Exosomes-X axis: endothelial-derived extracellular vesicles for precision diagnosis and therapy in cardiometabolic multimorbidity

Cardiometabolic multimorbidity (CMM) is an increasingly significant global public health concern. It refers to the coexistence of two or more cardiometabolic conditions such as hypertension, stroke, ischemic heart disease, atherosclerosis, and type 2 diabetes mellitus (T2DM). Endothelial dysfunction is implicated as both an early marker and a central driver of these interrelated disorders. Accumulating evidence has demonstrated that extracellular vesicles, particularly endothelial cells-derived exosomes (ECs-exo), modulated systemic metabolic homeostasis, inflammation, and tissue repair. This review synthesizes mechanistic insights into the exosomes-X Axis, focusing on ECs-exo including miRNAs, lncRNAs, circRNAs, proteins, and lipids, and how these cargos regulate the physiological and pathological of CMM. We summarize ECs-exo signatures with potential diagnostic, prognostic, and disease stratification utility, and evaluate therapeutic opportunities based on exosome engineering and targeted delivery, including multimodal formulations and advanced platform. By integrating mechanistic findings with emerging bioengineering strategies, ECs-exo emerge as a promising theragnostic platform to improve diagnosis, prognosis, and individualized treatment for CMM. Endothelial-derived exosomes act as mediators of intercellular crosstalk linking CMM through transfer of miRNAs and proteins. Dysregulated exosomes cargos propagate vascular inflammation, insulin resistance, and fibrotic remodeling in CMM. Protective exosomes miRNAs from healthy endothelium support vascular repair and suppress pathological inflammation. Circulating endothelial exosomes signatures hold promise as non-invasive biomarkers for early detection and risk stratification of CMM. Engineering endothelial exosomes to deliver therapeutic cargos represents an emerging strategy for restoring vascular homeostasis.