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Abstract To harmoniously coordinate the activities of all its different cell types, a multicellular organism critically depends on intercellular communication. One recently discovered mode of intercellular cross‐talk is based on the exchange of "extracellular vesicles" (EVs). EVs are nano‐sized heterogeneous lipid bilayer vesicles enriched in a variety of biomolecules that mediate short‐ and long‐distance communication between different cells, and between cells and their environment. Numerous studies have demonstrated important aspects pertaining to the dynamics of their release, their uptake, and sub‐cellular fate and roles in vitro. However, to demonstrate these and other aspects of EV biology in a relevant, fully physiological context in vivo remains challenging. In this review we analyze the state of the art of EV imaging in vivo, focusing in particular on zebrafish as a promising model to visualize, study, and characterize endogenous EVs in real‐time and expand our understanding of EV biology at cellular and systems level.

Abstract Extracellular vesicles (EVs) are promising carriers for the delivery of a variety of chemical and biological drugs. However, their efficacy is limited by the lack of cellular specificity. Available methods to improve the tissue specificity of EVs predominantly rely on surface display of proteins and peptides, largely overlooking the dense glycocalyx that constitutes the outermost layer of EVs. In the present study, we report a reconfigurable glycoengineering strategy that can endogenously display glycans of interest on EV surface. Briefly, EV producer cells are genetically engineered to co‐express a glycosylation domain (GD) inserted into the large extracellular loop of CD63 (a well‐studied EV scaffold protein) and fucosyltransferase VII (FUT7) or IX (FUT9), so that the engineered EVs display the glycan of interest. Through this strategy, we showcase surface display of two types of glycan ligands, sialyl Lewis X (sLeX) and Lewis X, on EVs and achieve high specificity towards activated endothelial cells and dendritic cells, respectively. Moreover, the endothelial cell‐targeting properties of sLeX‐EVs were combined with the intrinsic therapeutic effects of mesenchymal stem cells (MSCs), leading to enhanced attenuation of endothelial damage. In summary, this study presents a reconfigurable glycoengineering strategy to produce EVs with strong cellular specificity and highlights the glycocalyx as an exploitable trait for engineering EVs.

Abstract To keep abreast of developments in the biological sciences and in parallel fields such as medical education, FASEB BioAdvances (FBA) has created a special collections category, FBA special collections (FBA SC), that target, among other topics, emerging disciplines in the biomedical sciences. This FBA SC is focused on the emerging field of extracellular vesicles (EVs) and homeostasis. Leading investigators in the biology of EVs around the globe have contributed to this collection of articles that cover the gamut of research activities from biogenesis and secretion to physiological function.