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Bioimpacts. 2025;15:30989. doi: 10.34172/bi.30989

Systematic Review

microRNAs shuttled by mesenchymal stromal cell-derived exosomes in coronary artery disease: A systematic review of preclinical studies

Soroush Mostafavi Formal analysis, Methodology, Validation, Writing – original draft, Writing – review & editing, 1 ORCID logo
Amin Arasteh Data curation, Investigation, Methodology, Resources, 2, 3 ORCID logo
Seyedeh Mina Mostafavi Montazeri Data curation, Formal analysis, Investigation, 3 ORCID logo
Seyyedeh Mina Hejazian Resources, Writing – review & editing, 2, 4 ORCID logo
Farahnoosh Farnood Visualization, Writing – review & editing, 4 ORCID logo
Sima Abediazar Resources, Visualization, Writing – review & editing, 4 ORCID logo
Abolfazl Barzegari Conceptualization, Project administration, Writing – original draft, Writing – review & editing, 5, 6, 7, * ORCID logo
Sepideh Zununi Vahed Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing, 4, * ORCID logo

Author information:
1Department of Cardiology, Hazrat-e-Rasool General Hospital, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
2Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
3Clinical Research Development Center of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
5Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
6Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz, Iran
7Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France

*Corresponding authors: Abolfazl barzegari, Email: barzegari.abolfazl@gmail.com; Sepideh Zununi Vahed, Email: sepide.zununi@gmail.com

Abstract

Introduction:

Coronary artery disease (CAD) is a life-threatening cardiac condition with high morbidity and mortality worldwide. This systematic review article highlighted the therapeutic roles of mesenchymal stromal cells (MSCs)-derived exosomal microRNAs (exo-miRs) in preclinical models of CAD.

Methods:

A comprehensive search was conducted on PubMed, Web of Science, Scopus, and Google Scholar to identify relevant publications until 04 Apr 2025. The literature review focuses on the origin of MSCs, the technique employed for exosome extraction and identification, the route and frequency of exosomal administration, the mechanisms through which exo-miRs regulate paracrine activity, and their impact on cardiac outcome.

Results:

After meticulous evaluation, fifty-six studies were deemed eligible for inclusion in this systematic review. Bone marrow-derived MSCs were the most commonly utilized cell type in the preclinical studies. The majority of studies employed the ultracentrifugation method for exosome isolation from MSCs. The administration of exosomes was primarily achieved through a single intramyocardial injection, utilizing a wide range of exosome concentrations (ranging from 0.02-400 μg/μL).

Conclusion:

The included studies predominantly have reported the anti-inflammatory, anti-apoptotic, angiogenic, antifibrotic, and reparative effects of MSC-exo-miRs, especially under hypoxic conditions. These findings support the capacity of MSC-exo-miRs to regulate the immune system and facilitate cardiac recovery following an injury.

Keywords: Ischemic heart disease, Myocardial infarction, Coronary heart disease, microRNA, Mesenchymal stem cells, Exosomes

Copyright and License Information

© 2025 The Author(s).
This work is published by BioImpacts as an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited.

Funding Statement

This study was supported by Tabriz University of Medical Sciences, Tabriz, Iran (Grant No.: 73046).

Introduction

Coronary artery disease (CAD), also called ischemic heart disease, is a life-threatening cardiac condition characterized by impaired blood flow in the coronary arteries, primarily due to atherosclerosis. This process leads to the narrowing and stiffening of the arteries, limiting oxygen-rich blood supply to the heart muscle and potentially causing myocardial ischemia, angina, myocardial infarction (MI), or ultimately heart failure. Despite advances in medical and surgical therapies, the burden of CAD continues to rise,1 necessitating the exploration of new therapeutic strategies and biomarkers for both early diagnosis and effective treatment.

The role of multipotent mesenchymal stromal cells (MSCs) in preventing and treating CAD has become more prominent. MSCs can self-renew and differentiate into various types of cells thanks to their multipotency. Clinical studies have shown that MSC therapy can compensate for the limitation of the repair ability of myocardial cells. These cells promote angiogenesis and neovascularization, limit the infarcted area, regulate the immune system, and prevent fibrosis. Moreover, these cells can differentiate into smooth muscle cells, endothelial cells, and pericytes, generally improving heart function.2-5

MSCs secrete many paracrine factors, including growth factors, cytokines, chemokines, and extracellular vesicles (EVs), mainly exosomes, having multiple implications in regulating key biological processes. These effects include the modulation of immune responses, migration and proliferation of effector cells, and inhibition of apoptosis. Various components, such as proteins, nucleic acids [DNA, mRNAs, non-coding microRNAs (miRs/miRNAs), long non-coding RNAs (LncRNAs)], lipids, and enzymes are encapsulated within exosomes and contribute to preserving and mediating the functional effects of their parent cells.6 MSCs-derived exosomes are advantageous over parental MSCs due to lower immunogenicity, better crossing of membrane barriers, not being trapped in capillary beds, a higher safety profile, and less possibility of ectopic tumor formation. By transferring the contents of stromal cells to nearby or distant cells, exosomes present their biological effects and play a vital role in disease processes. These properties make MSC exosomes more favorable compared to the original cells.7

microRNAs have crucial functions in regulating gene expression.8 Dysregulation of miR expression has been implicated in the pathophysiology of CAD,9,10 causing inflammation, vascular remodeling, and endothelial dysfunction. As a result, miRs have garnered significant interest as potential diagnostic and therapeutic targets in cardiovascular diseases. Integrating findings from the study on human epicardial adipose tissue-exos-miRs profiles provides deeper insights into their roles in CAD pathophysiology and highlights their diagnostic and therapeutic potentials,11 which can complement preclinical studies on MSC-exos-miRs. The shuttling of miRs via MSC-derived exosomes represents a critical mechanism through which these stem cells exert their beneficial effects, particularly in the context of tissue repair and regeneration in CAD. This systematic review article highlights the therapeutic roles of MSC-exosomal miRs in CAD. Primary outcomes were cardiac function, apoptosis, inflammation, and fibrosis.


Methods

Search strategy and selection of papers

This systematic review was conducted on studies reporting the impact of exosomal miRs derived from MSCs (MSC-exos-miRs) on in vivo and in vitro cardiovascular models. This study was designed following PRISMA. A librarian searched PubMed, Web of Science, Scopus, and Google Scholar until 04 April 2025. Table S1 (Supplementary file 1) presents the terms and MeSH-based keywords used for the search strategy.

Inclusion and exclusion criteria

Original research articles in English describing preclinical in vitro and animal models with CAD using exosomes of MSCs as experimental intervention were included. MSC-derived exosomal miRs used for the regeneration and treatment of cardiovascular injuries, such as myocardial ischemia-reperfusion (I/R) damage, MI, acute coronary syndromes (ACS), vascular calcification, and atherosclerosis were included since they are either causes, complications, or related conditions to CAD. Coronary artery disease is the overarching term that includes the long-term pathological process and risk factors, while ACS is a critical and acute manifestation of CAD. Therefore, CAD is the most appropriate term to encompass the entire spectrum of related conditions. Review articles, abstracts, and articles written in a language other than English were excluded. Moreover, retracted articles and the ones with low quality were excluded. Two separate researchers (S.M, A.A) reviewed all the records from the primary search of the databases. The included studies by two researchers were matched and compared, and the third researcher controlled the controversial studies.

Extracting data

Two researchers (S.M and S.M.M.M) independently reviewed the included studies. They extracted the articles’ data regarding the type of study, animal/cellular CAD models, sample size, the source and origin of MSCs, the technique employed for exosome extraction and identification, the route, frequency, and dosage of exosomal administration, the mechanisms through which exo-miRs regulate paracrine activity, and their impact on cardiac outcome, and therapeutic potential. These data were controlled by the other researchers. The detailed extracted data of the included studies are presented in Tables 1 and 2.


