Mechanobiology of Exosome-Mediated Regeneration: Mechanisms, Translational Advances, and Future Therapeutic Directions

Abstract

Chronic musculoskeletal pain remains a leading cause of disability worldwide, driven by progressive degeneration of cartilage, bone, tendon, intervertebral discs, and peripheral nerves. Conventional interventional approaches primarily address symptoms without restoring structural integrity or tissue homeostasis. Regenerative strategies, including platelet-rich plasma, mesenchymal stem cells, and biomaterials, have demonstrated potential but are limited by variability in outcomes, poor cellular survival, and lack of standardization. Exosomes and extracellular vesicles are key mediators of intercellular communication in tissue repair, reproducing many of the paracrine effects of parent cells while offering improved safety and scalability. These nano-sized vesicles regulate inflammation, angiogenesis, extracellular matrix remodeling, and cell survival across musculoskeletal and neural tissues. Importantly, growing evidence suggests that mechanical cues such as compression, shear stress, and tensile loading not only regulate cellular behavior but also shape exosome biogenesis, cargo composition, and functional effects through mechanotransduction pathways involving integrins, ion channels, and YAP/TAZ signaling. This mechanobiology–exosome interface is particularly relevant in interventional pain medicine, where therapeutics are delivered into mechanically active environments such as joints, discs, tendons, and perineural spaces. Mechanical loading conditions may therefore modulate therapeutic efficacy by shaping both endogenous repair processes and the behavior of administered exosomes. The present investigation reviews the current literature and knowledge on mechanotransduction pathways and exosome biology, with a focus on their intersection in musculoskeletal regeneration. We further examine preclinical and clinical evidence supporting exosome-based therapies in osteoarthritis, degenerative disc disease, tendon and ligament injuries, and neuropathic pain states, alongside key translational challenges including heterogeneity in exosome isolation, dosing, biodistribution, and clinical standardization. Finally, we discuss future directions in mechanobiology-guided exosome engineering and their potential integration into interventional pain practice.