Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Extracellular vesicles in cardiovascular homeostasis and disease: potential role in diagnosis and therapy

Abstract

Communication between multicellular organs is essential to propagate signals and coordinate their function. Over the past decade, the role of extracellular vesicles in the molecular communication between cells in both physiological and pathological settings has received much attention. Extracellular vesicles can shuttle proteins, lipids and nucleic acids (such as RNA) between cells, thus inducing an array of functional changes in the recipient cells. In this Review, we describe the different extracellular vesicle subclasses and their heterogeneous nature, provide insights into extracellular vesicle-mediated signalling in the cardiovascular system, and highlight how extracellular vesicles can be used as diagnostic and prognostic biomarkers for a variety of pathological conditions. Finally, we also discuss the potential therapeutic applications of extracellular vesicles.

Key points

  • Extracellular vesicles (EVs) are effective mediators of cellular communication by transporting nucleic acids, proteins and lipids.

  • EVs are a heterogeneous population of vesicles that vary in size, cargo content, surface characteristics and intracellular origin, with differing pathways of biogenesis.

  • EVs or EV-linked molecules can be used to predict the progression and severity of numerous cardiovascular diseases.

  • Numerous techniques to isolate EVs have been employed for research, but they require careful validation for different applications given the differences in EV populations or profiles depending on the technique used.

  • A better understanding of the unique characteristics of EVs for intercellular communication will provide insights into how they can be used for diagnostic and therapeutic applications and will facilitate the design of better vehicles for drug delivery to reduce off-target effects.

This is a preview of subscription content, access via your institution

Access options

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Techniques to isolate, visualize, characterize or quantify extracellular vesicles or their cargo.
Fig. 2: Role of extracellular vesicles in intracellular communication in the heart in physiological and pathological circumstances.

Similar content being viewed by others

References

  1. Townsend, N. et al. Epidemiology of cardiovascular disease in Europe. Nat. Rev. Cardiol. 19, 133–143 (2022).

    Article  PubMed  Google Scholar 

  2. Perrino, C. et al. Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc. Res. 113, 725–736 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sluijter, J. P. G. et al. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: position paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc. Res. 114, 19–34 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Yates, A. G. et al. In sickness and in health: the functional role of extracellular vesicles in physiology and pathology in vivo. Part I: Health and normal physiology. J. Extracell. Vesicles 11, e12151 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yates, A. G. et al. In sickness and in health: the functional role of extracellular vesicles in physiology and pathology in vivo. Part II: Pathology. J. Extracell. Vesicles 11, e12190 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lässer, C., Jang, S. C. & Lötvall, J. Subpopulations of extracellular vesicles and their therapeutic potential. Mol. Asp. Med. 60, 1–14 (2018).

    Article  Google Scholar 

  7. Li, G. et al. Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases. J. Extracell. Vesicles 12, e12305 (2023).

    Article  PubMed  Google Scholar 

  8. Welsh, J. A. et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J. Extracell. Vesicles 13, e1240 (2024).

    Article  Google Scholar 

  9. Davidson, S. M. et al. Methods for the identification and characterization of extracellular vesicles in cardiovascular studies: from exosomes to microvesicles. Cardiovasc. Res. 119, 45–63 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. Chen, T., Guo, J., Yang, M., Zhu, X. & Cao, X. Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. J. Immunol. 186, 2219–2228 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Kim, J.-S. et al. Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells. J. Physiol. Heart Circ. Physiol. 309, 425–433 (2015).

    Article  Google Scholar 

  12. de Jong, O. G. et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J. Extracell. Vesicles 1, 18396 (2012).

    Article  Google Scholar 

  13. Bari, E. et al. Silk fibroin bioink for 3D printing in tissue regeneration: controlled release of MSC extracellular vesicles. Pharmaceutics 15, 383 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Leroyer, A. S. et al. Microparticles from ischemic muscle promotes postnatal vasculogenesis. Circulation 119, 2808–2817 (2009).

    Article  PubMed  Google Scholar 

  15. Van De Wakker, S. I., Meijers, F. M., Sluijter, J. P. G. & Vader, P. Extracellular vesicle heterogeneity and its impact for regenerative medicine applications. Pharmacol. Rev. 75, 1043–1061 (2023).