Table 1. Therapeutic role of MSC-derived exosomal microRNAs in CAD models
Authors Model CAD Animals Cells Sample size & groups MSC donor
organism
Source of MSCs MSCs preconditioning Outcome Therapeutic potential
Yang et al (2021)14 In vitro, In vivo MI SD male rats Rat primary CMECs under hypoxia (0.3% O2) Sham/ MI/ MI + hMSCs- Exo Human American Type Culture Collection (ATCC, USA Transfection with miR-543 inhibitor, pCDNA3.1-COL4A1, and their negative controls ↑LVEF
↓LVEDD
↓Infarct size
Diminished infarction size
attenuated MI-induced injuries
↑Ki-67 expression
Wang et al (2023)15 In vitro, In vivo MI C57BL/6J mice HUVECs 30: Sham/ MI/ MI + ADSC-Exo Mice AD-MSCs Transfected with a miRNA-205 inhibitor ↑EF and FS
↓Cardiomyocyte apoptosis
↑Number of neo-vessels
↑Angiogenesis
↑cardiac function
↓Fibrosis
Sun et al (2022)16 In vitro, In vivo MI C57BL/6J male mice Neonatal mouse ventricle myocytes 30: Sham/ MI/ MI + exosome Male C57BL/6J mice BM-MSCs Transfection with miR-182-5p mimics and control ↓LVEDD and LVESD
↑LVEF and LVFS
Anti-inflammatory on MI
Pu et al (2021)17 In vivo MI Male SD rats H9c2 cells 36: PBS/ Exo/ Exo-NC/ Exo-miR-30e Tibia and femur of healthy rats BM-MSCs Infected with LV-miR-30e-5p or empty vector with a MOI of 20 ↑LVEF and LVFS
↓LVEDD, LVESD, LVVs, and LVVd
↓Heart failure in rats with MI
Wang (2017)18 In vitro, In vivo MI Male C57BL/6J mice Human fibroblasts and HUVECs Sham/ control/ fibroblast-EV/ MSC-EV/MSC- scramble-EV/ MSC-siR210-EV C57BL/6 mice BM-MSCs - ↑LVEF and LVFS
↑Capillaries in peri-infarct regions
Angiogenesis
on MI
Xiao et al (2018)19 In vitro, In vivo MI Male C57BL/6J mice Neonatal mouse ventricle myocytes 27: Sham/MI/MI + MSC - BM-MSCs - ↓Autophagic Flux Cardioprotective effects: ↓Inflammation in the myocardial repair process
Peng et al (2020)20 In vitro, In vivo MI BALB/c mice Primary cardiomyocytes from adult BALB/c mice 50: sham, I/R I/, I/R + EXO, I/R + EXO/inhibitor NC,I/R + EXO/miR-25 inhibitor BALB/c mice BM-MSCs - ↓Infarct area
↓Upregulation of IL-1β, IL-6, and TNF-α
Cardioprotective effects: ↓inflammation in the myocardial repair process
Zheng et al (2022)21 In vivo MI SD rats - 100: sham/ MI/ Blank-Ex/ mimic-NC-Ex/miR-29b-3p mimic-Ex/ oe-NC / oe-ADAMTS16/ miR-29b-3p mimic-Ex + oe-NC/ miR-29b-3p mimic-Ex + oe- ADAMTS16 Femur and lumen bone of rats BM-MSCs - ↑Cardiac hemodynamic function ↑Angiogenesis and ventricular remodeling
MI
Xiong et al (2022)22 In vitro, In vivo MI SD rats H9c2 cells Sham/AMI/ MSCs-Exo/ MSCTXL-Exo Tibia and femur of male SD rats BM-MSCs Transfected with miR-146a-5p inhibitors or its negative control ↓Apoptotic cardiomyocytes
↓Levels of pro-apoptotic Bax and cleaved-Caspase 3 and inflammatory cytokines
↑LVEF
↓Infarct size
Cardiac repair after MI
Wang et al (2021)23 In vitro, In vivo MI C57BL/ 6JNifdc mice Cardiomyocytes 32: Sham/ MI group/ Exo-NC/ Exo-inhibitor Mouse AD-MSCs Transfected with NC inhibitor or miR-671 inhibitor ↓Myocardial fibrosis
↓Concentrations of IL-6 and TNF-α in the MI model mice
MI
Li et al (2019)24 In vivo MI Male SD rats - 20: Sham/ Model/ BMSC-Exos/ BMSC-301- Exos Male SD rats BM-MSCs Transfection with miR-301 mimics ↑LVEF and LVFS
↓LVESD and LVEDD
↓Myocardial autophagy protects against MI
Zhu et al (2022)25 In vitro, In vivo MI Male
C57BL/6 mice
HMVEC transduction with Lenti/F1H1 and a corresponding control 66: PBS, Exo, Exo/ anti-miR-Con, Exo/ anti miR-31 Human UC-MSC Transduced with a lentiviral antimiR-31 ↑Cardiac function ↓MI
Wan et al (2022)26 In vivo MI c57BL/6 mice - 198: PBS, MSCs-EVs, EVs-NC, EVs-miR-200b-3p, MSCs-EVs + lentivirus-expressing control short hairpin RNA, MSCs-EVs + lentivirus-expressing BCL2L11 short hairpin RNA, MSCs-EVs + overexpressed-negative lentivirus, MSCs-EVs + BCL2L11-overexpressing lentivirus, EVs-miR-200b-3p + Neg, EVs-miR-200b-3p + BCL2L11 - MSCs (Shanghai Zhongqiao Xinzhou Biotechnology Co.) Transfected with miRNA mimic NC or miR-200b-3p mimic ↓LVEDD and LVESD
↑LVEF and LVFS
↓MI-induced apoptosis of cardiomyocytes and inflammation
Xuan et al (2019)27 In vitro, In vivo MI NOD/SCID mice
C57/B6 mice
Human dermal fibroblast cell line
(CC-2511) and lung fibroblast cell line (CC-2512)
9: PBS, EV-hiPSC, or EV-CPCISX-9 Human iPSC cell line Transfected with 25 nM miR-373 mimic, anti-miR-373, negative controls, and RNAiMAX ↑CM Proliferation and angiogenesis
Reversed Ventricular Remodeling in Mice Post MI
↓Fibrosis
↑Angiogenesis in Infarcted Heart
Fu et al (2020)28 In vitro, In vivo MI Female SD rats H9c2 cells 40: Sham/ PBS/ EXO-control/ EXO-338 mimic Rat femur and tibia BM-MSCs Transfection of miR-338 mimics or negative control ↓LVESD and LVEDD
↑EF and FS
↓Cardiomyocyte apoptosis in MI
Ma et al (2018)29 In vitro, In vivo MI Female C57BL/6J mice HUVECs Saline control/ miR-132/ Exo-null/ Exo-132 Bone cavity of mouse femurs and tibias BM-MSCs - ↑LVEF ↑Angiogenesis in MI
Huang et al (2020)30 In vitro, In vivo MI Male SD rats H9C2 cells under hypoxia 105: AMI + PBS, AMI + hucMSC-exo, AMI + in-NC/hucMSC-exo, AMI + in-miR-19a/hucMSC-exo, AMI + NC/hucMSC-exo, and AMI + miR-19a/hucMSC-exo Human hUC-MSCs Transfected with miR-19a mimic, miR-19a inhibitor, and NC vectors The cardiomyocytes are arranged regularly ↓Acute MI
Yang et al (2022)31 In vitro, In vivo MI SD rats Rat cardiomyocyte H9c2 cells 60: Sham /MI + PBS/ MI + Vs-NC/MI + EVs-miR-223/ MI + EVs-miR-223 + pcDNA3.1-P53/ MI + EVs-miR-223 + pcDNA3.1-S100A9 Human hUC-MSCs Transfection with miR-223 mimic or NC mimic ↑Cardiac function ↓Fibrosis and inflammation of cardiomyocytes
↑Angiogenesis
Pu et al (2023)32 In vitro, In vivo MI SD rats HUVECs 20: Sham/MI/M-EVs/N-EVs Human hUC-MSCs -Incubation with 2.25 μM NMN for 48 h
-Transfected with miR-210-3p inhibitor or negative control
↓Fibrosis size and cell apoptosis in infarcted hearts ↑Angiogenesis
MI
Ji et al (2024)33 In vitro, In vivo MI Male SD rats H9c2 cells 40: Sham/ AMI/ Control-Exo/ miR-21-5p-Exo Rat MSCs (CP-R131) Transfected with miR-21-5p inhibitor or NC inhibitor ↓Myocyte apoptosis and fibroblast proliferation
Reverse ventricular remodeling
RNA-based therapies in cardiovascular disease
Wang et al (2024)34 In vitro, In vivo MI Mice Cardiac muscle cells - - BM-MSCs - ↓Expression of inflammatory cytokines ↑Cardiac function
