Extracellular vesicles in cardiac regeneration and aging: mechanisms and translation

Abstract

Myocardial infarction (MI) and age-related cardiac remodeling remain major causes of morbidity and mortality worldwide. Because the adult heart has only limited regenerative capacity, extracellular vesicles (EVs) have emerged as promising acellular mediators of tissue repair, with the potential to mitigate both ischemic injury and age-associated decline. Preclinical studies demonstrate that EVs derived from stem and progenitor cells exert anti-apoptotic, anti-fibrotic, anti-inflammatory, and pro-angiogenic effects. In aged hearts, EVs can help restore metabolic homeostasis, attenuate pro-senescent signaling, and improve functional resilience. Early-phase clinical trials suggest that EV-based or EV-enriched products are feasible and safe, although evidence of efficacy remains limited. This review synthesizes current mechanistic insights into EV-mediated regulation of inflammation, fibrosis, angiogenesis, oxidative and ferroptotic stress, and cellular senescence, underscoring the therapeutic potential of EVs in cardiac regeneration - particularly in older patients with impaired endogenous repair. Importantly, it uniquely integrates the dual roles of EVs in both myocardial infarction repair and cardiac aging, thereby addressing a critical gap in the literature. By linking mechanisms of post-infarction regeneration with age-related cardiac decline, we outline the translational challenges and opportunities of EV-based therapies. Further advances in EV engineering, targeting, dosing, potency assays, and standardization will be essential for successful clinical translation.

Keywords

Extracellular vesicles / myocardial infarction / cardiac aging / senescence / regeneration / stem cells / angiogenesis / inflammation

References

[1] Wood C,Garcia I.Age-associated changes in the heart: implications for COVID-19 therapies.Aging2025;17:1340-67 PMCID:PMC12151517

[2] Marín-Aguilar F,Alcocer-Gómez E.NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice.Aging Cell2020;19:e13050 PMCID:PMC6974709

[3] Lakatta EG.Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons.Heart Fail Rev2002;7:29-49

[4] Théry C,Aikawa E.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 Vesicles2018;7:1535750 PMCID:PMC6322352

[5] Yáñez-Mó M,Andreu Z.Biological properties of extracellular vesicles and their physiological functions.J Extracell Vesicles2015;4:27066

[6] Andaloussi S,Breakefield XO.Extracellular vesicles: biology and emerging therapeutic opportunities.Nat Rev Drug Discov2013;12:347-57

[7] Barile L.Exosomes: Therapy delivery tools and biomarkers of diseases.Pharmacol Ther2017;174:63-78

[8] Kalluri R.The biology, function, and biomedical applications of exosomes.Science2020;367:eaau6977 PMCID:PMC7717626

[9] Ibrahim AG,Marbán E.Exosomes as critical agents of cardiac regeneration triggered by cell therapy.Stem Cell Reports2014;2:606-19 PMCID:PMC4050492

[10] Gallet R,Valle J.Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction.Eur Heart J2017;38:201-11 PMCID:PMC5837390

[11] Lai RC,Lee MM.Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.Stem Cell Res2010;4:214-22

[12] Sanz-Ros J,Mas-Bargues C.Small extracellular vesicles from young adipose-derived stem cells ameliorate age-related changes in the heart of old mice.Stem Cell Res Ther2025;16:138 PMCID:PMC11907833

[13] Nicin L,Luxán G.Fibroblast-mediated intercellular crosstalk in the healthy and diseased heart.FEBS Lett2022;596:638-54

[14] Yuan Z.New developments in exosomal lncRNAs in cardiovascular diseases.Front Cardiovasc Med2021;8:709169 PMCID:PMC8295603

[15] Sluijter JPG,Boulanger CM.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 Res2018;114:19-34 PMCID:PMC5852624

[16] Caruso S.Apoptotic cell-derived extracellular vesicles: more than just debris.Front Immunol2018;9:1486 PMCID:PMC6031707

[17] Alvarez-Erviti L,Yin H,Lakhal S.Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.Nat Biotechnol2011;29:341-5

[18] Wang L,Ye Z.Engineering extracellular vesicles as delivery systems in therapeutic applications.Adv Sci2023;10:2300552 PMCID:PMC10265081

[19] Nieland L,Grandell E,Breakefield XO.Engineered EVs designed to target diseases of the CNS.J Control Release2023;356:493-506 PMCID:PMC10226535

[20] Shao L,Lan B.MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair.Biomed Res Int2017;2017:4150705 PMCID:PMC5292186

[21] Jansen F.Exosomes as diagnostic biomarkers in cardiovascular diseases. In: Xiao J, Cretoiu S, editors. Exosomes in cardiovascular diseases. Singapore: Springer; 2017. pp. 61-70.