    Article  PubMed  Google Scholar 

  16. van de Wakker, S. I. et al. Size matters: functional differences of small extracellular vesicle subpopulations in cardiac repair responses. J. Extracell. Vesicles 13, e12396 (2024).

    Article  PubMed  Google Scholar 

  17. Wang, X. et al. Essential role of Alix in regulating cardiomyocyte exosome biogenesis under physiological and stress conditions. J. Mol. Cell Cardiol. 190, 35–47 (2024).

    Article  CAS  PubMed  Google Scholar 

  18. Sun, R. et al. ALIX increases protein content and protective function of iPSC-derived exosomes. J. Mol. Med. 97, 829–844 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Oerlemans, M. I. F. J. et al. Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection. Int. J. Cardiol. 165, 410–422 (2013).

    Article  PubMed  Google Scholar 

  20. Gupta, K. et al. Necroptosis is associated with Rab27-independent expulsion of extracellular vesicles containing RIPK3 and MLKL. J. Extracell. Vesicles 11, e12261 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maring, J. A. et al. Cardiac progenitor cell-derived extracellular vesicles reduce infarct size and associate with increased cardiovascular cell proliferation. J. Cardiovasc. Transl. Res. 12, 5–17 (2019).

    Article  PubMed  Google Scholar 

  22. Ortega, F. G. et al. Interfering with endolysosomal trafficking enhances release of bioactive exosomes. Nanomedicine 20, 102014 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Fordjour, F. K. et al. Exomap1 mouse: a transgenic model for in vivo studies of exosome biology. Extracell. Vesicles 2, 100030 (2023).

    Article  Google Scholar 

  24. Van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).

    Article  PubMed  Google Scholar 

  25. Van Deun, J. et al. EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research. Nat. Methods 14, 228–232 (2017).

    Article  PubMed  Google Scholar 

  26. Fu, S. et al. Extracellular vesicles in cardiovascular diseases. Cell Death Discov. 6, 68 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cheung, S. W. Y., Chamley, L. W., Barrett, C. J. & Lau, S. Y. S. Extracellular vesicles and their effect on vascular haemodynamics: a systematic review. Hypertens. Res. 10, e12085 (2024).

    Google Scholar 

  28. Pironti, G. et al. Circulating exosomes induced by cardiac pressure overload contain functional angiotensin II type 1 receptors. Circulation 131, 2120–2130 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Good, M. E. et al. Circulating extracellular vesicles in normotension restrain vasodilation in resistance arteries. Hypertension 75, 218–228 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Webber, R. J., Sweet, R. M. & Webber, D. S. Inducible nitric oxide synthase in circulating microvesicles: discovery, evolution, and evidence as a novel biomarker and the probable causative agent for sepsis. J. Appl. Laboratory Med. 3, 698–711 (2019).

    Article  CAS  Google Scholar 

  31. Lee, Y. J. et al. Circulating small extracellular vesicles promote proliferation and migration of vascular smooth muscle cells via AXL and MerTK activation. Acta Pharmacol. Sin. 44, 984–998 (2023).

    Article  CAS  PubMed  Google Scholar 

  32. Royo, F. et al. Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism. Sci. Rep. 7, 42798 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Raeven, P., Zipperle, J. & Drechsler, S. Extracellular vesicles as markers and mediators in sepsis. Theranostics 8, 3348–3365 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wei, G. et al. Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/cyclin B2 pathway. J. Adv. Res. 53, 199–218 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Hegyesi, H. et al. Circulating cardiomyocyte-derived extracellular vesicles reflect cardiac injury during systemic inflammatory response syndrome in mice. Cell. Mol. Life Sci. 79, 84 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rodriguez, J. A. et al. Selective increase of cardiomyocyte derived extracellular vesicles after experimental myocardial infarction and functional effects on the endothelium. Thromb. Res. 170, 1–9 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Almeida Paiva, R. et al. Ischaemia alters the effects of cardiomyocyte-derived extracellular vesicles on macrophage activation. J. Cell Mol. Med. 23, 1137–1151 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Zhou, Y. et al. Peptide-anchored biomimetic interface for electrochemical detection of cardiomyocyte-derived extracellular vesicles. Anal. Bioanal. Chem. 415, 1305–1311 (2023).

