Mechanically engineered extracellular vesicles technology: Regulatory mechanisms and therapeutic applications in orthopedic diseases

Background: An increasing number of studies have shown that extracellular vesicles (EVs), as key mediators of intercellular communication, serve as a crucial bridge between the mechanical microenvironment and bone metabolic homeostasis. However, the molecular mechanisms underlying mechanically regulated EVs are not yet fully elucidated, and traditional EV cultivation suffers from low yield, non-standardized preparation protocols, and inadequate targeting and delivery efficiency, making it difficult to meet the requirements for orthopedic disease treatment. Technology: Mechanically engineered EVs technology is a strategy that involves applying specific types and parameters of mechanical force stimulation to donor cells to regulate their paracrine mechanisms, thereby directionally altering the biological composition and functions of the secreted EVs. It offers a novel “cell-free” therapeutic strategy for orthopedic diseases through efficient production, functional customization, and targeted delivery. In this review, we took an insight into the impact of mechanical stress on EVs derived from bone and cartilage tissues, revealing its regulatory effects on EVs via key signaling pathways such as Ca2+ signal dynamics and Rab GTPases. At the same time, we focused on the biomechanical simulation and reconstruction methods in orthopedic diseases, so as to inspire the optimization of mechanical loading modalities and the transparency and controllability of EV production. Notably, we have summarized several common mechanically engineered EVs technologies and explore the perspectives as effective means from the frontier needs in biomedicines, to facilitate the rapid development of orthopedic diseases treatment technologies. Results: Mechanically engineered EVs hold potential for integration with bioactive implants and organoid-derived systems, among other applications. Future efforts can integrate mechanobiology and nanotechnology to establish quantitative relationships between mechanical parameters and EVs omics profiles. This will optimize the technological application strategies of mechanically engineered EVs in orthopedic therapy and facilitate the translation of this field from basic research to clinical practice.