[22] Zhao Y,Cao W.Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury.Stem Cells Int2015;2015:761643 PMCID:PMC4461782

[23] Song Y,Zhang J.Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction.Theranostics2019;9:2346-60 PMCID:PMC6531307

[24] Li K,Li Q.The MicroRNA-210/Casp8ap2 pathway alleviates hypoxia-induced injury in myocardial cells by regulating apoptosis and autophagy.Heart Surg Forum2020;23:E797-802

[25] Zhao DZ,Wei HX.Advances in the research of immunomodulatory mechanism of mesenchymal stromal/stem cells on periodontal tissue regeneration.Front Immunol2024;15:1449411 PMCID:PMC11739081

[26] Zhao J,Hu J.Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization.Cardiovasc Res2019;115:1205-16 PMCID:PMC6529919

[27] Song Y,Li X.Exosomal miR-146a contributes to the enhanced therapeutic efficacy of interleukin-1β-primed mesenchymal stem cells against sepsis.Stem Cells2017;35:1208-21

[28] Liu J,Lei P,Huang P.Exosomes released by bone marrow mesenchymal stem cells attenuate lung injury induced by intestinal ischemia reperfusion via the TLR4/NF-κB pathway.Int J Med Sci2019;16:1238-44 PMCID:PMC6775266

[29] Bian S,Duan L,Min Y.Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model.J Mol Med2014;92:387-97

[30] Liu W,Rong Y.Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126.Acta Biomater2020;103:196-212

[31] Zhao Y,Chen S,Zhao J.New insights into the functions of micrornas in cardiac fibrosis: from mechanisms to therapeutic strategies.Genes2022;13:1390 PMCID:PMC9407613

[32] Duisters RF,Schroen B.miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling.Circ Res2009;104:170-8

[33] Nashtahosseini Z,Fazilat A.The crosstalk between exosomal miRNA and ferroptosis: a narrative review.Biol Cell2025;117:e2400077

[34] Zhang L,He G.Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.J Cell Mol Med2021;25:2148-62

[35] Cheng H,Xu R.Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis.Stem Cell Res Ther2020;11:224 PMCID:PMC7278138

[36] Liu Z,Yao J.Serum extracellular vesicles promote proliferation of H9C2 cardiomyocytes by increasing miR-17-3p.Biochem Biophys Res Commun2018;499:441-6

[37] Zhang J,Long K.Overexpression of exosomal cardioprotective miRNAs mitigates hypoxia-induced H9c2 cells apoptosis.Int J Mol Sci2017;18:711 PMCID:PMC5412297

[38] Bheri S,Park HJ,Takaesu F.Customized loading of microRNA-126 to small extracellular vesicle-derived vehicles improves cardiac function after myocardial infarction.ACS Nano2023;17:19613-24 PMCID:PMC10604069

[39] Khan M,Abramova T.Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction.Circ Res2015;117:52-64

[40] Wang Y,Li Y.Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium.Int J Cardiol2015;192:61-9 PMCID:PMC4469495

[41] Loyer X,Devue C.Intra-cardiac release of extracellular vesicles shapes inflammation following myocardial infarction.Circ Res2018;123:100-6

[42] Lai RC,Lim SK.Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease.Regen Med2011;6:481-92

[43] Wiklander OP,O’Loughlin A.Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting.J Extracell Vesicles2015;4:26316 PMCID:PMC4405624

[44] Mendt M,Sugimoto H.Generation and testing of clinical-grade exosomes for pancreatic cancer.JCI Insight2018;3:e99263 PMCID:PMC5931131

[45] Barile L,Marbán E.Roles of exosomes in cardioprotection.Eur Heart J2017;38:1372-9