    Article  CAS  PubMed  Google Scholar 

  39. Terriaca, S. et al. Endothelial progenitor cell-derived extracellular vesicles: potential therapeutic application in tissue repair and regeneration. Int. J. Mol. Sci. 22, 6375 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, L. et al. Effect of endothelial progenitor cell-derived extracellular vesicles on endothelial cell ferroptosis and atherosclerotic vascular endothelial injury. Cell Death Discov. 7, 235 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen, C. W. et al. Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction. Cardiovasc. Res. 114, 1029–1040 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zheng, S. et al. microRNA-129 overexpression in endothelial cell-derived extracellular vesicle influences inflammatory response caused by myocardial ischemia/reperfusion injury. Cell Biol. Int. 8, 1743–1756 (2021).

    Article  Google Scholar 

  43. Yadid, M. et al. Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip. Sci. Transl. Med. 12, eaax8005 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peters, M. M. C., Sampaio-Pinto, V. & da Costa Martins, P. A. Non-coding RNAs in endothelial cell signalling and hypoxia during cardiac regeneration. Biochim. Biophys. Acta Mol. Cell Res. 1867, 118515 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Zhu, Y., Liao, Z. F., Mo, M. H. & Xiong, X. D. Mesenchymal stromal cell-derived extracellular vesicles for vasculopathies and angiogenesis: therapeutic applications and optimization. Biomolecules 13, 1109 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Spinosa, M. et al. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J. 32, fj201701138RR (2018).

    Article  PubMed  Google Scholar 

  47. Zhang, C., Wang, H., Li, J. & Ma, L. Circular RNA involvement in the protective effect of human umbilical cord mesenchymal stromal cell-derived extracellular vesicles against hypoxia/reoxygenation injury in cardiac cells. Front. Cardiovasc. Med. 8, 626878 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Łabędź-Masłowska, A. et al. Mesenchymal stem cell-derived extracellular vesicles exert pro-angiogenic and pro-lymphangiogenic effects in ischemic tissues by transferring various microRNAs and proteins including ITGa5 and NRP1. J. Nanobiotechnol. 22, 60 (2024).

    Article  Google Scholar 

  49. Malvicini, R. et al. Influence of the isolation method on characteristics and functional activity of mesenchymal stromal cell-derived extracellular vesicles. Cytotherapy 26, 157–170 (2024).

    Article  CAS  PubMed  Google Scholar 

  50. Hsu, C. Y. et al. Characterization and proteomic analysis of endometrial stromal cell-derived small extracellular vesicles. J. Clin. Endocrinol. Metab. 106, 1516–1529 (2021).

    Article  PubMed  Google Scholar 

  51. Liu, Q. et al. Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J. Clin. Invest. 126, 2805–2820 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yang, J. et al. T-cell-derived extracellular vesicles regulate B-cell IgG production via pyruvate kinase muscle isozyme 2. FASEB J. 33, 12780–12799 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lugo-Gavidia, L. M. et al. Circulating platelet-derived extracellular vesicles correlate with night-time blood pressure and vascular organ damage and may represent an integrative biomarker of vascular health. J. Clin. Hypertens. 24, 738–749 (2022).

    Article  CAS  Google Scholar 

  54. Kong, L. et al. Mediating effects of platelet-derived extracellular vesicles on PM2.5-induced vascular endothelial injury. Ecotoxicol. Env. Saf. 198, 110652 (2020).

    Article  CAS  Google Scholar 

  55. Manakeng, K. et al. Elevated levels of platelet- and red cell-derived extracellular vesicles in transfusion-dependent β-thalassemia/HbE patients with pulmonary arterial hypertension. Ann. Hematol. 98, 281–288 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Reddel, C. J., Pennings, G. J., Lau, J. K., Chen, V. M. & Kritharides, L. Circulating platelet-derived extracellular vesicles are decreased after remote ischemic preconditioning in patients with coronary disease: a randomized controlled trial. J. Thrombosis Haemost. 19, 2605–2611 (2021).

