Synthetically Engineered Bacterial Extracellular Vesicles and IL-4-Encapsulated Hydrogels Sequentially Promote Osteoporotic Fracture Repair

Osteoporosis (OP) is a systemic disease characterized by decreased bone density and quality, leading to fragile bones and osteoporotic fractures (OPF). Conventional treatments for OPF often exhibit limited therapeutic efficacy and significant side effects. Synthetic biology-based bacterial extracellular vesicles (BEVs) offer a safe and effective alternative for OPF treatment. Here, we constructed bioengineered BEVs loaded with pBMP-2-VEGF (BEVs-BP) and encapsulated them together with IL-4 in GelMA hydrogels to form IL-4/BEVs-BP@GelMA. Initially, IL-4 alleviated chronic inflammation by modulating immune cells, while BEVs-BP subsequently enhanced osteogenesis and vascularization by upregulating BMP-2 and VEGF expression. <i>In vitro,</i> IL-4/BEVs-BP@GelMA polarized M1 macrophages toward the M2 phenotype, enhanced osteogenesis, and increased angiogenesis. Moreover, BEVs-BP effectively promoted the maturation and mineralization of bone organoids <i>in vivo</i>. Finally, IL-4/BEVs-BP@GelMA successfully accelerated osteoporotic fracture repair in mice. In summary, we developed an easy-to-build and powerful bone repair biomaterial, IL-4/BEVs-BP@GelMA, which offers a therapeutic strategy for osteoporotic fracture management.