Extracellular vesicles (EV) include a wide range of lipid membrane particles secreted by all types of cells, distinctive in size, biogenesis, cargo molecules, and function. After being secreted upon the fusion of multivesicular bodies with the plasma membrane, extracellular vesicles play central roles in a variety of processes, including intercellular communication, recycling of membrane proteins and lipids, immunomodulation, senescence, angiogenesis, proliferation, differentiation, and migration. Interestingly, shed under both normal and pathological conditions, extracellular vesicles have been found in blood and other biological fluids and are considered relevant diagnostic tools and a key source in the search for novel biomarkers for disease.
On the other hand, undesired immune responses have drastically hampered outcomes after allogeneic organ transplantation and cell therapy, and also lead to inflammatory diseases and autoimmunity. Mesenchymal stem cells have powerful regenerative and immunomodulatory potential, and their secreted EV are envisaged as a promising natural source of nanoparticles to increase outcomes in organ transplantation and control inflammatory diseases. Indeed, since EVs are apparently well-tolerated, their use paves the way for innovative and more efficient cell-free therapies based in nanomedicine avoiding the putative side effects associated to stem cell transplantation.
In terms of future directions, to achieve full translation into viable therapeutic candidates from a manufacturing perspective, extravcellular vesicles processing has to further develop major issues, which include large‐scale processing in obligatory Good Manufacturing Practice conditions, quality and potency controls, and instrumentation. Accordingly, many factors in the downstream isolation, characterization, and analysis processes may have an impact on the outcome of extracellular vesicles production, but also refine their efficacy. Although the design and development of extracellular vesicles‐based products progresses toward standardized, controlled processes at the appropriate scale, the yield of extracellular vesicles is limiting. There are different cell culture or microenvironment conditions, including cell density, aging and passage, stage of differentiation, and substrate topography, which can greatly affect extracellular vesicles yield or intrinsic properties. Moreover, the use of bioreactors with high cell growth surface, media recirculation, and repeated extracellular vesicles recovery are promising for meeting clinical standards. Furthermore, implementation of routine tests of extracellular vesicles potency and optimal dose are of paramount importance. Currently, with no robust techniques for extracellular vesicles enumeration, controlling batch‐to‐batch variations is also thought‐provoking. Lastly, a huge effort has to be invested in developing precise extracellular vesicles analytical platforms to study their specific cargo and predict the potential benefits or side effects upon delivery in humans according to current regulatory restrictions. To this end, advances in purification strategies and omics‐based quantitation and analysis must be further achieved to accurately describe the molecular composition and diversity of extracellular vesicles, as well as to gain insights into understanding associated funcions.
Extracellular vesicles in a peripheral blood sample from a healthy donor
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