↓Expression of inflammatory cytokines
You et al (2024)35 In vivo, in vitro MI C57B/6 male mice H9C2 cells under hypoxia (1% O2) Sham/MI/ MI + exos/ MI + exos + miR-let-7i-5p inhibitor/ MI + exos + miR-let-7i-5p inhibitor NC SD mice BM-MSCs Transfected with MiRNA-let-7i-5p mimic, miRNA-let-7i-5p mimic NC, miRNA-let-7i-5p inhibitor, or miRNA-let- 7i-5p inhibitor NC ↓Myocardial apoptosis ↓Infarction progression ↓Myocardial apoptosis
↓MI progression
↓MI
Zhu et al (2022)36 In vitro, In vivo MI Male C57BL/6 J mice HUVECs 10: PBS, Exo, Exo/ antimiR-Cont, Exo/ antimiR-31 Human hAD-MSC Transduction with a lentiviral antimiR-31 or antimiR-control ↑Cardiac function
↓Infarct size
↑Angiogenesis
Angiogenesis
on MI
Zhao et al (2019)37 In vivo I/R C57BL/6 mice RAW264.7 cells or peritoneal macrophages Untreated/ LPS/ LPS + NC-mimic/ LPS + miR-182-mimic Mouse BM-MSCs Transfection with miR-182 inhibitor NC inhibitor ↑EF and FS Anti-inflammatory on MI
Chen et al (2020)38 In vitro, In vivo I/R Male SD rats I/R myocardium cells 20: Sham, I/R, Exo-67, Exo-125b Femur and tibia of 2 male SD rats BM-MSCs Transfected with Lv-cel-miR-67 or Lv-miR-125b ↑LVEF, LVFS, and LVSP
↓LVESD, LVEDD, and LVEDP
Protects against myocardial I/R
Mao et al (2022)39 In vivo I/R Male SD rats - Sham, I/R, I/R ± Exo, I/R ± NC-Exo, I/R ± miR-183-5p-Exo, I/R ± anti-miR-183-5p-Exo 6 male SD rats BM-MSCs Transduction with LV-miR-183-5p, LVanti-miR-183-5p, or NC ↓MI size ↓Apoptosis and oxidative stress in I/R cardiomyocytes
↑Cardiac function
Protecting against MI/R injury
Chen et al (2021)40 In vitro, In vivo I/R SD rats H9c2 cells Control, I/R, I/R + exosome, I/R + miR-143-3p KD exosome, I/R + miR-143-3p OE Femur and tibia of SD rats BM-MSCs Transfection with NC mimic, miR-145-5p mimic, NC inhibitor, or miR-145-5p inhibitor ↓Apoptosis and autophagy of rat cardiomyocytes Myocardial I/R injury
regulating autophagy
Wang et al (2022)41 In vitro, In vivo I/R Male SD rats H9c2 cells under H/R or transfection 30: Sham group, Exo-miR-455-3p, I/R, I/R + Exo-miR-455-3p Rats BM-MSCs -Stimulated with H/R (O2 < 1%, hypoxia 48 h, reoxygenation 24 h)
-Transfection with MEKK1 overexpression plasmid, miR-455-3p mimics, or miR-455-3p inhibitor
↓Myocardial cell apoptosis Myocardial I/R damage
Zhang et al (2021)42 In vivo I/R SD rats - 120: Sham, model,
normal BMSC-exos, Hypoxic exos, exos-miR-98-5p Antagomir, miR-98-5p Agomir, miR-98-5p Agomir NC,
miR-98-5p Agomir + oeTLR4
6 male SD rats BM-MSCs -Stimulated by hypoxia (1% O2 for 24 h)
-Transfected with miR-98-5p antagomir
↓LVEDP
↑LVSP
↓Myocardial I/R injury
Li et al (2020)43 In vitro, In vivo I/R Male C57BL/6 N mice Neonatal rat cardiomyocyte transfected with miR-NC or miR-29c mimic I/R + PBS, I/R + Nor-exo, and I/R + Hypo-exo Mouse BM-MSCs H/R (O2 < 1%, hypoxia 48 h, reoxygenation 24 h) ↓Infarcted size ↓Excessive Autophagy ↓Cardiac I/R Injury
Gao et al (2023)44 In vitro, In vivo I/R Female C57BL/6 mice -Murine macrophage RAW 264.7 cells stimulated with 100 ng/mL LPS
-Primary neonatal mouse cardiomyocytes, cardiac fibroblasts, and endothelial cells isolated from C57BL/6
18: Sham, I/R control, MSC, MSC-Exo, NC agomir, miR-125-5p Mouse BM-MSCs Transfected with mmu-miR-125a-5p antagomir and NC antagomir for 24 h ↑Cardiac function on day 28 post-myocardial I/R ↑Recovery from myocardial I/R injury
Zou et al (2020)45 In vitro I/R - H9c2 cells transfected with 10 pmol/mL miR-149, let-7c, or control mimics Control, H/R, H/R + Exo, H/R + NC,H/R + mimics-149, H/R + mimics-7c Rat BM-MSCs H/R (Hypoxic atmosphere for 4 h followed by reoxygenation for another 24 h) ↓H/R-induced apoptosis Cardiomyoblast H/R injury
Wei et al (2019)46 In vitro, In vivo I/R C57BL/6 male mice PBMCs transfected with the miRNA-181a precursor, NC, mimic inhibitor, or inhibitor NC 12: Sham /PBS/ WT-EXO, miRNA- 181a-EXO Human UC blood-MSCs Transduction with GV309-neg-EGFP-LV or GV309-miRNA-181a-EGFP-LV ↑EF and FS Influenced the inflammatory response after myocardial I/R injury
Yue et al (2022)47 In vitro, In vivo I/R Male C57BL/6 mice -H/R-exposed myocardial cells co-incubated with Exo-mimic-NC, exo-miR-182-5p mimic, Exoinhibitor-NC, or exo-miR-182-5p inhibitor
-HUVECs
30: Sham, I /R, I/ R + Exo-mimic-NC, I/ R + Exo- miR-182-5p mimic Well-grown C57BL/6 mice BM-MSCs Treated with 10% GW4869 or 0.005% DMSO ↓MI size and recovery of cardiac function ↓I/R-evoked inflammation, apoptosis, and injury
Ou et al (2020)48 In vitro, In vivo I/R Male SD rats Neonatal cardiomyocytes under hypoxia (1% O2) and transducted with 1000 ng/ mL EVagomir-NC, EVmiR-150-5p-agomir, EVantagomir-NC, or EVmiR-150-5p-antagomir 72: I/R,I/R + sh-NC, I /R + sh-TXNIP, I/ R + EVmiR-150-5pagomir, I/ R + EVagomir-NC, I/ R + EVmiR- 150-5p-agomir + oeTXNIP Healthy SD rats MSCs Transduction with agomir-NC (50 nM), miR-150-5p-agomir (50 nM), antagomir-NC (100 nM), or miR-150-5p-antagomir (100 nM) ↓LVEDV, LVEDD, LVESV, and LVESD
↑LVEEF and LVEFS
↓Apoptosis and myocardial I/R injury
Tang et al (2020)49 In vitro, In vivo I/R Male SD rats Primary cardiomyocytes under H/R for 18 h Sham, I/R, I/R + PBS, I/R + exosome Human MSCs miR-320b mimic and its control - Anti-pyroptosis
↓I/R Injury
Chen et al (2024)50 In vivo, in vitro I/R SD rats H9c2 cells under H/R (95% N2 and 5% CO2 for 3 h) and 100 nM miRNA/NC inhibitor Control /model/ BMSC exo/BMSC exo + anti-miR-93-5p /BMSC exo + DSD/BMSC exo + DSD + anti-miR-93-5p Rat BM-MSCs H/R
Pretreated with DSD or miRNA inhibitor
↓Cardiac damage ↓Activation of the TXNIP/NLRP3/Caspase-1 signaling pathway and cardiomyocyte pyroptosis
Du et al (2024)51 In vivo, in vitro I/R SD male rats H9C2 cells under hypoxia (95% N2 and 5% CO2) 40: Sham, I/R + PBS, I/R + BMSC- Exo, I/R + BMSC- Exo-25-3p 20 male rats BM-MSCs - ↓Cardiac infarct size
↓Incidence of malignant arrhythmias
↓Myocardial enzyme activity
↓Inflammatory response
↓Myocardial I/R injury
Gu et al (2024)52 In vivo, in vitro I/R Male C57BL/6 mice H9c2 cells under hypoxia (5% CO2 and 95% N2 for 6 h) pretreated with DSPE-PEG-CMP, DSPE-PEG-CMP-EXO, DSPE-PEG-CMP-miR302-EXO, or miR302 30: Control / model/ DSPE- PEG-CMP/ DSPE- PEG- CMP- EXO/ DSPE- PEG-P- miR302- EXO/ miR302 Tibia and femur of C57BL/6 mice BM-MSCs - ↓Myocardial I/R injury ↓Cell apoptosis, inflammation
