High density lipoproteins and extracellular vesicles-distinct but overlapping circulating particles and their role in atherosclerosis.

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with atherosclerosis representing its principal pathological basis. High-density lipoproteins (HDL) and extracellular vesicles (EVs) are abundant circulating particles implicated in lipid metabolism, vascular inflammation, intercellular communication, and thrombotic processes relevant to atherosclerosis. Although HDLs and EVs differ in origin, structure, biogenesis, and canonical function, they share overlapping physicochemical and molecular features. Their density ranges substantially overlap, and small EV populations may approach the upper size range of HDL particles, making their separation from plasma technically challenging. As a result, common isolation workflows may generate HDL-enriched or EV-enriched fractions rather than fully particle-specific preparations, complicating the interpretation of proteomic, lipidomic, nucleic acid, and functional studies. This review compares the structural and biophysical characteristics, biogenesis pathways, molecular cargo, and atherosclerosis-related functions of HDLs and EVs. We highlight how both particle classes contribute to endothelial activation, inflammation, cholesterol handling, foam cell formation, plaque progression, and thrombosis, while also emphasizing their distinct biological roles. Finally, we discuss whether HDL-EV overlap should be interpreted solely as methodological co-isolation or may also reflect biologically relevant interactions within circulating nanoparticle networks in atherosclerosis.