMP2 retention (61% after 14 days). In a mouse femoral defect model, the BMP2-EVs/hydrogel system effectively promoted bone regeneration following minimally invasive injection. This strategy enables localized and sustained BMP2 delivery, mitigates burst release, reduces side effect risks, and presents a clinically promising approach for bone repair.