    Article  CAS  Google Scholar 

  57. Lugo-Gavidia, L. M. et al. Platelet-derived extracellular vesicles correlate with therapy-induced nocturnal blood pressure changes. J. Hypertens. 40, 2210–2218 (2022).

    Article  CAS  PubMed  Google Scholar 

  58. Zhu, Z. et al. A double-edged sword of platelet-derived extracellular vesicles in tissues, injury or repair: the current research overview. Tissue Cell 82, 102066 (2023).

    Article  CAS  PubMed  Google Scholar 

  59. Al Halawani, A., Mithieux, S. M., Yeo, G. C., Hosseini-Beheshti, E. & Weiss, A. S. Extracellular vesicles: interplay with the extracellular matrix and modulated cell responses. Int. J. Mol. Sci. 23, 3389 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dolo, V. et al. Matrix-degrading proteinases are shed in membrane vesicles by ovarian cancer cells in vivo and in vitro. Clin. Exp. Metastasis 17, 131–140 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Ruiz, J. L., Weinbaum, S., Aikawa, E. & Hutcheson, J. D. Zooming in on the genesis of atherosclerotic plaque microcalcifications. J. Physiol. 594, 2915–2927 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rogers, M. A. et al. Annexin A1-dependent tethering promotes extracellular vesicle aggregation revealed with single-extracellular vesicle analysis. Sci. Adv. 6, eabb1244 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kalra, H. et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10, e1001450 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Blaser, M. C. et al. Multiomics of tissue extracellular vesicles identifies unique modulators of atherosclerosis and calcific aortic valve stenosis. Circulation 148, 661–678 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Das, S., Lyon, C. J. & Hu, T. A panorama of extracellular vesicle applications: from biomarker detection to therapeutics. ACS Nano 18, 9784–9797 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tian, C., Gao, L., Rudebush, T. L., Yu, L. & Zucker, I. H. Extracellular vesicles regulate sympatho-excitation by Nrf2 in heart failure. Circ. Res. 131, 687–700 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Matan, D. et al. Extracellular vesicles in heart failure – a study in patients with heart failure with preserved ejection fraction or heart failure with reduced ejection fraction characteristics undergoing elective coronary artery bypass grafting. Front. Cardiovasc. Med. 9, 952974 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wang, L., Liu, J., Xu, B., Liu, Y. L. & Liu, Z. Reduced exosome miR-425 and miR-744 in the plasma represents the progression of fibrosis and heart failure. Kaohsiung J. Med. Sci. 34, 626–633 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wu, T. et al. Circulating exosomal miR-92b-5p is a promising diagnostic biomarker of heart failure with reduced ejection fraction patients hospitalized for acute heart failure. J. Thorac. Dis. 10, 6211–6220 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Matsumoto, S. et al. Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ. Res. 113, 322–326 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Khandagale, A. et al. MircoRNA in extracellular vesicles from patients with pulmonary arterial hypertension alters endothelial angiogenic response. Int. J. Mol. Sci. 23, 11964 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Khandagale, A. et al. Role of extracellular vesicles in pulmonary arterial hypertension modulation of pulmonary endothelial function and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 40, 2293–2309 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. de Hoog, V. C. et al. Serum extracellular vesicle protein levels are associated with acute coronary syndrome. Eur. Heart J. Acute Cardiovasc. Care 2, 53–60 (2013).

    PubMed  PubMed Central  Google Scholar 

  74. Steogonekpień, E. et al. Number of microparticles generated during acute myocardial infarction and stable angina correlates with platelet activation. Arch. Med. Res. 43, 31–35 (2012).

    Article  Google Scholar 

  75. Oerlemans, M. I. F. J. et al. Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs. EMBO Mol. Med. 4, 1176–1185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mørk, M. et al. Elevated blood plasma levels of tissue factor-bearing extracellular vesicles in patients with atrial fibrillation. Thromb. Res. 173, 141–150 (2019).

