The ‘sugar’ side of extracellular vesicle—glycome: a panorama from basic characteristics, deciphering technologies, functions, to applications

BACKGROUND: Extracellular vesicles (EVs) represent a heterogeneous group of lipid-enclosed vesicular structures. Despite their tiny bodies, EVs harbor a rich repertoire of functional molecular entities. Therein, the glycome-a diverse ensemble of glycan structures-is increasingly recognized as an essential piece of the EV biology jigsaw. MAIN BODY: This review presents a comprehensive overview of the research advances in EV glycome, recapitulating its fundamental characteristics (i.e., multiformity and heterogeneity), deciphering methodologies, biological functions, and biomedical applications. EVs are found to be enriched with diverse glycosylated components, including glycoproteins, glycolipids, proteoglycans, glycoRNAs, and free glycans. These glycome features can exhibit considerable differences across EV samples due to factors such as cellular origin, parent-cell state, EV subtype, and even isolation method. The toolkit for deciphering is undergoing substantial expansion. Besides classical glycomic methods, a series of advanced technologies has been developed to meet the specific demands of EV glycome analysis. Delving into its biological functions, EV glycome is widely involved in EV biogenesis, EV cargo sorting, EV-cell communication, immune regulation, and disease progression. It also holds immense promise across a broad range of biomedical applications, particularly in developing disease biomarkers, designing therapeutic platforms, modulating immunological activities, and advancing EV isolation methodologies. CONCLUSION: The past two decades have witnessed a progressive advancement in the understanding of EV glycome. Nevertheless, the field remains in its nascent phase. A multitude of unresolved issues and challenges persist, such as underexplored basic biology characteristics, limitations in analytical sensitivity and resolution due to inadequate deciphering techniques, poorly understood mechanisms underlying biological functions, and insufficiency for practical clinical implementation. This review outlines the current knowledge of EV glycome and underscores its significance in basic biology and translational applications, thereby serving as a robust foundational resource to support and accelerate future advancement.