Exosomes as Cellular Communicators and Therapeutic Agents in Orthopedic Diseases: From Mechanisms to Intervention.

Exosome-mediated intercellular communication has become a critical mechanism in the pathogenesis, progression, and regenerative repair of orthopedic diseases. By delivering bioactive molecules, exosomes dynamically regulate bone remodeling, cartilage homeostasis, and inflammatory responses-processes that are commonly disrupted in conditions such as osteoporosis, osteoarthritis, and bone non-union. Current therapeutic approaches often fail to achieve complete tissue repair or reverse disease progression, representing a major clinical challenge in orthopedics. This systematic review examines how exosome secretion, cargo loading, and cellular uptake are modulated by physical, chemical, biological, and pharmacological factors, thereby influencing disease progression and tissue repair. Furthermore, we evaluate the translational potential of engineered exosomes as targeted therapeutic strategies and analyze the dual dilemmas currently faced in exosome research and clinical translation: on one hand, exosomes themselves encounter technical bottlenecks such as standardization of isolation, drug-loading efficiency, large-scale production, and targeted delivery; on the other hand, their clinical application remains limited by unclear in vivo metabolic mechanisms, lack of efficacy evaluation systems, and insufficient clinical validation. Overcoming these challenges will be essential to advancing the real-world clinical application of exosomes in orthopedics.