    Article  PubMed  Google Scholar 

  77. Bai, C. et al. Circulating exosome-derived miR-122-5p is a novel biomarker for prediction of postoperative atrial fibrillation. J. Cardiovasc. Transl. Res. 15, 1393–1405 (2022).

    Article  PubMed  Google Scholar 

  78. Kang, J. Y., Mun, D., Kim, H., Yun, N. & Joung, B. Serum exosomal long noncoding RNAs as a diagnostic biomarker for atrial fibrillation. Heart Rhythm. 19, 1450–1458 (2022).

    Article  PubMed  Google Scholar 

  79. Zhang, Y. et al. Characterization of circRNA-associated ceRNA networks in patients with nonvalvular persistent atrial fibrillation. Mol. Med. Rep. 19, 638–650 (2019).

    CAS  PubMed  Google Scholar 

  80. Joo, S. J. et al. Transcriptomic landscape of circulating extracellular vesicles in heart transplant ischemia–reperfusion. Genes 14, 2101 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gallet, R. et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur. Heart J. 38, 201–211 (2017).

    CAS  PubMed  Google Scholar 

  82. Arslan, F. et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 10, 301–312 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Correa, B. L. et al. Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts. Cardiovasc. Res. 117, 292–307 (2021).

    Article  CAS  Google Scholar 

  84. Roefs, M. T. et al. Cardiac progenitor cell-derived extracellular vesicles promote angiogenesis through both associated- and co-isolated proteins. Commun. Biol. 6, 800 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rogers, R. G., Ciullo, A., Marbán, E. & Ibrahim, A. G. Extracellular vesicles as therapeutic agents for cardiac fibrosis. Front. Physiol. 11, 479 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Cheng, G., Zhu, D., Huang, K. & Caranasos, T. G. Minimally invasive delivery of a hydrogel-based exosome patch to prevent heart failure. J. Mol. Cell Cardiol. 169, 113–121 (2022).

    Article  CAS  PubMed  Google Scholar 

  87. Deddens, J. C. et al. Circulating extracellular vesicles contain miRNAs and are released as early biomarkers for cardiac injury. J. Cardiovasc. Transl. Res. 9, 291–301 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Vicencio, J. M. et al. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J. Am. Coll. Cardiol. 65, 1525–1536 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Deddens, J. C., Vrijsen, K. R., Girao, H., Doevendans, P. A. & Sluijter, J. P. G. Cardiac-released extracellular vesicles can activate endothelial cells. Ann. Transl. Med. 5, 64 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Giricz, Z. et al. Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J. Mol. Cell Cardiol. 68, 75–78 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, H. et al. Percutaneous intracoronary delivery of plasma extracellular vesicles protects the myocardium against ischemia-reperfusion injury in canis. Hypertension 78, 1541–1554 (2021).

    Article  CAS  PubMed  Google Scholar 

  92. Gollmann-Tepekoylu, C. et al. miR-19a-3p containing exosomes improve function of ischaemic myocardium upon shock wave therapy. Cardiovasc. Res. 116, 1226–1236 (2021).

    Article  Google Scholar 

  93. Sun, P. et al. Low-intensity pulsed ultrasound protects from inflammatory dilated cardiomyopathy through inciting extracellular vesicles. Cardiovasc. Res. 120, 1177–1190 (2024).

    Article  CAS  PubMed  Google Scholar 

  94. Kang, J. Y. et al. Engineered small extracellular vesicle-mediated NOX4 siRNA delivery for targeted therapy of cardiac hypertrophy. J. Extracell. Vesicles 12, e12371 (2023).

    Article  PubMed  Google Scholar 

  95. de Boer, C. & Davies, N. H. Blood derived extracellular vesicles as regenerative medicine therapeutics. Biochimie 196, 203–215 (2022).

    Article  PubMed  Google Scholar 

  96. Livkisa, D. et al. Extracellular vesicles purified from serum-converted human platelet lysates offer strong protection after cardiac ischaemia/reperfusion injury. Biomaterials 306, 122502 (2024).

    Article  CAS  PubMed  Google Scholar 

  97. Soler-Botija, C. et al. Mechanisms governing the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles: a scoping review of preclinical evidence. Biomed. Pharmacother. 147, 112683 (2022).

