Biomimetic synthesis and optimization of extracellular vesicles for bone regeneration.

Critical-size bone defect repair is in high demand but is difficult to treat. Modern therapies, such as autograft and cell-based treatments, face limitations, including potential immunological rejection and tumorigenesis. Therefore, extracellular vesicle (EV)-based strategies have been proposed as a novel approach for tissue regeneration owing to EVs' complex composition of lipids, proteins, and nucleic acids, as well as their low immunogenicity and congenital cell-targeting features. Despite these remarkable features of EVs, biomimetic synthesis and optimization of natural EVs can lead to enhanced bioactivity, increased cellular uptake, and specific cell targeting, aiming to achieve optimal therapeutic efficacy. To maximize their function, these nanoparticles can be integrated into bone graft biomaterials for superior bone regeneration. Herein, we summarize the role of naturally occurring EVs from distinct cell types in bone regeneration, the current strategies for optimizing biomimetic synthetic EVs in bone regeneration, and discuss the recent advances in applying bone graft biomaterials for the delivery of EVs to bone defect repair. We focused on distinct strategies for optimizing EVs with different functions and the most recent research on achieving time-controlled release of nanoparticles from EV-loaded biomaterials. Furthermore, we thoroughly discuss several current challenges and proposed solutions, aiming to provide insight into current progress, inspiration for future development directions, and incentives for clinical application in this field.