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  • Review Article
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Native and bioengineered extracellular vesicles for cardiovascular therapeutics

Nature Reviews Cardiology volume 17, pages 685–697 (2020)Cite this article

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Abstract

Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation.

Key points

  • Extracellular vesicles (EVs) secreted from stem or progenitor cells and from differentiated somatic cells have regenerative properties in the context of myocardial infarction, ischaemic limb disease and stroke.

  • Despite the benefits of native EVs as delivery agents, their application in the cardiovascular context is hindered by intrinsic drawbacks, such as their undefined and heterogeneous nature and limited tropism.

  • EVs can be improved by bioengineering approaches using both pre-isolation and post-isolation methods to increase the targeting, bioactivity, kinetics, biodistribution and contents of EVs.

  • Bioengineering of EVs is necessary to improve their clinical potential for cardiovascular applications.

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Fig. 1: Limitations and challenges in the use of native EVs as cardiovascular therapies.
Fig. 2: Modulation of EVs for cardiovascular therapies.
Fig. 3: Examples of EV-modulation strategies for cardiac therapies.

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References

  1. Roth, G. A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol. 70, 1–25 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Passier, R., van Laake, L. W. & Mummery, C. L. Stem-cell-based therapy and lessons from the heart. Nature 453, 322–329 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Vagnozzi, R. J. et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature 577, 405–409 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Wysoczynski, M., Khan, A. & Bolli, R. New paradigms in cell therapy: repeated dosing, intravenous delivery, immunomodulatory actions, and new cell types. Circ. Res. 123, 138–158 (2018).

    Article  PubMed  CAS  Google Scholar 

  5. György, B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 68, 2667–2688 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Deatherage, B. L. & Cookson, B. T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect. Immun. 80, 1948–1957 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thery, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Witwer, K. W. & Thery, C. Extracellular vesicles or exosomes? On primacy, precision, and popularity influencing a choice of nomenclature. J. Extracell. Vesicles 8, 1648167 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Sahoo, S. et al. Exosomes from human CD34+ stem cells mediate their proangiogenic paracrine activity. Circ. Res. 109, 724–728 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Beltrami, C. et al. Human pericardial fluid contains exosomes enriched with cardiovascular-expressed microRNAs and promotes therapeutic angiogenesis. Mol. Ther. 25, 679–693 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rautou, P. E. et al. Abnormal plasma microparticles impair vasoconstrictor responses in patients with cirrhosis. Gastroenterology 143, 166–176.e6 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Minghua, W. et al. Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24. Cell Death Dis. 9, 320 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Qiao, L. et al. microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential. J. Clin. Invest. 129, 2237–2250 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yamaguchi, T. et al. Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction. Int. J. Cardiol. 178, 239–246 (2015).

    Article  PubMed  Google Scholar 

  19. Jansen, F., Nickenig, G. & Werner, N. Extracellular vesicles in cardiovascular disease: potential applications in diagnosis, prognosis, and epidemiology. Circ. Res. 120, 1649–1657 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Lai, R. C. et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 4, 214–222 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Zhu, L. P. et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics 8, 6163–6177 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wei, Z. et al. miRNA-181a over-expression in mesenchymal stem cell-derived exosomes influenced inflammatory response after myocardial ischemia-reperfusion injury. Life Sci. 232, 116632 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. 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  CAS  PubMed  Google Scholar 

  26. Mathieu, M., Martin-Jaular, L., Lavieu, G. & Thery, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 21, 9–17 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Théry, C., Amigorena, S., Raposo, G. & Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 3, 3.22 (2006).