    Article  CAS  PubMed  Google Scholar 

  98. Roefs, M. T., Sluijter, J. P. G. & Vader, P. Extracellular vesicle-associated proteins in tissue repair. Trends Cell Biol. 30, 990–1013 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Barile, L. et al. Cardioprotection by cardiac progenitor cell-secreted exosomes: role of pregnancy-associated plasma protein-A. Cardiovasc. Res. 114, 992–1005 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Emmert, M. et al. Intracoronary delivery of extracellular vesicles from human cardiac progenitor cells reduces infarct size in porcine acute myocardial infarction. Eur. Heart J. 45, 728–732 (2024).

    Article  CAS  PubMed  Google Scholar 

  101. Xing, Z., Zhao, C., Liu, H. & Fan, Y. Endothelial progenitor cell-derived extracellular vesicles: a novel candidate for regenerative medicine and disease treatment. Adv. Healthc. Mater. 9, e2000255 (2020).

    Article  PubMed  Google Scholar 

  102. Yu, B. et al. Extracellular vesicles engineering by silicates-activated endothelial progenitor cells for myocardial infarction treatment in male mice. Nat. Commun. 14, 2094 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Khan, K. et al. Extracellular vesicles as a cell-free therapy for cardiac repair: a systematic review and meta-analysis of randomized controlled preclinical trials in animal myocardial infarction models. Stem Cell Rev. Rep. 18, 1143–1167 (2022).

    Article  PubMed  Google Scholar 

  104. Yang, L. et al. Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies. Aging 11, 1129–1150 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zwetsloot, P. P. et al. Cardiac stem cell treatment in myocardial infarction: a systematic review and meta-analysis of preclinical studies. Circ. Res. 118, 1223–1232 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. De Jong, O. G. et al. Drug delivery with extracellular vesicles: from imagination to innovation. Acc. Chem. Res. 52, 1761–1770 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kooijmans, S. A. A. et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Controlled Rel. 172, 229–238 (2013).

    Article  CAS  Google Scholar 

  108. Fabiani, M. et al. Effectiveness of the Comirnaty (BNT162b2, BioNTech/Pfizer) vaccine in preventing SARS-CoV-2 infection among healthcare workers, Treviso province, Veneto region, Italy, 27 December 2020 to 24 March 2021. Eurosurveillance 26, 2100420 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Urits, I. et al. A review of patisiran (ONPATTRO®) for the treatment of polyneuropathy in people with hereditary transthyretin amyloidosis. Neurol. Ther. 9, 301–315 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Murphy, D. E. et al. Natural or synthetic RNA delivery: a stoichiometric comparison of extracellular vesicles and synthetic nanoparticles. Nano Lett. 21, 1888–1895 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee, Y., Jeong, M., Park, J., Jung, H. & Lee, H. Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics. Exp. Mol. Med. 55, 2085–2096 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Evers, M. J. W. et al. Functional siRNA delivery by extracellular vesicle–liposome hybrid nanoparticles. Adv. Healthc. Mater. 11, e2101202 (2022).

    Article  PubMed  Google Scholar 

  113. Ilahibaks, N. F. et al. TOP-EVs: technology of protein delivery through extracellular vesicles is a versatile platform for intracellular protein delivery. J. Controlled Rel. 355, 579–592 (2023).

    Article  CAS  Google Scholar 

  114. Ilahibaks, N. F. et al. Extracellular vesicle-mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin-kexin type 9 (Pcsk9) in primary mouse hepatocytes. J. Extracell. Vesicles 13, e12389 (2024).

    Article  PubMed  Google Scholar 

  115. Ivanova, A. et al. Creating designer engineered extracellular vesicles for diverse ligand display, target recognition, and controlled protein loading and delivery. Adv. Sci. 10, e2304389 (2023).

    Article  Google Scholar 

  116. Van der Spoel, T. I. G. et al. Transendocardial cell injection is not superior to intracoronary infusion in a porcine model of ischaemic cardiomyopathy: a study on delivery efficiency. J. Cell Mol. Med. 16, 2768–2776 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  117. van den Akker, F. et al. Intramyocardial stem cell injection: go(ne) with the flow. Eur. Heart J. 38, 184–186 (2017).

