Extracellular Vesicles in Cardiovascular Disease: Intercellular Signaling, Liquid Biopsy Biomarkers, and Therapeutic Translation.

Cardiovascular diseases remain the leading global cause of mortality, highlighting the need for improved early detection and targeted interventions. Extracellular vesicles (EVs) are nano-sized, bilipid-layered particles released by all cell types that carry RNAs, proteins, lipids, and metabolites reflective of their parent cells. They mediate intercellular communication by transferring cargo that alters recipient cell transcriptomic and proteomic states, and this property may be leveraged for therapeutic delivery. This review provides a comprehensive, cardiovascular disease-focused synthesis of EV biology with emphasis on what is clinically actionable and mechanistically novel. The review describes EV biogenesis and their multiomic cargo composition, followed by tissue-resolved and cell type-resolved EV signaling across cell types relevant to cardiovascular disease. A dedicated section addresses EV-mediated interorgan crosstalk across the heart-kidney, heart-liver, brain-heart, and adipose-heart axes as a systems-level framework for cardiometabolic disease. We next turn to translational applications, describing EV cargo composition under pathological conditions with implications for disease-related signaling and the potential for biomarker development. For liquid biopsy applications, the review introduces a 3-tier evidence framework classifying circulating EV biomarkers by clinical validation status, supported by a practical preanalytical checklist for cardiovascular plasma studies. Engineered, stem cell-derived, and RNA-loaded EV therapeutic modalities are evaluated, and active clinical trials are catalogued along with key challenges in cargo loading, biodistribution, immunogenicity, and regulatory standardization. We conclude with a structured future directions and perspectives section identifying the most tractable open questions required to advance EVs from discovery to cardiovascular clinical practice.