[46] Wu HY,Jia BB.Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acetaminophen-induced acute liver failure through activating ERK and IGF-1R/PI3K/AKT signaling pathway.J Pharmacol Sci2021;147:143-55

[47] Wang X,Wu C,He Y.Adipose-derived mesenchymal stem cells-derived exosomes carry MicroRNA-671 to alleviate myocardial infarction through inactivating the TGFBR2/Smad2 axis.Inflammation2021;44:1815-30 PMCID:PMC8460592

[48] Huang J,Yang Y.Mesenchymal cell-derived exosomes and miR-29a-3p mitigate renal fibrosis and vascular rarefaction after renal ischemia reperfusion injury.Stem Cell Res Ther2025;16:135 PMCID:PMC11905586

[49] Beltrami AP,Torella D.Adult cardiac stem cells are multipotent and support myocardial regeneration.Cell2003;114:763-76

[50] Laugwitz KL,Lam J.Postnatal isl1⁺ cardioblasts enter fully differentiated cardiomyocyte lineages.Nature2005;433:647-53 PMCID:PMC5578466

[51] Xuan W,Ashraf M.Extracellular vesicles from notch activated cardiac mesenchymal stem cells promote myocyte proliferation and neovasculogenesis.Front Cell Dev Biol2020;8:11 PMCID:PMC7047205

[52] Gross JC.The mingle-mangle of wnt signaling and extracellular vesicles: functional implications for heart research.Front Cardiovasc Med2018;5:10 PMCID:PMC5850280

[53] Meng WT,Wang YC.Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury.J Nanobiotechnology2024;22:382 PMCID:PMC11218161

[54] Li H,Liu W.Plasma exosomes from patients with acute myocardial infarction alleviate myocardial injury by inhibiting ferroptosis through miR-26b-5p/SLC7A11 axis.Life Sci2023;322:121649

[55] Chen J,Wang LL.Mitochondrial transfer in cardiovascular disease: from mechanisms to therapeutic implications.Front Cardiovasc Med2021;8:771298 PMCID:PMC8661009

[56] Ceja L,Hughes L.Neonatal cardiovascular-progenitor-cell-derived extracellular vesicles activate yap1 in adult cardiac progenitor cells.Int J Mol Sci2023;24:8088 PMCID:PMC10179407

[57] Micco R,Baker D.Cellular senescence in ageing: from mechanisms to therapeutic opportunities.Nat Rev Mol Cell Biol2021;22:75-95 PMCID:PMC8344376

[58] Dai DF,Johnson SC,Rabinovitch PS.Cardiac aging: from molecular mechanisms to significance in human health and disease.Antioxid Redox Signal2012;16:1492-526 PMCID:PMC3329953

[59] Xia W,Chen D,Xie C.PD-1 inhibitor inducing exosomal miR-34a-5p expression mediates the cross talk between cardiomyocyte and macrophage in immune checkpoint inhibitor-related cardiac dysfunction.J Immunother Cancer2020;8:e001293

[60] Feng R,Chen K,Lin Y.Stem cell-derived extracellular vesicles mitigate ageing-associated arterial stiffness and hypertension.J Extracell Vesicles2020;9:1783869

[61] Estévez-Souto V,Collado M.The role of extracellular vesicles in cellular senescence.FEBS J2023;290:1203-11

[62] Terlecki-Zaniewicz L,Latreille J.Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype.Aging2018;10:1103-32 PMCID:PMC5990398

[63] Borghesan M,Eleftheriadou O.Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3.Cell Rep2019;27:3956-3971.e6 PMCID:PMC6613042

[64] Riquelme JA,Santiago-Fernández C.Increased production of functional small extracellular vesicles in senescent endothelial cells.J Cell Mol Med2020;24:4871-6 PMCID:PMC7176858

[65] Mensà E,Giuliani A.Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells.J Extracell Vesicles2020;9:1725285

[66] Jeon OH,Clement CC.Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers.JCI Insight2019;4:e125019

[67] Suraih MS,Splinter PL,O’Hara SP.Senescent cholangiocytes release extracellular vesicles that alter target cell phenotype via the epidermal growth factor receptor.Liver Int2020;40:2455-68 PMCID:PMC7669612