    PubMed  Google Scholar 

  118. Roefs, M. T. et al. Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles. Front. Pharmacol. 13, 1052091 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wiklander, O. P. B. et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 4, 26316 (2015).

    Article  PubMed  Google Scholar 

  120. Lázaro-Ibánez, E. et al. Selection of fluorescent, bioluminescent, and radioactive tracers to accurately reflect extracellular vesicle biodistribution in vivo. ACS Nano 15, 3212–3227 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Xu, C. M. et al. Visualization of cardiac uptake of bone marrow mesenchymal stem cell-derived extracellular vesicles after intramyocardial or intravenous injection in murine myocardial infarction. Physiol. Rep. 11, e15568 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mol, E. A. et al. Injectable supramolecular ureidopyrimidinone hydrogels provide sustained release of extracellular vesicle therapeutics. Adv. Healthc. Mater. 8, 1900847 (2019).

    Article  CAS  Google Scholar 

  123. Monguió-Tortajada, M. et al. Acellular cardiac scaffolds enriched with MSC-derived extracellular vesicles limit ventricular remodelling and exert local and systemic immunomodulation in a myocardial infarction porcine model. Theranostics 6, 4656–4670 (2022).

    Article  Google Scholar 

  124. Gao, H. et al. Injectable hydrogel-based combination therapy for myocardial infarction: a systematic review and meta-analysis of preclinical trials. BMC Cardiovasc. Disord. 24, 119 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Zou, Y. et al. Restoring cardiac functions after myocardial infarction-ischemia/reperfusion via an exosome anchoring conductive hydrogel. ACS Appl. Mater. Interfaces 13, 56892–56908 (2021).

    Article  CAS  PubMed  Google Scholar 

  126. Zhu, D. et al. Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair. Nat. Commun. 12, 1412 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yuan, J. et al. Microneedle patch loaded with exosomes containing microRNA-29b prevents cardiac fibrosis after myocardial infarction. Adv. Healthc. Mater. 12, e2202959 (2023).

    Article  PubMed  Google Scholar 

  128. Gu, J. et al. Engineered bone marrow mesenchymal stem cell-derived exosomes loaded with miR302 through the cardiomyocyte specific peptide can reduce myocardial ischemia and reperfusion (I/R) injury. J. Transl. Med. 22, 168 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mun, D., Kang, J.-Y., Kim, H., Yun, N. & Joung, B. Small extracellular vesicle-mediated CRISPR-Cas9 RNP delivery for cardiac-specific genome editing. J. Controlled Rel. 370, 798–810 (2024).

    Article  CAS  Google Scholar 

  130. Tian, Y. et al. Quality and efficiency assessment of six extracellular vesicle isolation methods by nano-flow cytometry. J. Extracell. Vesicles 9, 1697028 (2020).

    Article  CAS  PubMed  Google Scholar 

  131. Guo, J. et al. Establishment of a simplified dichotomic size-exclusion chromatography for isolating extracellular vesicles toward clinical applications. J. Extracell. Vesicles 10, e12145 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Escudé Martinez de Castilla, P. et al. Extracellular vesicles as a drug delivery system: a systematic review of preclinical studies. Adv. Drug. Delivery Rev. 175, 113801 (2021).

    Article  Google Scholar 

  133. Courageux, Y. et al. Clinical translation of mesenchymal stromal cell extracellular vesicles: considerations on scientific rationale and production requisites. J. Cell Mol. Med. 26, 937–939 (2022).

    Article  PubMed  Google Scholar 

  134. Saftics, A. et al. Single extracellular vesicle nanoscopy. J. Extracell. Vesicles 12, e12346 (2023).

    Article  PubMed  Google Scholar 

  135. Bettin, B. A., Varga, Z., Nieuwland, R. & van der Pol, E. Standardization of extracellular vesicle concentration measurements by flow cytometry: the past, present, and future. J. Thrombosis Haemost. 21, 2032–2044 (2023).