↑Cardiac function
Lee et al (2025)53 In vivo, in vitro I/R C57BL/6J mice Embryonic rat cardiomyocyte-derived H9c2 cardiac myoblasts exposed to PM (10 µg/ mL or 50 µg/mL) for 6 h, H/R (hypoxia (1% O2) for 6 h followed by reoxygenation for 12 h), and transfected with miR-221 and miR-222 mimics or inhibitors (100 nM/well) Control, PM + I/ R, PM + I/ R + ADSC-Exo, PM + I/ R + miR-221 miR-222 mimics Human AD-MSCs - ↓Cardiomyocyte mitophagy and apoptosis ↓Cardiac damage caused by PM + I/R
Du et al (2017)54 In vitro, In vivo Ischemia Transgenic mice expressing VEGFR2-Luc HUVECs with NO stimulation (with chitosan NO-releasing polymer and β-galactosidase) 60: PBS/EXO/NO EXO Human P-MSCs Transfected with 100 nmol/L miR-126 inhibitor and a NC inhibitor ↓PIK3R2/↑Level of AKT phosphorylation
↑Angiogenic processes
↑Angiogenesis
Feng et al (2014)55 In vivo Ischemia C57BL/6J mice - 48: microRNA Scramble / siRNA-Mecp2/miR-22-mimic/Exonon-IPC, ExoIPC/ ExoIPC + miR-22Inhibitor C57Black -6 mice BM-MSCs -Starved overnight of glucose followed by ischemia (Repeated cycles of anoxia (30 min) with intermittent reoxygenation (10 min) for two cycles in an anoxic chamber)
-Transfected with miR-22 mimics FOR 24 h
↓Fibrotic area Anti-fibrotic
Sánchez-Sánchez et al (2021)57 In vitro, In vivo Ischemia Nude rats Neonatal rat cardiomyocytes and HUVECs transfected with 20 nM miR-4732-3p for 6 h 70: Control /glucose deprivation/ glucose deprivation + EVs /glucose deprivation + miR-NC/glucose deprivation + miR-4732 - Immortal MSC-TERT line - Recovery of systolic function ↑Angiogenic and cardioprotective responses
Luo et al (2017)56 In vitro, In vivo Ischemia Male SD rats H9c2 cells under hypoxia (93% N2, 2% O2 and 5% CO2) for 24 h Normal/AMI + PBS/ AMI + Exosome /AMI + miR-126-Exosome - AD-MSCs Transfection of miR-126 mimics or miR-126 NC for 48 h ↓Cardiac fibrosis
↑Cell proliferation in the border zone
Protecting myocardial cells: ↓Apoptosis, inflammation, fibrosis, and ↑angiogenesis
Yu et al (2015)58 In vitro, In vivo Hypoxia Female SD rats Primary rat neonatal cardiomyocytes under hypoxia (1% O2, 5% CO2, and 94% N2) Sham / Saline control / ExoGATA-4/ ExoNull Femurs and tibias of SD rats BM-MSCs Transduction with recombinant GATA-4 ↓Infarct size in heart tissue Anti-apoptotic
MI
Zhao et al (2024)59 In vitro Hypoxia/reperfusion - H9c2 rat cardiomyocytes under H/R (incubated in 3.3 mmol/L H2O2 for 10 min followed by reoxygenation for 30 min) - Femur and tibia of SD rats BM-MSCs - ↑Cardiomyocyte
apoptosis
↓Pik3c3 expression and
phosphorylation of AKT/mTOR
Sun et al (2019)60 In vitro, In vivo Ischemia, Hypoxia Male SD rats H9C2 cells under H/R (hypoxia (95% N2 and 5% CO2 for 16 h, followed by reoxygenation for 3 h) and transfection with pre-miRNA of miR-468-5p andanti-miR-486-5p 28: H/R, BMSC-exo, exo-miR-486-5p, exo- anti-miR-486-5p Femur and tibia of SD rats BM-MSCs - ↓Area of MI ↓Myocardial I/R injury
Yang et al (2021)61 In vitro, In vivo Atherosclerosis ApoE−/− female C57BL/6J mice HUVECs Blank, AS model, AS model + miR- 145 exosome Human hUC-MSCs Transfected with 10 nM Cy3-labeled miR-145 mimic ↓Atherosclerotic plaques ↓Atherosclerosis
Ma et al (2021)62 In vitro, In vivo Atherosclerosis ApoE–/– mice RAW264.7 cells transfected with miR-21a-5p inhibitor or inhibitor NC 20: PBS/MSC-exo Male C57BL/6 J mice BM-MSCs Transfection with miR-21a-5p mimic, mimic NC, miR-21a-5p inhibitor, or inhibitor NC ↓Plaque area and macrophage infiltration in AS mice ↑M2 macrophage polarization
↓Macrophage infiltration
Wang et al (2015)63 In vitro, In vivo Sepsis Male WT C57BL/6 mice RAW264.7 cells
Primary cardiomyocytes isolated from adult rat hearts
40: sham, CLP + PBS control, CLP + PBS, WT- MSC, miR- 223- KO-MSC Mouse tibia and femur BM-MSCs - ↑Survival rate
↑Values of left ventricular EF and FS
Anti-inflammation, Cardioprotection in polymicrobial sepsis
Pei et al (2021)64 In vitro, In vivo Sepsis Male KM mice Mouse primary cardiomyocytes transfected with miR-141 mimic or miR-141 inhibitor 31: control, CLP, exo, exo- NC, exo- knockout, PBS Mouse BM-MSCs Transfection with miR-141 inhibitor ↓Number of apoptotic cells in mouse myocardial tissues ↓Myocardial injury in septic mice
Luo et al (2022)65 In vitro Calcification - Human aortic vascular smooth muscle cells - Human BM-MSCs Transfection with hsa-miR-15a-5p mimics/inhibitors, hsa-miR-15b-5p mimics/inhibitors, hsa-miR-16-5p mimics/inhibitors, or mimics NC/inhibitors NC ↓HA-VSMCs osteogenic transdifferentiation ↓Atherosclerosis
Chen et al (2021)66 In vitro Endothelial dysfunction - Primary EC cells from male C57BL/6 mice transfected with Keap1 overexpressed and knockdown plasmids and NC Untreated /ox-LDL/ ox-LDL + EXO- miR-NC/ ox-LDL + EXO- miR-512-3p Bilateral leg bones of mice BM-MSCs Transfection with miR-512-3p mimics and miR-NC ↓EC cell apoptosis and inflammatory
Response
↑Proliferation
↓Apoptosis and inflammatory response
↓Atherosclerosis
Lei et al (2021)67 In vitro, In vivo Myocardial toxicity Healthy SPF SD female rats H9c2 cells 85: normal/ doxorubicin/ Exo/ Exo + mimic NC/ Exo + miR-96 mimic/ Exo + inhibitor NC/ Exo + miR-96 inhibitor Rats BM-MSCs Transfected with miR-96 mimic, mimic NC, miR-96 inhibitor or inhibitor NC ↓Proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and collagen fibers ↓Doxorubicin-Induced Myocardial Toxicity
Wang et al (2021)68 In vitro, In vivo Chronic heart failure Male SD rats H9C2 cells and HUVECs treated with OGD/R for simulating myocardial and under H/ R (hypoxia (5% CO2 and 95% N2 for 3 h), followed by reoxygenation (5% CO2 for 48 h) injury 20: Sham/LAD /LAD + PBS/LAD + hucMSC-Exo Human UC-MSCs Transfected with miR-1246 inhibitor or the corresponding NC ↓LVSD, IVSS, LVIDD, and LVIDS
↑EF
Hypoxia-induced myocardial tissue damage in chronic heart failure
Yan et al (2022)69 In vitro, In vivo Heart failure Male C57BL/6 J mice Mouse cardiomyocytes HL-1 24: Sham/HF /HF + PBS/HF + MSC-Exos Mouse BM-MSCs Transfection with miR-129-5p inhibitor, small interfering RNA (si)-TRAF3, or negative controls for 24 h ↑Level of stroke volume ↓Apoptosis and Oxidative Stress in Heart Failure

