Extracellular Vesicles in Cardiac Cell Crosstalk: from Intercellular Communication to Clinical Translation

Abstract Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, accounting for nearly one-third of deaths worldwide. Intercellular communication between cardiomyocytes and non-cardiomyocytes is fundamental to maintaining cardiac homeostasis and adapting to stress or injury. Among the mediators of this communication, extracellular vesicles (EVs) have emerged as pivotal regulators of cardiac function and remodelling, transporting bioactive molecules that reflect the state and origin of their parent cells. This review provides a systems-level synthesis of EV-mediated crosstalk in the heart, integrating evidence from cardiomyocyte- and non-cardiomyocyte-derived EVs, including fibroblast, endothelial, vascular smooth muscle, and immune cell sources. We discuss how these vesicles orchestrate signalling networks that influence cardiac remodelling, injury response, and disease progression. Distinct from prior reviews, our article extends beyond mechanistic summaries to explore the translational continuum of cardiac EVs—from their potential as diagnostic and prognostic biomarkers to emerging therapeutic and bioengineering strategies. Finally, we critically evaluate current technical and regulatory barriers impeding clinical translation, including isolation, characterisation, and validation challenges, and propose a forward-looking roadmap to advance EV-based diagnostics and therapeutics in cardiovascular medicine.