    Google Scholar 

  28. Zhang, H. et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat. Cell Biol. 20, 332–343 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nordin, J. Z. et al. Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. Nanomedicine 11, 879–883 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Toy, R., Hayden, E., Shoup, C., Baskaran, H. & Karathanasis, E. The effects of particle size, density and shape on margination of nanoparticles in microcirculation. Nanotechnology 22, 115101 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Lim, J. P. & Gleeson, P. A. Macropinocytosis: an endocytic pathway for internalising large gulps. Immunol. Cell Biol. 89, 836–843 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, J., Cao, L., Shvartsman, D., Silva, E. A. & Mooney, D. J. Targeted delivery of nanoparticles to ischemic muscle for imaging and therapeutic angiogenesis. Nano Lett. 11, 694–700 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Costa Verdera, H., Gitz-Francois, J. J., Schiffelers, R. M. & Vader, P. Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis. J. Control. Release 266, 100–108 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Conner, S. D. & Schmid, S. L. Regulated portals of entry into the cell. Nature 422, 37–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Klumperman, J. & Raposo, G. The complex ultrastructure of the endolysosomal system. Cold Spring Harb. Perspect. Biol. 6, a016857 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Akagi, T., Kato, K., Hanamura, N., Kobayashi, M. & Ichiki, T. Evaluation of desialylation effect on zeta potential extracellular vesicles secreted from human prostate cancer cells by on-chip microcapillary electrophoresis. Jpn J. Appl. Phy. 53, 6S (2014).

    Article  CAS  Google Scholar 

  38. Yao, C. et al. Highly biocompatible zwitterionic phospholipids coated upconversion nanoparticles for efficient bioimaging. Anal. Chem. 86, 9749–9757 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Ayala, V., Herrera, A. P., Latorre-Esteves, M., Torres-Lugo, M. & Rinaldi, C. Effect of surface charge on the colloidal stability and in vitro uptake of carboxymethyl dextran-coated iron oxide nanoparticles. J. Nanopart. Res. 15, 1874 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Van Deun, J. et al. The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J. Extracell. Vesicles 3, 24858 (2014).

    Article  Google Scholar 

  41. Ramirez, M. I. et al. Technical challenges of working with extracellular vesicles. Nanoscale 10, 881–906 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Skotland, T., Sandvig, K. & Llorente, A. Lipids in exosomes: current knowledge and the way forward. Prog. Lipid Res. 66, 30–41 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Osteikoetxea, X. et al. Improved characterization of EV preparations based on protein to lipid ratio and lipid properties. PLoS One 10, e0121184 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Osteikoetxea, X. et al. Differential detergent sensitivity of extracellular vesicle subpopulations. Org. Biomol. Chem. 13, 9775–9782 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Kooijmans, S. A. A. et al. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J. Control. Release 224, 77–85 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Vinas, J. L. et al. Receptor-ligand interaction mediates targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury. Sci. Rep. 8, 16320 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Verweij, F. J. et al. Live tracking of inter-organ communication by endogenous exosomes in vivo. Dev. Cell 48, 573–589.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  48. Sung, B. H., Ketova, T., Hoshino, D., Zijlstra, A. & Weaver, A. M. Directional cell movement through tissues is controlled by exosome secretion. Nat. Commun. 6, 7164 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Del Conde, I., Shrimpton, C. N., Thiagarajan, P. & Lopez, J. A. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106, 1604–1611 (2005).

    Article  PubMed  CAS  Google Scholar 

  50. Christianson, H. C., Svensson, K. J., van Kuppevelt, T. H., Li, J. P. & Belting, M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc. Natl Acad. Sci. USA 110, 17380–17385 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mulcahy, L. A., Pink, R. C. & Carter, D. R. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3, 24641 (2014).

    Article  CAS  Google Scholar 

  52. Charoenviriyakul, C., Takahashi, Y., Morishita, M., Nishikawa, M. & Takakura, Y. Role of extracellular vesicle surface proteins in the pharmacokinetics of extracellular vesicles. Mol. Pharm. 15, 1073–1080 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Royo, F., Cossio, U., Ruiz de Angulo, A., Llop, J. & Falcon-Perez, J. M. Modification of the glycosylation of extracellular vesicles alters their biodistribution in mice. Nanoscale 11, 1531–1537 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Wiklander, O. P. 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 

  55. Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Wolfers, J. et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat. Med. 7, 297–303 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Jeppesen, D. K. et al. Reassessment of exosome composition. Cell 177, 428–445.e18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6, 22519 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl Acad. Sci. USA 113, E968–E977 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ageta, H. et al. UBL3 modification influences protein sorting to small extracellular vesicles. Nat. Commun. 9, 3936 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Liang, Y. et al. Complex N-linked glycans serve as a determinant for exosome/microvesicle cargo recruitment. J. Biol. Chem. 289, 32526–32537 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Choi, D. S., Kim, D. K., Kim, Y. K. & Gho, Y. S. Proteomics of extracellular vesicles: exosomes and ectosomes. Mass Spectrom. Rev. 34, 474–490 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Mangi, A. A. et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat. Med. 9, 1195–1201 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Kawamoto, A. et al. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation 114, 2163–2169 (2006).

