Engineered extracellular vesicles for bone therapy

Extracellular vesicles, which are secreted by living cells and play a critical role in cellular communication, have emerged as a promising cell-free strategy in the treatment of many diseases. Recently, EVs are considered excellent delivery systems for various therapeutic agents, including nucleic acids, proteins, drugs, and nanomaterials, owing to their superior physiochemical stability and biocompatibility. Yet, drawbacks such as the the uncertain distribution, unfavorable therapeutic efficiency and low yields are still the primary obstacles that hinder the application of EVs in the clinical. An increasing number of studies show that EVs can be "internally" engineered via cargo loading and "externally" engineered via surface modification to track their distributions, obtain scalable production and improve bone-targeting capacity for bone therapy. Herein, we provide a brief overview of the present applications and therapeutic mechanism of EVs for bone-related diseases. Thereafter, a comprehensive overview of methodological advances made recently in internally and externally engineering EVs is presented. Moreover, the potential applications of modified EVs are discussed by presenting prominent examples for the treatment of osteoarthritis, osteoporosis, and bone fracture and defects, as well as the prospective engineering approaches to address these issues.