Scalable Production of Extracellular Vesicles and Its Therapeutic Values: A Review

Extracellular vesicles (EVs) are minute vesicles with lipid bilayer membranes. EVs are secreted by cells for intercellular communication. Recently, EVs have received much attention, as they are rich in biological components such as nucleic acids, lipids, and proteins that play essential roles in tissue regeneration and disease modification. In addition, EVs can be developed as vaccines against cancer and infectious diseases, as the vesicle membrane has an abundance of antigenic determinants and virulent factors. EVs for therapeutic applications are typically collected from conditioned media of cultured cells. However, the number of EVs secreted by the cells is limited. Thus, it is critical to devise new strategies for the large-scale production of EVs. Here, we discussed the strategies utilized by researchers for the scalable production of EVs. Techniques such as bioreactors, mechanical stimulation, electrical stimulation, thermal stimulation, magnetic field stimulation, topographic clue, hypoxia, serum deprivation, pH modification, exposure to small molecules, exposure to nanoparticles, increasing the intracellular calcium concentration, and genetic modification have been used to improve the secretion of EVs by cultured cells. In addition, nitrogen cavitation, porous membrane extrusion, and sonication have been utilized to prepare EV-mimetic nanovesicles that share many characteristics with naturally secreted EVs. Apart from inducing EV production, these upscaling interventions have also been reported to modify the EVs' cargo and thus their functionality and therapeutic potential. In summary, it is imperative to identify a reliable upscaling technique that can produce large quantities of EVs consistently. Ideally, the produced EVs should also possess cargo with improved therapeutic potential.

Automated summary

Extracellular vesicles (EVs) are small vesicles secreted by cells for intercellular communication. They are rich in biological components such as nucleic acids, lipids, and proteins, and play essential roles in tissue regeneration and disease modification. Researchers have employed various strategies, such as bioreactors, mechanical, electrical, thermal, and magnetic field stimulation, to improve the secretion of EVs by cultured cells. Additionally, techniques like nitrogen cavitation, porous membrane extrusion, and sonication have been used to prepare EV-mimetic nanovesicles. These interventions not only induce EV production but also modify their cargo and enhance their therapeutic potential.