BMP2 enhance the osteogenic effect of BMSCs-derived exosomes in skull defect of diabetic rats

• BMP2-Exos enhance osteogenesis and reduce inflammation in diabetic bone repair. • GelMA hydrogel with BMP2-Exos provides a sustained-released effect, which boosts bone regeneration in diabetic rats. • BMP2-Exos promote BMSC osteogenesis via the PI3K/AKT pathway. Diabetic patients often face poor repair of bone defects, which may be related to the reduced osteogenic capacity of bone marrow mesenchymal stem cells (BMSCs) and the polarization of M1/M2 macrophage imbalance leading to an inflammatory response. The ability of BMSC-derived exosomes (BMSC-Exos) and BMP2 to exert both bone tissue regeneration and immunomodulation is expected to resolve this clinical dilemma. In this study, we demonstrate that exosomes derived from BMP2-treated BMSCs (BMP2-Exos) in a diabetic microenvironment exhibit enhanced osteogenic effects. Additionally, compared to the blank control group, macrophages stimulated by BMP2-Exos were more polarized towards the M2 type. These results were verified in vivo by GelMA loaded exosomes in the diabetic rat skull defect model. Importantly, we found that BMP2-Exos can upregulate the PI3K/AKT signaling pathway in diabetic BMSCs and improved osteogenic function and M2 macrophage polarization in diabetes-impaired BMSC-Exos in vitro. In conclusion, the present study revealed that BMP2 pretreatment can enhance the ability of BMSC-Exos to promote osteogenesis in diabetic bone defect areas, provides a preliminary exploration of the underlying mechanisms. Our study provided important experimental basis and innovative ideas for the application of exosomes therapy in the field of bone tissue regeneration.