Roles of extracellular vesicles in pathogenesis and treatment of osteoporosis and their functionalized delivery strategies

Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and disrupted bone microarchitecture, representing a major cause of disability and diminished quality of life among middle-aged and older adults while imposing a substantial socioeconomic burden worldwide. Extracellular vesicles (EVs) are membrane-bound nanoparticles that mediate intercellular communication by transferring proteins, lipids, and nucleic acids between cells. In the skeletal system, EVs participate in multiple stages of bone remodeling by promoting osteogenic differentiation, inhibiting osteoclast formation and function, and regulating angiogenesis, making them promising candidates for osteoporosis therapy. Nevertheless, the therapeutic application of native EVs is restricted by rapid clearance after administration and limited bone-targeting efficiency. Recent advances in EV engineering have provided new opportunities to address these limitations. This review summarizes the biological characteristics of EVs and discusses their regulatory roles in the bone microenvironment. It further focuses on emerging strategies for EV-based osteoporosis therapy, including donor-cell preconditioning to improve the biological activity of native EVs, cargo engineering and surface modification to enhance therapeutic efficacy and bone-targeting capability, and the combination of engineered EVs with biomaterial platforms such as hydrogels and three-dimensional printed scaffolds to construct delivery systems that enable localized retention, controlled release, and synergistic tissue repair. Finally, the current challenges associated with EV-based therapeutics and the prospects for their clinical translation are discussed. This review provides a theoretical basis and research perspective for the development of effective and safe cell-free bone regeneration therapies.