    Article  PubMed  Google Scholar 

  65. Timmers, L. et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 1, 129–137 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Gnecchi, M. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat. Med. 11, 367–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Mathiyalagan, P. et al. Angiogenic mechanisms of human CD34+ stem cell exosomes in the repair of ischemic hindlimb. Circ. Res. 120, 1466–1476 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Barile, L. et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc. Res. 103, 530–541 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Ibrahim, A. G., Cheng, K. & Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2, 606–619 (2014).

    Article  CAS  Google Scholar 

  70. Agarwal, U. et al. Experimental, systems, and computational approaches to understanding the microRNA-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients. Circ. Res. 120, 701–712 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Henriques-Antunes, H. et al. The kinetics of small extracellular vesicle delivery impacts skin tissue regeneration. ACS Nano 13, 8694–8707 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Liu, B. et al. Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat. Biomed. Eng. 2, 293–303 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Saha, P. et al. Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium. Sci. Transl Med. 11, eaau1168 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen, L. et al. Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PLoS One 12, e0185406 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Lapchak, P. A., Boitano, P. D., de Couto, G. & Marban, E. Intravenous xenogeneic human cardiosphere-derived cell extracellular vesicles (exosomes) improves behavioral function in small-clot embolized rabbits. Exp. Neurol. 307, 109–117 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Yang, J., Zhang, X., Chen, X., Wang, L. & Yang, G. Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Mol. Ther. Nucleic Acids 7, 278–287 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu, B. et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int. J. Cardiol. 182, 349–360 (2015).

    Article  PubMed  Google Scholar 

  78. Ma, J. et al. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cell Transl Med. 6, 51–59 (2017).

    Article  CAS  Google Scholar 

  79. Luther, K. M. et al. Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells. J. Mol. Cell. Cardiol. 119, 125–137 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. Bian, S. et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J. Mol. Med. 92, 387–397 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Feng, Y., Huang, W., Wani, M., Yu, X. & Ashraf, M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9, e88685 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Zhao, Y. et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cell Int. 2015, 761643 (2015).

    Google Scholar 

  83. Teng, X. et al. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell. Physiol. Biochem. 37, 2415–2424 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. de Couto, G. et al. Exosomal microRNA transfer into macrophages mediates cellular postconditioning. Circulation 136, 200–214 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Cambier, L. et al. Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol. Med. 9, 337–352 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sharma, S. et al. A deep proteome analysis identifies the complete secretome as the functional unit of human cardiac progenitor cells. Circ. Res. 120, 816–834 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Kervadec, A. et al. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J. Heart Lung Transplant. 35, 795–807 (2016).

    Article  PubMed  Google Scholar 

  88. Gray, W. D. et al. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ. Res. 116, 255–263 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Adamiak, M. et al. Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs. Circ. Res. 122, 296–309 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Wang, Y. et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int. J. Cardiol. 192, 61–69 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  91. El Harane, N. et al. Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. Eur. Heart J. 39, 1835–1847 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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 

  93. Khan, M. et al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ. Res. 117, 52–64 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu, H. et al. Exosomes derived from dendritic cells improve cardiac function via activation of CD4+ T lymphocytes after myocardial infarction. J. Mol. Cell. Cardiol. 91, 123–133 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. 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 

  96. Ribeiro-Rodrigues, T. M. et al. Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis. Cardiovasc. Res. 113, 1338–1350 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Rogers, R. G. et al. Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice. JCI Insight 4, 130202 (2019).

    Article  PubMed  Google Scholar 

  98. Pitt, J. M. et al. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J. Immunol. 193, 1006–1011 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Aminzadeh, M. A. et al. Exosome-mediated benefits of cell therapy in mouse and human models of Duchenne muscular dystrophy. Stem Cell Rep. 10, 942–955 (2018).

    Article  CAS  Google Scholar 

  100. Gollmann-Tepekoylu, C. et al. miR-19a-3p containing exosomes improve function of ischemic myocardium upon shock wave therapy. Cardiovasc. Res. 116, 1226–1236 (2020).

