Two decades of regenerative medicine have brought progress, yet complex fractures, sports injuries, and degenerative bone disorders still often result in non-union, osteoporosis, or infection. Extracellular vesicles (EVs) are gaining traction as an alternative to cell therapies, sidestepping issues like limited cell sources, side effects, and the need for invasive procedures. Their biocompatibility, strong cargo capacity, and roles in intercellular signaling allow EVs to modulate inflammation, angiogenesis, and osteogenesis. Their bioactive cargo, which includes miRNAs, lncRNAs, and proteins, influences major pathways such as Wnt/β-catenin, BMP/Smad, PI3K/Akt, and MAPK, coordinating osteoblast differentiation, vascularization, and immune responses. Rapid blood clearance and uncontrolled release, however, limit their therapeutic efficacy. Nanotechnology addresses these limitations through surface engineering, cargo loading, and nanostructured platforms. This review covers recent advances in controlled release, osteoimmunology, compromised microenvironments, process control, and AI applications for characterization, design, and data analysis. We also discuss strategies to engineer EVs and biomaterials for better retention, vascularization, osteogenesis, and immune homeostasis. Finally, we consider key translational barriers: heterogeneity, inconsistent isolation, lack of quantification standards, limited large-animal models, and GMP requirements.