ADAM19: A Disintegrin and metalloproteinase 19, ADAMTS16: A disintegrin and metalloproteinase with thrombospondin motifs 16, AD-MSCs: Adipose derived mesenchymal stem cells, AKT: protein kinase, B, BCL2L11: Bcl-2-like protein 11, BM-MSCs: Bone marrow derived MSCs, Bnip3: B-cell lymphoma 2–interacting protein 3, DAAM1: Disheveled-associated activator of morphogenesis 1, DSD: Danshen decoction, EMT: Epithelial–myofibroblast transdifferentiation, ESRK1/2: Extracellular signal-related kinases 1 and 2, Faslg: Fas ligand gene, FG: Fractional shortening, FIH: Factor-inhibiting HIF, GDF11: Growth differentiation factor 11, GSDMD: Gasdermin D, HDAC2: Histone deacetylase 2, HIF: Hypoxia-inducible factor, H/R: Hypoxia-reperfusion, HUVECs: human umbilical vein endothelial cells, IMI: Intramyocardial injection, I/R: Ischemia-reperfusion, IRAK: Interleukin-1 receptor-associated kinase, IV: Intravenously injection, JAM-A: Junctional adhesion molecule A, JNK: c-Jun NH2-terminal kinase, Keap1: Keleh-like ECH-associated protein 1, KLF-6: Kruppel-like factor 6, LVD: LV diastolic dimension, LVEDD: Left ventricular end-diastolic diameter, LVEDV: LV enddiastolic volume, LVEF: LV ejection fraction, LVESD: LV end-systolic diameter, LVESV: LV end-systolic volume, MAPK: Mitogen-activated protein kinase, Mecp2: Methyl CpG binding protein 2, MI: Myocardial infarction, NAT1: N-Acetyltransferase 1, NFAT: Nuclear factor of activated T cells, NLRP3: NLR Family pyrin domain containing 3, NO: Nitric oxide, Nrf2: NF-E2-related factor 2, P53: Tumor protein 53, PDK4: Pyruvate dehydrogenase kinase 4, PI3K: Phosphatidylinositol 3 kinase, PM: Particulate matter, P-MSCs: Placenta-derived MSCs, PRSS23: Protein serine protease 23, PTEN: Phosphatase and tensin homolog, RASA1: RAS P21 protein activator 1, ROCK2: Rho associated coiled-coil containing protein kinase 2, SD: Sprague-dawley, SMAD: Suppressor of mothers against decapentaplegic, SNRK: Sucrose non-fermenting-1 related kinase, S100A9: S100 calcium-binding protein A9, SOX6: Sry-related high-mobility group box6, TERT: Telomerase reverse transcriptase, TGF-β: Transforming Growth Factor beta, TGF-βR: TGF-β receptor, TLR4: Toll-like receptor 4, TRAF6: Tumor necrosis factor receptor-associated factor 6, TXNIP: Thioredoxin interacting protein, UC-MSCs: Umbilical cord derived MSCs, VEGFA: Vascular endothelial growth factor A, YAP1: Yes-associated protein 1.