    Article  PubMed  CAS  Google Scholar 

  101. Boon, R. A. & Dimmeler, S. MicroRNAs in myocardial infarction. Nat. Rev. Cardiol. 12, 135–142 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Yue, Y. et al. Interleukin-10 deficiency alters endothelial progenitor cell-derived exosome reparative effect on myocardial repair via integrin-linked kinase enrichment. Circ. Res. 126, 315–329 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Middleton, R. C. et al. Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes. J. Extracell. Vesicles 7, 1456888 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Yang, Y. et al. Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia. J. Mol. Med. 94, 711–724 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. Davidson, S. M. et al. Endothelial cells release cardioprotective exosomes that may contribute to ischaemic preconditioning. Sci. Rep. 8, 15885 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Loyer, X. et al. Intra-cardiac release of extracellular vesicles shapes inflammation following myocardial infarction. Circ. Res. 123, 100–106 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhang, H. C. et al. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cell Dev. 21, 3289–3297 (2012).

    Article  CAS  Google Scholar 

  108. Timmers, L. et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res. 6, 206–214 (2011).

    Article  PubMed  Google Scholar 

  109. An, M. et al. Extracellular matrix-derived extracellular vesicles promote cardiomyocyte growth and electrical activity in engineered cardiac atria. Biomaterials 146, 49–59 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Tian, T. et al. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials 150, 137–149 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Hwang, D. et al. Chemical modulation of bioengineered exosomes for tissue-specific biodistribution. Adv. Ther. 2, 8 (2019).

    Google Scholar 

  112. Lai, C. P. et al. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8, 483–494 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Banerjee, A. et al. A positron-emission tomography (PET)/magnetic resonance imaging (MRI) platform to track in vivo small extracellular vesicles. Nanoscale 11, 13243–13248 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Hwang, D. W. et al. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99mTc-HMPAO. Sci. Rep. 5, 15636 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Varga, Z. et al. Radiolabeling of extracellular vesicles with 99mTc for quantitative in vivo imaging studies. Cancer Biother. Radiopharm. 31, 168–173 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Guduric-Fuchs, J. et al. Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics 13, 357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shao, L. et al. Knockout of beta-2 microglobulin enhances cardiac repair by modulating exosome imprinting and inhibiting stem cell-induced immune rejection. Cell. Mol. Life Sci. 77, 937–952 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. van Balkom, B. W. et al. Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 121, 3997–4006 (2013).

    Article  PubMed  CAS  Google Scholar 

  120. Kanada, M. et al. Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proc. Natl Acad. Sci. USA 112, E1433–E1442 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ibrahim, A. G. E. et al. Augmenting canonical Wnt signalling in therapeutically inert cells converts them into therapeutically potent exosome factories. Nat. Biomed. Eng. 3, 695–705 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kang, T. et al. Adipose-derived stem cells induce angiogenesis via microvesicle transport of miRNA-31. Stem Cell Transl Med. 5, 440–450 (2016).

    Article  CAS  Google Scholar 

  123. Yim, N. et al. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat. Commun. 7, 12277 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kojima, R. et al. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat. Commun. 9, 1305 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Hung, M. E. & Leonard, J. N. A platform for actively loading cargo RNA to elucidate limiting steps in EV-mediated delivery. J. Extracell. Vesicles 5, 31027 (2016).

    Article  PubMed  CAS  Google Scholar 

  126. Antes, T. J. et al. Targeting extracellular vesicles to injured tissue using membrane cloaking and surface display. J. Nanobiotechnol. 16, 61 (2018).

    Article  CAS  Google Scholar 

  127. Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  129. Lamichhane, T. N., Raiker, R. S. & Jay, S. M. Exogenous DNA loading into extracellular vesicles via electroporation is size-dependent and enables limited gene delivery. Mol. Pharm. 12, 3650–3657 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fuhrmann, G., Serio, A., Mazo, M., Nair, R. & Stevens, M. M. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release 205, 35–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Kalani, A. et al. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Int. J. Biochem. Cell Biol. 79, 360–369 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, D., Lee, H., Zhu, Z., Minhas, J. K. & Jin, Y. Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 312, L110–L121 (2017).

