Extracellular vesicles in osteoimmunomodulation: Orchestrating immune-driven bone regeneration

Large bone fractures pose a substantial challenge to orthopedists and place a significant burden on patients and healthcare systems, necessitating innovative therapeutic strategies. Modulating the interactions between the immune and skeletal systems within the bone microenvironment offers a promising avenue. The immune system plays a role in regulating bone homeostasis and healing, and conversely, skeletal cells influence immune responses. Maintaining a balanced relationship between immune and bone cells is critical for successful fracture repair, as its disruption can lead to excessive inflammation and impaired bone healing. Extracellular vesicles (EVs) are key mediators of the intercellular communication occurring during bone fracture healing, playing a vital role in modulating the immune response. They influence inflammation, regulate immune cell function, and mediate the interactions between immune and bone cells. This review explores the role of immune cells in bone regeneration, with a particular focus on the immunomodulatory function of EVs during fracture repair. Furthermore, it highlights recent advancements in bioengineering approaches aimed at accelerating the translation of EVs for bone repair. Taken together, osteoimmunomodulatory EVs hold immense promise to fundamentally transform regenerative orthopedics, establishing them as the smart, nanotherapeutic frontier capable of turning chronic non-unions into predictable healing outcomes.