Bone-targeted bioengineered bacterial extracellular vesicles delivering siRNA to ameliorate osteoporosis

Osteoporosis (OP), characterized by decreased bone mass and destruction of bone microarchitecture, is the most common bone degenerative disease. Conventional treatments for OP have several side effects, new treatment approaches are needed. Bacterial extracellular vesicles (BEVs) carrying curative molecules have emerged as a promising alternative due to their unique nanosized structures, stable loading capacity, good biocompatibility, ease of modification, and industrialization. In this study, we modified probiotics Escherichia coli Nissle 1917 (ECN) to overexpress hCXCR4 fused with the ClyA on the membrane surface of BEVs. The bone targeted BEVs took advantage of the intrinsic anti-OP function and loaded with SOST siRNA to generate BEVs-hCXCR4-SOST siRNA (BEVs-CSs). The customized BEVs-CSs have exhibited great bone targeting ability without long-term cytotoxicity. In addition, the bioengineered BEVs-CSs can be internalized by bone marrow mesenchymal stem cell and promote their osteogenic differentiation with significant cytocompatibility. Finally, the bifunctional BEVs-CSs successfully reversed the OP in an ovariectomized mouse model. Taken together, such a bioengineered BEVs-based strategy provides an innovative, safe, efficient and promising therapeutic solution for intractable OP treatment.