    Article  PubMed  Google Scholar 

  133. Parry, H. A. et al. Bovine milk extracellular vesicles (EVs) modification elicits skeletal muscle growth in rats. Front. Physiol. 10, 436 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Sun, D. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606–1614 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhuang, X. et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 19, 1769–1779 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Haraszti, R. A. et al. Optimized cholesterol-siRNA chemistry improves productive loading onto extracellular vesicles. Mol. Ther. 26, 1973–1982 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. O’Loughlin, A. J. et al. Functional delivery of lipid-conjugated siRNA by extracellular vesicles. Mol. Ther. 25, 1580–1587 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Castano, C., Kalko, S., Novials, A. & Parrizas, M. Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc. Natl Acad. Sci. USA 115, 12158–12163 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zeng, Z. et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat. Commun. 9, 5395 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pi, F. et al. Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nat. Nanotechnol. 13, 82–89 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Kang, J. Y. et al. Human peripheral blood-derived exosomes for microRNA delivery. Int. J. Mol. Med. 43, 2319–2328 (2019).

    CAS  Google Scholar 

  142. Youn, S. W. et al. Modification of cardiac progenitor cell-derived exosomes by miR-322 provides protection against myocardial infarction through Nox2-dependent angiogenesis. Antioxidants 8, E18 (2019).

    Article  PubMed  CAS  Google Scholar 

  143. Faruqu, F. N. et al. Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice — a novel and universal approach. Theranostics 9, 1666–1682 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Smyth, T. et al. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control. Release 199, 145–155 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Morishita, M. et al. Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. J. Pharm. Sci. 104, 705–713 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Suk, J. S., Xu, Q., Kim, N., Hanes, J. & Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28–51 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Vandergriff, A. et al. Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide. Theranostics 8, 1869–1878 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wang, X. et al. Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction. J. Am. Heart Assoc. 7, e008737 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mentkowski, K. I. & Lang, J. K. Exosomes engineered to express a cardiomyocyte binding peptide demonstrate improved cardiac retention in vivo. Sci. Rep. 9, 10041 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Kim, H. et al. Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes. Biochem. Biophys. Res. Commun. 499, 803–808 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Wang, J. et al. The use of RGD-engineered exosomes for enhanced targeting ability and synergistic therapy toward angiogenesis. Nanoscale 9, 15598–15605 (2017).

    Article  CAS  PubMed  Google Scholar 

  152. Rana, S., Yue, S., Stadel, D. & Zoller, M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int. J. Biochem. Cell Biol. 44, 1574–1584 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Biglino, G. et al. Modulating microRNAs in cardiac surgery patients: novel therapeutic opportunities? Pharmacol. Ther. 170, 192–204 (2017).

    Article  CAS  PubMed  Google Scholar 

  154. Geeurickx, E. et al. The generation and use of recombinant extracellular vesicles as biological reference material. Nat. Commun. 10, 3288 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Heusermann, W. et al. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J. Cell Biol. 213, 173–184 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Feng, D. et al. Cellular internalization of exosomes occurs through phagocytosis. Traffic 11, 675–687 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Tian, T. et al. Dynamics of exosome internalization and trafficking. J. Cell. Physiol. 228, 1487–1495 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Nakase, I. & Futaki, S. Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. Sci. Rep. 5, 10112 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Nakase, I., Noguchi, K., Fujii, I. & Futaki, S. Vectorization of biomacromolecules into cells using extracellular vesicles with enhanced internalization induced by macropinocytosis. Sci. Rep. 6, 34937 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Nakase, I. et al. Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular delivery. Sci. Rep. 7, 1991 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. 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 

  162. Chung, J. J. et al. Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics. J. Thorac. Cardiovasc. Surg. 159, 1825-1835.e2 (2020).

    Article  PubMed  CAS  Google Scholar 

  163. Guo, S. C. et al. Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics 7, 81–96 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lv, K. et al. Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction. Theranostics 9, 7403–7416 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Tao, S. C. et al. Chitosan wound dressings incorporating exosomes derived from microRNA-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model. Stem Cell Transl Med. 6, 736–747 (2017).

    Article  CAS  Google Scholar 

  166. Zhang, K. et al. Enhanced therapeutic effects of mesenchymal stem cell-derived exosomes with an injectable hydrogel for hindlimb ischemia treatment. ACS Appl. Mater. Interfaces 10, 30081–30091 (2018).