    Article  Google Scholar 

  136. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT03674255 (2020).

  137. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06298682 (2024).

  138. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05524506 (2022).

  139. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05584943 (2022).

  140. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06169540 (2023).

  141. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT04731987 (2024).

  142. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06071559 (2023).

  143. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06209359 (2024).

  144. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05323487 (2025).

  145. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT03249532 (2021).

  146. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06319742 (2024).

  147. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06275399 (2024).

  148. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06408961 (2024).

  149. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06316271 (2024).

  150. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05199454 (2025).

  151. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT02931045 (2020).

  152. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT04698447 (2021).

  153. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05774509 (2023).

  154. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05243368 (2023).

  155. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT04652531 (2023).

  156. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06319287 (2024).

  157. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06198543 (2024).

  158. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT04578223 (2020).

  159. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05855317 (2023).

  160. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT04191044 (2019).

  161. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05490173 (2022).

  162. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05645081 (2024).

  163. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05326724 (2022).

  164. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT04266639 (2022).

  165. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT06257823 (2024).

  166. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT02458755 (2017).

  167. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT03481777 (2025).

  168. US National Library of Medicine. ClinicalTrials.gov clinicaltrials.gov/study/NCT05370105 (20252).

  169. Buntsma, N. C. et al. EDTA stabilizes the concentration of platelet-derived extracellular vesicles during blood collection and handling. Platelets 33, 764–771 (2022).

    Article  CAS  PubMed  Google Scholar 

  170. International Society for Extracellular Vesicles. Scientific Reproducibility Task Forces. ISEV www.isev.org/taskforces (2021).

  171. Johnsen, K. B., Gudbergsson, J. M., Andresen, T. L. & Simonsen, J. B. What is the blood concentration of extracellular vesicles? Implications for the use of extracellular vesicles as blood-borne biomarkers of cancer. Biochim. Biophys. Acta Rev. Cancer 1871, 109–116 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Wolf, M. et al. A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation. J. Extracell. Vesicles 11, e12207 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lucien, F. et al. MIBlood-EV: minimal information to enhance the quality and reproducibility of blood extracellular vesicle research. J. Extracell. Vesicles 12, e12385 (2023).

    Article  PubMed  Google Scholar 

  174. Lehrich, B. M., Liang, Y. & Fiandaca, M. S. Foetal bovine serum influence on in vitro extracellular vesicle analyses. J. Extracell. Vesicles 10, e12061 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Lehrich, B. M., Liang, Y., Khosravi, P., Federoff, H. J. & Fiandaca, M. S. Fetal bovine serum-derived extracellular vesicles persist within vesicle-depleted culture media. Int. J. Mol. Sci. 19, 3538 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Shlomovitz, I. et al. Proteomic analysis of necroptotic extracellular vesicles. Cell Death Dis. 12, 1059 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Hurwitz, S. N., Olcese, J. M. & Meckes, D. G. Extraction of extracellular vesicles from whole tissue. J. Vis. Exp. https://doi.org/10.3791/59143 (2019).

Download references

Acknowledgements

The authors’ work was supported by grants from the National Natural Science Foundation of China (82225005 and 82020108002 to J.X.) and the Science and Technology Commission of Shanghai Municipality (23410750100, 20DZ2255400 and 21XD1421300 to J.X.). J.P.G.S. is supported by H2020-EVICARE (#725229) and TOP-EVICARE (#101138069) of the European Research Council, and by ZonMw Psider-Heart (10250022110004) and NWO-TTP HARVEY (2021/TTW/01038252), Health-Holland 2022TKI2306 EV-PROTECT and ERA for Health Cardinnov (RESCUE- 2024/KIC/01627794).

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed to researching data for the article, discussion of content, writing the article, and reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Joost P. G. Sluijter.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks Lucio Barile, Santiago Roura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, J., Sluijter, J.P.G. Extracellular vesicles in cardiovascular homeostasis and disease: potential role in diagnosis and therapy. Nat Rev Cardiol 22, 883–895 (2025). https://doi.org/10.1038/s41569-025-01141-2

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41569-025-01141-2

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing