Gene-activated engineered exosome directs osteoblastic differentiation of progenitor cells and induces vascularized osteogenesis in situ

Exosome as an advanced carrier has been extensively used in gene and drug delivery due to its excellent biocompatibility, efficient cell uptake and convenient targeted modification. Apart from the conventionally controlled release of bioactive molecules, some other exosome roles should be further explored. Herein, we report to construct a specifically gene-activated engineered exosome that not only can effectively modulate the gene release of the vascular endothelial growth factor 165 (VEGF165), but also can play a pivotal role in enhancing therapy in vascular bone regeneration. Our findings revealed that the transfection efficiency of the VEGF165 plasmid gene was extremely elevated via the exosome-based vector. Both alone exosomes and engineered exosomes exhibited a certain osteoblastic differentiation of precursor cells (MC3T3-E1) in vitro. More importantly, the engineered exosomes that internalized the VEGF165 gene combined with electrospun nanofiber films played a dual role in osteogenesis and angiogenesis based on the evaluation of a rat critical-sized calvarial defect model in vivo. Consequently, our current work creates a bifunctional engineered exosome-based biomaterial that can direct progenitor cell differentiation in vitro and promote the vascularized bone regeneration in vivo, extending exosome applications from simple biomolecular carriers to exosome-enhanced therapy.