UNLABELLED: Background/Aims: Cardiomyocyte-derived small extracellular vesicles (CM-sEVs) have emerged as important mediators of intercellular communication in cardiovascular diseases (CVDs). However, their origin-tracing markers, molecular signatures, and clinical applications remain incompletely characterized and lack systematic synthesis. This systematic review aimed to comprehensively evaluate CM-sEVs-specific markers, disease-associated cargos alterations, and their roles in intercellular communication. METHODS: A PRISMA-guided systematic search was conducted across major databases, including Web of Science, PubMed, Embase, and the Cochrane Library. Study screening, data extraction, and quality assessment were independently performed by two investigators according to predefined eligibility criteria. RESULTS: Thirty-four studies were included and three sets of information were systematically analyzed. Ldb3, Ambra1, and CD172a were verified as potential origin-tracing markers of CM-sEVs, and miR-208a, cTnT/Tnnt2, and α-MHC/Myh6 served as auxiliary markers. Several CM-sEVs-associated molecules, including CD172a, Ambra1, miR-9-5p, and lncRNA HCG15, demonstrated diagnostic or prognostic potential in CVDs populations. Functionally, CM-sEVs regulate fibrosis, angiogenesis, autophagy, and immune responses through cardiomyocyte-noncardiomyocyte communication networks. CONCLUSION: This review systematically summarizes current evidence on potential origin-tracing markers, cargos characteristics, and intercellular communication roles of CM-sEVs, providing a theoretical basis for their identification and translational application in cardiovascular diseases.