Extracellular vesicles as inter-organ messengers in atherogenesis: convergent pathways linking systemic comorbidities to vascular dysfunction

Atherosclerosis remains a leading cause of death, yet traditional risk frameworks fail to account for a substantial residual cardiovascular burden that arises from systemic comorbidities. This review advances the concept that extracellular vesicles (EVs) constitute a conserved inter-organ communication language, translating diverse pathological states, including obesity, diabetes, MASLD, chronic H. pylori infection, sleep disturbances, asthma, and other conditions such as chronic kidney disease, cancer, and neuropsychiatric disorders into convergent vascular dysfunction. We propose an encode-transport-decode working model as an integrative framework, wherein diseased tissues selectively package pathogenic microRNAs and proteins into EVs, that circulate stably to vascular recipient cells and activate a restricted repertoire of pro-atherogenic signaling. Despite distinct origins, these EVs converge on three synergistic axes: NF-κB-driven endothelial barrier disruption, PPARγ-LXRα-ABCA1/ABCG1 suppression impairing cholesterol efflux, and systemic inflammatory immune reprogramming. Building on this convergence, we introduce a convergent synergy hypothesis proposing that coexisting comorbidities may produce cumulative and synergistic vascular damage beyond the sum of individual effects, reframing atherosclerosis as a systemic disorder of disrupted inter-organ crosstalk. Translational opportunities include EV signatures for dynamic risk stratification and engineered EV therapeutics complementing existing regimens. However, major hurdles remain, including standardizing isolation methodologies, deciphering stress-responsive cargo-sorting rules, and validating composite EV scores in multimorbid cohorts. Addressing these challenges will enable precision interventions targeting network-level drivers of atherogenesis.