Exosome-Based Therapeutics for Musculoskeletal Disorders: Advances in Engineering, Targeting, and Biomaterial Integration.

Musculoskeletal disorders represent an escalating global challenge that adversely affects both the quality of life and healthcare systems. Despite the availability of conventional therapeutic approaches, these methods are constrained by inadequate targeting, limited tissue regeneration capabilities, and potential long-term safety concerns. In recent years, exosomes have emerged as promising agents for precise intervention and functional regeneration, owing to their properties of active targeting, cargo delivery capability, modifiability, and biocompatibility, particularly when used in conjunction with engineering and biomaterial delivery strategies. While the therapeutic potential of exosomes in the management of musculoskeletal diseases is increasingly acknowledged, the current literature lacks a comprehensive integration of three critical dimensions: exosome engineering strategies, advanced biomaterial delivery systems, and their prospective therapeutic applications across various diseases. Therefore, this study concentrates on engineering methodologies aimed at augmenting the therapeutic efficacy of exosomes, encompassing the pretreatment of blast cells, the modification of exosomes, and their incorporation with biomaterials. Furthermore, we systematically introduce delivery systems utilizing hydrogels, scaffolds, microneedles, and fiber membranes, which enhance exosome delivery by facilitating spatial positioning control and achieving sustained release effects. Building on this foundation, we conduct an in-depth examination of the mechanisms and applications of exosomes in the treatment of musculoskeletal disorders. Additionally, this review provides the analysis of biogenesis, isolation, extraction, and preservation strategies of exosomes while also identifying the key factors impeding their clinical application. Based on this synthesis, we propose that exosomes represent a transformative paradigm for targeted, minimally invasive, and tissue-specific interventions in musculoskeletal medicine.