Table 2. Characteristics of MSCs and their exosomal microRNAs in CAD models
Authors Exosome isolation Characterization Exosome markers Exosome concentration miRs Deliver target miRs into exosomes/ cell lines Administration routes Treatment route/time miRNA Targets
Yang et al (2021)14 Exosome extraction kit (Sigma-Aldrich, Merck KgaA, Darmstadt, Germany) Particle size analysis
TEM
Western blotting
TSG101, HSP70, and CD63 0.13 μg/μl miR-543 IV 40 μg protein in 300 μl PBS per rat Downregulating COL4A1 expression
Wang et al (2023)15 ExoQuick-TCTM kit TEM
NTA
Bradford assay
Western blotting
CD63 and CD9 100 μg protein, 50 μL miR-205 Intramuscularly / IV Five locations along the anterior wall of the left ventricle’s border zone Cardiac function and HIF-1a and VEGF increased expression
Sun et al (2022)16 Ultracentrifugation method TEM
NTA
Western blotting
CD9, CD63 and Alix 5 μg miR-182-5p IMI several sites around the infarct region TLR4/NF-κB signaling pathway
Pu et al (2021)17 Ultracentrifugation method TEM
NTA
Western blotting
TSG101, Alix, and CD81 20 μg/mL miR-30e IV Exosomes were injected via the tail vein for 3 consecutive days 7 days after MI surgery LOX1/ NF-κB p65/ Caspase-9 axis
Wang (2017)18 Ultracentrifugation method TEM
Western blotting
LAMP-1, CD44,
CD105, and TSG 101
- miR-210 IV MSC-EVs in mice subjected with MI injury Efna3
Xiao et al (2018)19 Ultracentrifugation method Electron microscopy and immunoblotting CD63, CD9, and Alix 0.2 μg/μl miR-125b IMI Injection of 5 μl exosomes into 5 sites at the border of the infarct 30 min after ligation p53-Bnip3 signaling
Peng et al (2020)20 Total Exosome Isolation Reagent TEM
NanoSight NS500
Western blotting
HSP70, CD63, and CD9 0.05 μg/μl miR-25-3p IMI 5 μg in 100 μL PBS injected into the border zone of the infarcted heart at three sites 30 min after ligation Pro- apoptotic genes FASL and PTEN
Zheng et al (2022)21 Ultracentrifugation method Western blotting
TEM
NTA
CD81 and
TSG101
- miR-29b-3p Injection ADAMTS16
Xiong et al (2022)22 Ultracentrifugation method Micro BCA protein assay
TEM
NTA
Western blotting
CD63, TSG101, and Alix 0.2 μg/μl miR-146a-5p IMI 20 μg exosomes in 100 μL PBS injected into the border zone of the infarcted heart at three sites IRAK1/ NF-κB p65 pathway
Wang et al (2021)23 Total Exosome Isolation Reagent TEM
NTA
Western blotting
CD63 and CD81 100 μg miR-671 IMI 100 μg Exo-NC or Exo-inhibitor was dissolved in PBS and injected in the boundary area of the infarcted cardiac near the ligation site TGFBR2/ Smad2 Axis
Li et al (2019)24 Exosomes isolation kit TEM
Western blotting
CD81, CD63, and CD9 - miR-301 IMI 30 min after LAD artery ligation, BMSCExos were injected at 5 points in the peripheral area of the MI -
Zhu et al (2022)25 Ultracentrifugation method 2 μg/μl miR-24-3p IMI Plcb3 and NF-κB pathway
↑M2 Macrophage Polarization
Wan et al (2022)26 Ultracentrifugation method TEM
NTA
Western blotting
CD9, CD81, and GRP94 6.66 μg/μl miR-200b-3p IMI EVs (100 μg) or recombinant lentivirus (5 × 107 viral genome particles per mouse heart) injection around the infarct area (anterior wall, lateral wall, and apical area) after LAD artery ligation BCL2L11
Xuan et al (2019)27 Ultracentrifugation method TEM
TRPS
Western blotting
Tsg101, CD9, Hsp70, and flotillin-1 1012 particles/ml miR-373 IMI 10 mins after LAD ligation, EVs (1 × 1012/ml) were injected
into the myocardium along the border zone with a total of 20 μl
GDF-11 and ROCK-2
Fu et al (2020)28 Exosome Isolation Reagent TEM
Western blotting
CD9,CD63, and CD81 - miR-338 IMI 50 μL of exosome were injected before the chest was closed Regulate the JNK pathway via targeting MAP3K2
Ma et al (2018)29 Total exosome isolation reagent TEM
Western blotting
CD63 and CD9 30 μg/μl miR-132 Loading miR-132 via electroporation IMI Injection of exosome (600 μg) after LAD ligation ↓The expression level of its target gene RASA1
Huang et al (2020)30 Ultracentrifugation method TEM
NTA
Western blotting
CD9, CD63, Alix 3, and GM130 400 μg/g miR-19a - IV 400 μg/g exosome injection SOX6
Yang et al (2022)31 Ultracentrifugation method BCA assay
TEM
Western blotting
CD9, CD81, and CD63 50 μg/mL miR-223 Transfection of EVs with miR-223 mimic or NC mimic IMI EV injection (50 μg/mL) after the ligation at three different sites around the infarcted area Modulate the P53/S100A9 axis
Pu et al (2023)32 Ultracentrifugation method TEM
NTA
Western blotting
TSG101and CD63 4 × 107 particles/ μl miR-210-3p IMI EVs (50 uL or 2 × 109 particles) were injected in the border zone of the infarction area 30 min after ligation EphrinA3
Ji et al (2024)33 Ultracentrifugation method TEM
NTA
Western blotting
CD81 and TSG101 100 µg miR-21-5p IV 100 µg of exosomes suspended in 100 µL sterile PBS via tail vein injection YAP1 signaling pathway
Wang et al (2024)34 - miR-223-3p IMI Peri-infarct myocardial region was injected ↓NLRP3
You et al (2024)35 Ultracentrifugation method TEM
Western blotting
BCA assay
CD63, CD81, and TSG101 0 or 50 µg/ml miR-let-7i-5p IMI Immediately after ligation, the peri-infarct myocardial region was injected at three different points with a total of 10 uL of exosomes Bcl-2
Zhu et al (2022)36 Ultracentrifugation method NTA
TEM
Western blotting
BCA assay
CD9 and TSG101 5 μg (IM)
100 μg (IV)
miR-31 IMI, IV IMI: Exosomes (5 μg, 2.2 × 107 particles) were injected in the infarct border area two times on each side of the ligation
IV: Exosomes (100 μg, 4.3 × 108 particles) were injected at the tail vein at 7, 14, and 21 days post-surgery
FIH1/ HIF-1α pathway
Zhao et al (2019)37 Ultracentrifugation method NTA
TEM
Western blotting
BCA assay
CD9, CD63 TSG101, and Alix - miR-182 IMI Exosomes (5, 30, or 50 ug) 3 days following myocardial I/R injury TLR4 signal
Chen et al (2020)38 ExoQuick-TC kit TEM
Western blotting
CD9 and CD63 50 µg miR-125b IMI After LAD, exosomes (50 µg) were injected into the ligation zone adjacent to the left anterior free wall after left ventricle exposure Sirtuin7
Mao et al (2022)39 Ultracentrifugation method NTA
TEM
Western blotting
CD9, CD63, and CD81 2 μg/μl miR-183-5p IV Exosomes (400 µg in 200 µL PBS) were injected via the tail vein within 5 min of the beginning of reperfusion FOXO1
Chen et al (2021)40 Hieff TM Quick exosome isolation kit NTA
TEM
Western blotting
CD63 and CD81 0.5 μg/μl miR-143-3p IMI Exosomes (200 μg suspended in 400 μl PBS) were injected into the myocardium CHK2- Beclin2 pathway
Wang et al (2022)41 Ultracentrifugation method TEM
Western blotting
CD63, CD9, and Alix 10 μg miR-455-3p IMI Exosomes (10 μg) were transfused into the left ventricular wall of rats MEKK1- MKK4-JNK signaling pathway
Zhang et al (2021)42 Ultracentrifugation method TEM
BCA assay
Western blotting
CD63 and CD9 1 μg/μl miR-98-5p IMI 100 μL exosomes (1 μg/μL) were injected into 4 different sites of the anterior wall of the left ventricle ↓TLR4 and activating the PI3K/ Akt signaling pathway
Li et al (2020)43 Ultracentrifugation method Western blotting CD9, CD63, and Alix 1 μg/μl miR-29c IMI Exosomes (20 μg resuspended in 20μL PBS) were injected in 2 sides of the border zones right after LAD coronary ligation PTEN/ Akt/ mTOR Signaling Pathway
Gao et al (2023)44 Ultracentrifugation method NTA
TEM
BCA assay
Western blotting
CD63, CD9, TSG101, and Alix 0.66 μg/μl miR-125a-5p IMI 10 μg exosomes or 20 nmol miR-125a-5p agomir into the border zone at the onset of reperfusion Klf13, Tgfbr1, and DAAM1
Zou et al (2020)45 Ultracentrifugation method TEM
Western blotting
CD63, ALIX, and TSG101 - miR-149 - - - Faslg and w/β- catenin signaling pathway
Wei et al (2019)46 Ultracentrifugation method NTA
TEM
Western blotting
CD9, CD63, TSH, and ALIX-101 200 μg miR-181 IMI 200 μg of exosomes suspended in PBS were injected before the chest was closed T-cell receptor signaling and TGF-β signaling
Yue et al (2022)47 Ultracentrifugation method NTA
TEM
Western blotting
CD63, HSP70, TSG 101, Alix, and Calnexin 1 μg/μl miR-182-5p IMI 10 μg exosomes dissolved in 10 μL PBS injected at the front and outside of the visible injury area GSDMD
Ou et al (2020)48 ExoQuick-TC EV purify reagent NTA
TEM
BCA assay
Western blotting
CD9, CD63, Alix, and GRP94 107 U/μl miR-150-5p IMI EVs (10 μL per injection, 5.8 × 1012 particles) were injected 5 times 10 min before perfusion TXNIP
Tang et al (2020)49 Ultracentrifugation method NTA
TEM
Western blotting
CD9, CD81 and TSG101 - miR-320b - Exosomes (50μg/25μL PBS) NLRP3 protein
Chen et al (2024)50 Ultracentrifugation method TEM
NTA
PKH67 staining
miRNA sequencing
TSG101, CD63, and calnexin 20 μg miR-93-5p IMI 20 μl of exosomes (50 µg) were injected in situ into the original location of the infarcted myocardium TXNIP/ NLRP3/ Caspase-1
Du et al (2024)51 Ultracentrifugation method NTA
TEM
Western blotting
CD63 and CD9 - miR-25-3p Electroporation of 100 µg of miR-25-3p in 500 µl BMSC-Exo (250 µM) IV Exosomes (100 µg/kg) were injected through the tail vein 2 h before I/R surgery JAK2 / STAT3 signaling pathway
Gu et al (2024)52 Exosome isolation reagent kit NTA
TEM
Flow cytometry
CD29 and CD44 2.5 to 40 μM miR-302 -4 μL ethanolic solution (100 nM) including DSPE-PEG-CMP was incubated with the exosomes (200 μL, 1 × 1010 particles)
-electroporation of exosomes via miR302 mimic
IV Engineered exosomes were injected via the tail vein (0.25 μg/100 μL PBS/mouse) 12 h after reperfusion after coronary artery ligation every 2 days for 4 weeks Cardiomyocyte specific peptide
Lee et al (2025)53 ExoQuick-TC Exosome Precipitation Solution NTA
TEM
BCA assay
Western blotting
CD9 and CD63 - miR-221- and miR-222 Intratracheally, intraperitoneally, and intramuscularly injection Exosomes (100 μg of protein in 50 μL) were uniformly injected into the left ventricular marginal zone BNIP3-MAP1LC3B-BBC3/ PUMA pathway
Du et al (2017)54 Ultracentrifugation method ELISA
TEM
BCA assay
- - miR-126 - IMI Exosomes (100 µg in 100 μl PBS) were immediately injected post-ischemia at 3 sites in the right adductor muscle adjacent to and within 1 mm proximal or distal to the ligation site VEGF
Feng et al (2014)55 ExoQuick + Ultracentrifugation TEM
Western blotting
Bioanalyzer for RNA
CD63 1 μg miR-22 - IMI 1 mg exosomes
were injected along the border between the infarct zone and normal myocardium after LAD
MeCP2
Sánchez-Sánchez et al (2021)57 Ultracentrifugation method NTA
TEM
BCA assay
Western blotting
EVs Small RNA Sequencing
ALIX, HSP70, TSG101, and CD9 3.5 × 109 EVs/ μl miR-4732-3p Electroporation of miR- 4732-3p (40 nM) into EVs IMI EVs (3.5 × 1010 per animal) were transplanted immediately after permanent LAD artery ligation in two injections of 10 mL, at two discrete locations of the infarct border zone SMAD2 and SMAD4 components of the TGF-β pathway
Luo et al (2017)56 ExoQuick-TC NTA
TEM
Western blotting
CD63, CD9, and TSG101 2 μg/μl miR-126 - IV Exosomes (400 μg of protein suspended in 200 μl PBS) were injected at the tail vein immediately after the ligation operation -
Yu et al (2015)58 ExoQuick-TC kit TEM
Western blotting
CD9, CD63, and HSP70 - miR-19a - IMI Exosomes (harvested from 4 × 106 MSCs in 50 μl saline) were injected after LAD coronary artery PTEN/ Akt/ ERK signaling pathways
Zhao et al (2024)59 Exo Quick-TC kit NTA
TEM
Western blotting
CD63, CD9, and CD81 - miR-101a-3p Transfected with miR- 101a- 3p inhibitor (2 μg/ mL) - - PIK3-Akt signaling
pathway
Sun et al (2019)60 Total Exosome Isolation kit NTA
TEM
Western blotting
CD9, CD63, ALIX, and TSG101 2 μg/μl miR-486-5p - IV rats with exosomes (400 µg in 200 µL PBS) were injected into the tail vein at the beginning of the reperfusion and 3 h later coronary artery was re-ligated PTEN/ PI3K/ AKT signaling pathway
Yang et al (2021)61 Total exosome isolation reagent NTA
TEM
Western blotting
CD63 and CD9 0.932 × 103 copies/μL miR-145 - IV Exosomes (80 mg) were injected every week, one week after carotid atherosclerotic plaque induction in the right common carotid artery JAM-A
Ma et al (2021)62 Total Exosome Isolation Reagent Kit NTA
TEM
- 0.5 mg/ml miR-21a-5p - IV Exosomes (200 µl, 0.5 mg/ml) were injected into the caudal vein once a day for 2 weeks KLF6 and ERK1 /2 signaling pathways
Wang et al (2015)63 Ultracentrifugation method NTA
TEM
BCA assay
Western blotting
CD63 and CD81 - miR-223miR-233SEMA3A; STAT3 - IV Exosomes (2μg/g body weight in 150 μl of incomplete culture medium) were injected through the tail or jugular vein, 1 hour after CLP surgery SEMA3A, STAT3
Pei et al (2021)64 Ultracentrifugation method NTA
TEM
Western blotting
CD63 and CD9 - miR-141 - IV Exosomes (2 μg/g) were injected through caudal veins 1 hour after CLP PTEN and activates β-catenin
Luo et al (2022)65 Complete exosome isolation kit NTA
TEM
Western blotting
CD9, CD81, Tsg101, and Histone H3 - miR-15a/15b/16 - - - NFAT-3
Chen et al (2021)66 Ultracentrifugation method TEM
Western blotting
CD63, CD81, and CD9 - miR-512-3p - - - Keap1/ Nrf2 signaling pathway
Lei et al (2021)67 Ultracentrifugation method BCA assay
NTA
TEM
Western blotting
CD63 and CD81 3 × 1011 particles/ml miR-96 - IV 2 doses of exosomes (3 × 1010 particles suspended in 0.1 mL PBS) were injected into the tail vein of the rats on days 5 and 11 Inhibiting the Rac1/Nuclear Factor-κB Signaling Pathway
Wang et al (2021)68 Gradient centrifugation NTA
TEM
Western blotting
CD63, PDCD6IP, TSG101, and LC3A 1 μg/μl miR-1246 - IMI Exosomes (20 μg in 20 μl PBS) were directly injected into two lesions of the infarcted myocardial boundary area Targeting PRSS23
↓Activation of the Snail/alpha-smooth muscle actin signaling
Yan et al (2022)69 Ultracentrifugation method BCA assay
DLS
TEM
Western blotting
CD81 and TSG101 0.1 μg/μl miR-129-5p - IV Exosomes (50 μL, 100 μg/mL) were postoperatively injected through the tail vein once a week for 3 times TRAF3, NF-κB signaling

