Beyond spherical vesicles: morphological diversity of extracellular vesicles in health and disease

The field of extracellular vesicles (EVs) has advanced considerably in recent years with new findings stemming from technical improvements in their isolation and characterization, expanding their potential as tools in vaccines, drug delivery, and timely diagnosis using biomarkers. Consequently, a new area of interest has recently gained prominence: the study of changes in EV morphology and their potential involvement in diseases.

Using cryo-TEM analysis, a technique that helps preserve the near-natural state of EVs, multiple morphological and structural variants have been demonstrated in isolates from bodily fluids, cell cultures, and cell lines of mammals, as well as some protozoa and plants. In addition to the classic sphere with a lipid bilayer and hyaline content, pleomorphic, tubular and sac-like EVs, with double, multilayered or lamellar membranes, and in some cases, with electrodense content, have been described. Furthermore, several studies have found alterations in the morphological pattern and/or proportions of these morphological variants in diseases associated with cellular or metabolic dysfunction such as Parkinson's and diabetes, as well as in infectious diseases such as Zika virus and prions. Here, we review the key findings that have propelled the field, provide a catalog of the EVs variants identified to date, discuss mechanisms underlying their formation and their potential biological implication in the course of various pathologies, and identify key challenges that need to be addressed.

The information analyzed demonstrate that EVs are highly variable structures, not only in their content but also in their morphology, and that this variation could be related to cellular, metabolic, and infectious pathologies. This underscore the need to understand the origin, regulation, and function of each morphological type of EVs, which could lead to their possible use as diagnostic or therapeutic tools in the future.