The physico-chemical landscape of extracellular vesicles

Extracellular vesicles are defined as nanosized to microsized particles, delimited by a lipid bilayer membrane, that seem to be released by all cell types and that can transport bioactive molecules between cells, tissues, organs and organisms. Therefore, extracellular vesicles are being explored as biomaterials, drug delivery nanocarriers, therapeutics and multiplexed biomarkers. However, the isolation, characterization and large-scale manufacturing of extracellular vesicles remains challenging. In this Review, we delineate the landscape of the physico-chemical properties of extracellular vesicles, originating from their composition and conformational ensemble, and outline how this landscape is defined by the heterogeneity of their size, composition, membrane structure, surface interactions, cargo and co-isolates. We explore the implications of this heterogeneity on the definition of the purity, identity and function of extracellular vesicles. The comparison of this landscape with the landscape of antibody therapeutics and viral vectors can identify lessons to be learned from the bioprocessing of these products, and the distinct challenges associated with the manufacturing and isolation of extracellular vesicles from biofluids, which will require new concepts and technologies. We highlight the importance of a thorough understanding of the physico-chemical properties of extracellular vesicles for their clinical translation. This includes the development of bioprocessing approaches, assignment of product quality attributes, consistency of extracellular vesicle products and manufacturing at scale.