Study on VEGFA mRNA delivery via GelMA hydrogel-encapsulated extracellular vesicles for enhanced bone regeneration

Bone regeneration remains a clinical challenge due to the inherent limitations of conventional grafts and synthetic materials. While mRNA-based strategies offer promising therapeutic potential, their clinical application is hindered by systemic delivery barriers and rapid degradation. Here, we present a hybrid extracellular vesicle (EV)-GelMA hydrogel system for the localized delivery of VEGFA mRNA to enhance both angiogenesis and osteogenesis through precise spatiotemporal control. <i>In vitro,</i> the VEGFA-EVs-GelMA system significantly enhanced migration and osteogenic differentiation of pre-osteoblastic cells, as evidenced by upregulation of ALP, RUNX2, and OPN expression compared to GelMA controls. In a rat cranial defect model, the VEGFA-EVs-GelMA group showed a marked increase in bone volume/total volume (BV/TV), supported by microcomputed tomography (Micro-CT), at both 4 and 8 weeks post-implantation. Mechanistically, this dual-component platform leverages the biomolecular protection and targeted delivery afforded by EVs, together with the tunable release properties of GelMA hydrogels, to overcome key mRNA delivery barriers. Our results highlight the potential of this system as a clinically translatable strategy for promoting vascularized bone regeneration and provide new insights for the treatment of complex bone defects.