ADAM19: A Disintegrin and metalloproteinase 19, ADAMTS16: A disintegrin and metalloproteinase with thrombospondin motifs 16, AKT: protein kinase, B, BCL2L11: Bcl-2-like protein 11, Bnip3: B-cell lymphoma 2–interacting protein 3, DAAM1: Disheveled-associated activator of morphogenesis 1, DSPE-PEG-NHS: 1,2-distearoyl-sn-glycero-3-phosphoethanolamineN-[hydroxysuccinimidyl polyethylene glycol-2000], EMT: Epithelial–myofibroblast transdifferentiation, ESRK1/2: Extracellular signal-related kinases 1 and 2, Faslg: Fas ligand gene, FG: Fractional shortening, FIH: Factor-inhibiting HIF, GDF11: Growth differentiation factor 11, GSDMD: Gasdermin D, HDAC2: Histone deacetylase 2, HIF: Hypoxia-inducible factor, H/R: Hypoxia-reperfusion, HUVECs: human umbilical vein endothelial cells, IMI: Intramyocardial injection, I/R: Ischemia-reperfusion, IRAK: Interleukin-1 receptor-associated kinase, IV: Intravenously injection, JAM-A: Junctional adhesion molecule A, JNK: c-Jun NH2-terminal kinase, Keap1: Keleh-like ECH-associated protein 1, KLF-6: Kruppel-like factor 6, LVD: LV diastolic dimension, LVEDD: Left ventricular end-diastolic diameter, LVEDV: LV enddiastolic volume, LVEF: LV ejection fraction, LVESD: LV end-systolic diameter, LVESV: LV end-systolic volume, MAPK: Mitogen-activated protein kinase, Mecp2: Methyl CpG binding protein 2, MI: Myocardial infarction, NAT1: N-Acetyltransferase 1, NC: Negative control, NFAT: Nuclear factor of activated T cells, NLRP3: NLR Family pyrin domain containing 3, NMN: Nicotinamide mononucleotide, Nrf2: NF-E2-related factor 2, P53: Tumor protein 53, PDK4: Pyruvate dehydrogenase kinase 4, PI3K: Phosphatidylinositol 3 kinase, PRSS23: Protein serine protease 23, PTEN: Phosphatase and tensin homolog, RASA1: RAS P21 protein activator 1, ROCK2: Rho associated coiled-coil containing protein kinase 2, SD: Sprague-dawley, SMAD: Suppressor of mothers against decapentaplegic, SNRK: Sucrose non-fermenting-1 related kinase, S100A9: S100 calcium-binding protein A9, SOX6: Sry-related high-mobility group box6, TERT: Telomerase reverse transcriptase, TGF-β: Transforming Growth Factor beta, TGF-βR: TGF-β receptor, TLR4: Toll-like receptor 4, TRAF6: Tumor necrosis factor receptor-associated factor 6, TRPS: Tunable resistive pulse sensing, TXNIP: Thioredoxin interacting protein, VEGFA: Vascular endothelial growth factor A, YAP1: Yes-associated protein 1