[68] Gimona M,Choo ABH.Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles.Cytotherapy2021;23:373-80

[69] Chen H,Hou M.LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway.Stem Cell Res Ther2020;11:31 PMCID:PMC6975066

[70] Zhuang L,Chen D.Exosomal LncRNA-NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p.J Nanobiotechnology2020;18:157

[71] Ma T,Chen Y.MicroRNA-132, delivered by mesenchymal stem cell-derived exosomes, promote angiogenesis in myocardial infarction.Stem Cells Int2018;2018:3290372 PMCID:PMC6151206

[72] Boulanger CM,Rautou PE.Extracellular vesicles in coronary artery disease.Nat Rev Cardiol2017;14:259-72

[73] Gasecka A,Budnik M.Randomized controlled trial protocol to investigate the antiplatelet therapy effect on extracellular vesicles (AFFECT EV) in acute myocardial infarction.Platelets2020;31:26-32

[74] ClinicalTrials.gov. Safety evaluation of intracoronary infusion of extracellular vesicles in patients following coronary stent implantation. U.S. National Library of Medicine; 2025 Mar. Report No.: NCT04327635. Available from: https://clinicaltrials.gov/study/NCT04327635 [Last accessed on 27 Oct 2025]

[75] ClinicalTrials.gov. Treatment of non-ischemic cardiomyopathies by intravenous extracellular vesicles of cardiovascular progenitor cells (SECRET-HF). U.S. National Library of Medicine; 2023 Sep. Report No.: NCT05774509. Available from: https://clinicaltrials.gov/study/NCT05774509 [Last accessed on 27 Oct 2025]

[76] Lightner AL,Qian S.Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for the treatment of respiratory failure from COVID-19: a randomized, placebo-controlled dosing clinical trial.CHEST2023;164:1444-53 PMCID:PMC10289818

[77] Lu Y,Lamothe G.CRISPR-Cas9 delivery strategies with engineered extracellular vesicles.Mol Ther Nucleic Acids2023;34:102040 PMCID:PMC10571031

[78] García-Manrique P,Gutiérrez G,Blanco-López MC.Therapeutic biomaterials based on extracellular vesicles: classification of bio-engineering and mimetic preparation routes.J Extracell Vesicles2018;7:1422676

[79] Li P,Lee SH,Gao Z.Progress in exosome isolation techniques.Theranostics2017;7:789-804 PMCID:PMC5327650

[80] Ahmadian S,Tamadon A,Rahbarghazi R.Different storage and freezing protocols for extracellular vesicles: a systematic review.Stem Cell Res Ther2024;15:453 PMCID:PMC11600612

[81] Jeyaram A.Preservation and storage stability of extracellular vesicles for therapeutic applications.AAPS J2017;20:1 PMCID:PMC6582961

[82] Williams T,Burns M.Versatility of mesenchymal stem cell-derived extracellular vesicles in tissue repair and regenerative applications.Biochimie2023;207:33-48

[83] Almeria C,Weber V,Kasper C.Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions.Cell Biosci2022;12:51 PMCID:PMC9063275

[84] Vandergriff A,Shen D.Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide.Theranostics2018;8:1869-78 PMCID:PMC5858505

[85] Qi H,Long L.Blood exosomes endowed with magnetic and targeting properties for cancer therapy.ACS Nano2016;10:3323-33

[86] Li Q,Wang Q.Engineering extracellular vesicles with platelet membranes fusion enhanced targeted therapeutic angiogenesis in a mouse model of myocardial ischemia reperfusion.Theranostics2021;11:3916-31 PMCID:PMC7914364

[87] Li YJ,Liu J.Artificial exosomes for translational nanomedicine.J Nanobiotechnology2021;19:242 PMCID:PMC8359033

[88] Greenberg ZF,He M.Towards artificial intelligence-enabled extracellular vesicle precision drug delivery.Adv Drug Deliv Rev2023;199:114974

[89] Topol EJ.High-performance medicine: the convergence of human and artificial intelligence.Nat Med2019;25:44-56

[90] Li Z.Therapeutic targeting of microRNAs: current status and future challenges.Nat Rev Drug Discov2014;13:622-38