    Article  CAS  PubMed  Google Scholar 

  167. Han, C. et al. Human umbilical cord mesenchymal stem cell derived exosomes encapsulated in functional peptide hydrogels promote cardiac repair. Biomater. Sci. 7, 2920–2933 (2019).

    Article  CAS  PubMed  Google Scholar 

  168. Xu, N. et al. Wound healing effects of a Curcuma zedoaria polysaccharide with platelet-rich plasma exosomes assembled on chitosan/silk hydrogel sponge in a diabetic rat model. Int. J. Biol. Macromol. 117, 102–107 (2018).

    Article  CAS  PubMed  Google Scholar 

  169. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03478410 (2020).

  170. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04127591 (2019).

  171. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02565264 (2018).

  172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03384433 (2020).

  173. De Wever, O. & Hendrix, A. A supporting ecosystem to mature extracellular vesicles into clinical application. EMBO J. 38, e101412 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Lotvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicles 3, 26913 (2014).

    Article  PubMed  Google Scholar 

  175. Kordelas, L. et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28, 970–973 (2014).

    Article  CAS  PubMed  Google Scholar 

  176. Ng, K. S. et al. Bioprocess decision support tool for scalable manufacture of extracellular vesicles. Biotechnol. Bioeng. 116, 307–319 (2019).

    Article  CAS  PubMed  Google Scholar 

  177. Watson, D. C. et al. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials 105, 195–205 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Balbi, C. et al. Reactivating endogenous mechanisms of cardiac regeneration via paracrine boosting using the human amniotic fluid stem cell secretome. Int. J. Cardiol. 287, 87–95 (2019).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors were supported by the Portuguese National Funding Agency for Science, Research and Technology (fellowship to R.C.d.A. (SFRH/SFRH/BD/129317/2017) and Project Exo-Heart (POCI-01-0145-FEDER-029919) to H.F.). P.A.d.C.M. is funded by a Dutch Heart Foundation grant (NHS2015T066). P.A.d.C.M., C.E. and L.F. are members of the EEU COST Action CardioRNA CA17129. S.S. has received grants from the NIH (HL124187, HL140469, HL148786 and NYSTEM C32562GG) and Transatlantic Foundation Leducq. C.E. has received funding via a British Heart Foundation (BHF) programme grant, personal Chair awards (RG/15/5/31446 and CH/15/1/31199) and the BHF Centre of Vascular Regeneration. L.F. is supported by Program Interreg Atlantic Space through the European Fund for Regional Development (Project NeuroAtlantic (EAPA_791/2018) and Project 2IQBIONEURO (0624_2IQBIONEURO_6_E)) and EC Project ERAatUC (669088).

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Authors and Affiliations

  1. CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands

    Ricardo Cerqueira de Abreu & Paula A. da Costa Martins

  2. Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, Netherlands

    Ricardo Cerqueira de Abreu & Paula A. da Costa Martins

  3. CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Ricardo Cerqueira de Abreu & Lino Ferreira

  4. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Hugo Fernandes & Lino Ferreira

  5. Division of Cardiology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Susmita Sahoo

  6. National Heart & Lung Institute, Imperial College London, London, UK

    Costanza Emanueli

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  1. Ricardo Cerqueira de Abreu
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All the authors contributed to researching data for article, discussion of content, writing the article, and reviewing and editing the manuscript before submission.

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Correspondence to Lino Ferreira.

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Nature Reviews Cardiology thanks L. Barile, E. Marbán and P. Menasché for their contribution to the peer review of this work.

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Glossary

Macropinocytosis

A regulated form of endocytosis that mediates non-selective uptake of extracellular material, such as soluble molecules, nutrients and antigens.

Electroporation

A transfection method in which biological membranes are permeabilized by exposure to an electrical pulse.

Heat–shock

A transformation technique that relies on heat to induce membrane permeabilization.

Sonication

The use of ultrasound technology to physically disrupt biological membranes and facilitate the entry of exogenous compounds.

Passive loading

A strategy that relies on passive diffusion or complexation of a molecule with a cell or organelle; loading can be dependent on various factors, such as pH, osmotic pressure, electric charge and hydrophobicity.

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de Abreu, R.C., Fernandes, H., da Costa Martins, P.A. et al. Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat Rev Cardiol 17, 685–697 (2020). https://doi.org/10.1038/s41569-020-0389-5

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