Extracellular vesicles from adipose-derived stem cells in bone regeneration: Mechanisms and therapeutic advances

Abstract

Extracellular vesicles (EVs) secreted by adipose-derived stem cells (ADSCs) have emerged as a promising cell-free therapeutic tool for bone regeneration. These EVs deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, thereby modulating the bone microenvironment, activating key signaling pathways, and promoting bone regeneration. Innovative strategies involving preconditioning, genetic modification, and biomaterial-assisted delivery have been explored, with preclinical studies demonstrating synergistic effects that enhance targeting specificity and therapeutic efficacy. Functionally, EVs derived from ADSCs promote osteogenesis by enhancing osteoblast and mesenchymal stem cell activity, support angiogenesis through vascular endothelial growth factor signaling, and modulate inflammation by shifting macrophages from pro-inflammatory to anti-inflammatory phenotypes. In disease-specific contexts, they reduce cartilage degradation and support subchondral bone restoration in osteoarthritis, while in osteoporosis, they help restore the balance between bone formation and resorption and mitigate bone loss. Despite these promising developments, challenges remain in standardizing production protocols, optimizing delivery systems, and confirming long-term safety and efficacy in clinical settings. This review summarizes current insights into the mechanisms of EVs derived from ADSCs in bone-related diseases and highlights recent innovations and future directions that may accelerate their clinical application as a regenerative therapy.

Keywords: Adipose-derived stem cell; Bone regeneration; Extracellular vesicle; Fracture healing; Osteoarthritis; Osteoporosis; Therapeutic mechanism.

Figure 1

Translational strategies of adipose-derived stem cell-derived extracellular vesicles in therapeutic use. Adipose-derived stem cell-derived extracellular vesicles (EVs) are optimized through three core strategies to enhance their therapeutic efficacy. Biological or physical preconditioning of adipose-derived stem cells, including osteogenic induction, inflammatory priming with cytokines, pulsed electromagnetic field stimulation, and others, refines the regenerative capacity of secreted EVs. Genetic and pharmacological engineering strategies, such as microRNA overexpression, curcumin loading, surface modification with Cys-Arg-Glu-Lys-Ala peptide or biotin-avidin systems, and additional approaches, modulate EV cargo and targeting ability. Biomaterial-assisted delivery, via platforms like poly-lactic-co-glycolic acid/polydopamine scaffolds, decellularized extracellular matrix hydrogels, injectable gelatin-nanoparticle hydrogels, and more, improves EV retention and release kinetics at defect sites. These optimized EVs collectively contribute to bone regeneration, supporting their application in preclinical models and potential translation to clinical settings. Created in BioRender (Supplementary material). ADSC: Adipose-derived stem cell; ADSC-EVs: Adipose-derived stem cell-derived extracellular vesicles; PLGA: Poly-lactic-co-glycolic acid; PDA: Polydopamine; 3D: Three-dimensional.