Hypoxia-triggered exosome-mimetics accelerate vascularized osteogenesis

Angiogenesis plays a pivotal role in tissue development and regeneration, but few safe and efficient pro-angiogenic factors are available for long-term clinical therapy. Although stem cell-derived exosomes exhibit excellent biocompatibility and considerable pro-angiogenic capacity, their low yield extremely limits their clinical potential. Exosome-mimetics (EMs) employ similar features to exosomes and can be produced in a higher yield. In this study, the HY-EMs were produced to enhance in vitro and in vivo pro-angiogenic ability from hypoxia-preconditioned bone marrow mesenchymal stem cells (BMSCs) using a serial extrusion method. The yield of EMs was over 10 times greater than that of exosomes. Furthermore, compared with the EMs group, the tube number of human umbilical vein endothelial cells (HUVECs) in vitro doubled in the HY-EMs treated group, and the number of blood vessels increased by 186% in subcutaneously implanted scaffold with HY-EMs. More importantly, the HY-EMs effectively promoted vascularized osteogenesis in a critical-sized cranial defect model, with the new bone volume and vessel number in regenerated bone increased to 120% and 175%, respectively. Consequently, our current work provides a promising strategy to customize and mass-produce functional EMs for vascularized osteogenesis.