Assessment of the quality of studies

The quality of the included studies was assessed based on the ARRIVE guidelines 2.0.12 Besides, the risk of bias in studies was evaluated by SYRCLE's risk of bias tool.13


Results

Included studies

The primary database search resulted in 1300 articles, out of which 578 were eliminated due to duplicate records. Some studies (n = 565) were excluded based on the subject and abstract screening. Forty-seven studies were excluded due to the unavailability of the full text. One hundred and ten full texts were reviewed and screened to finalize the included studies. A total of 56 studies were included in the review. Fig. 1 shows the detailed PRISMA flow diagram of the literature search.

bi-15-30989-g001
Fig. 1.

PRISMA flow diagram of literature search and selection process.


Characteristics of the included studies

Preclinical models of CAD were MI (n = 23),14-36 I/R (n = 17),37-53 ischemia (n = 4),54-57 hypoxia (n = 1),58 hypoxia/reperfusion,59 ischemia/hypoxia,60 atherosclerosis (n = 2),61,62 sepsis (n = 2),63,64 calcification (n = 1),65 endothelial dysfunction,66 myocardial toxicity,67 and heart failure.68,69

Of the 56 included studies, 44 articles had a mixed methodology (in vitro studies were followed by in vivo studies),14-16,18-20,22,23,25,27-36,38,40-54,56-58,60-64,67-69 8 were in vivo,17,21,24,26,37,39,42,55 and 4 were in vitro45,59,65,66 studies. Mice were the model animals in 18 in vivo studies,15,16,18-20,23,25,26,29,33-37,43,44,46,47,52,53,55,61-64,66,69 and the rest of the articles used rats as their study models. Most in vitro studies utilized animal model cardiomyocytes [neonatal rat cardiomyocytes or H9C2 cells (a rat cardiomyoblast cell line)]; however, 9 studies examined human umbilical vein endothelial cells (HUVECs)15,29,32,36,47,54,57,61,68 and 1 article studied both human fibroblasts and HUVEC.18

Sources of MSCs and their preconditioning methods

The included studies utilized a diverse range of MSCs, including bone marrow-derived MSCs (BM-MSCs), umbilical cord MSCs (UC-MSCs), placenta-derived MSCs (P-MSCs), and adipose-derived MSCs (AD-MSCs). Specifically, BM-MSCs were the most prevalent source being used in 37 studies (66.07%), followed by UC-MSCs in 6 studies (10.71%),25,30-32,61,68 AD-MSCs in 5 studies (8.92%),15,23,36,53,56 and human placenta-derived MSCs (hP-MSCs) in one study.54 Cell lines (Shanghai Zhongqiao Xinzhou Biotechnology Co.),26 immortal MSC-TERT lines,57 human MSC (American Type Culture Collection),14,49 and rat MSCs (CP-R131)33 along with induced pluripotent stem cell (iPS)27 were also applied. The tissue of origin was unspecified in a minority of studies.48 Nineteen, eighteen, and fourteen articles used rats,17,21,22,24,28,33,38-42,45,48,50,51,58-60,67 mice,15,16,18,20,23,29,35,37,43,44,47,52,55,62-64,66,69 and human-derived tissue,14,25,27,30-32,36,46,49,53,54,61,65,68 respectively, as a donor of MSC organism. The donor organism of MSCs was not defined in 5 studies19,26,34,56,57 (Table 1). Regarding preconditioning methods, the majority of studies did not employ specific techniques. However, 6 studies (10.71%)41-43,45,50,55 utilized a hypoxic environment to precondition MSCs before exosome isolation, and 16 studies (28.57%)14,30,35,41,47-53,56,58-60,68 used preconditioning for H9c2, HUVEC, myocardial, and cardiomyocyte cells (Table 1).

For exosome isolation, ultracentrifugation was the dominant method used in 34 out of 56 studies (60.71%). Other methods included the use of exosome extraction kits such as ExoQuick (used in 7 studies, 12.5%),15,38,48,53,56,58,59 the Total/complete Exosome Isolation Reagent Kit (10 studies, 17.85%),20,23,24,28,29,52,60-62,65 Hieff Quick (used in 1 study, 1.78%),40 Sigma (1 study, 1.78%),14 and Gradient centrifugation (1 study, 1.78%).68 ExoQuick and ultracentrifugation were employed in one study.55 The isolation method of one study was not defined.34

The identification of exosomes primarily relied on transmission electron microscopy (TEM) to examine their morphology. Western blotting and Flow cytometry were used to detect specific biomarkers. Other techniques, such as dynamic light scattering (DLS), and nanoparticle tracking analysis (NTA) were employed to characterize and analyze the size, distribution, and concentration of exosomes. In terms of miRNA insertion, transfection into MSC cells was used in 31 out of 56 studies (55.35%)14,16,22-24,26-28,30-33,35,37,38,40-42,44,49,54-56,61,62,64-69 and 5 studies of 56 studies used transduction (8.92%).25,36,39,46,48 On the other hand, 2 studies used transfection to insert microRNAs into exosomes (3.57%) and 4 of them used electroporation for this approach (7.14%)29,51,52,57 to deliver target miRs into exosomes and cell lines. For more details, see Table 2.

Route and frequency of MSC-exosomal miR administration

In 31 in vivo studies,16,19,20,22-29,31,32,34,35,37,38,40-44,46-48,50,54,55,57,58,68 the exosomes were injected intramyocardially around the infarct area, and in 16 studies,14,17,18,30,33,39,51,52,56,60-64,67,69 the intravenous route was used for exosome administration. Interestingly, one study used both intramyocardial and intravenous routes for their experiment,36 one study used both intramuscular and intravenous routes,15 and another study used simultaneous intratracheally, intraperitoneally, and intramuscularly injection.53 Two studies did not explain the exact route of administration in the methodology.21,49 Most studies used a single intramyocardial injection of exosomes after surgical I/R induction. Studies used a broad spectrum of exosome concentrations varying from 0.02 μg/μL to 400 μg/μL. In some studies, the exosome concentration was not declared, and the total amount of injected exosomes was just mentioned.

Improvement/outcomes

In vitro studies focused on the anti-inflammatory and anti-apoptotic effects of exosomes under hypoxic conditions.14,30,35,41-43,45,47-53,56,58-60,68 On the other hand, the in vivo studies mainly focused on cardiac function improvement (increased left ventricular ejection fraction and fractional shortening (LVEF and LVFS), decreased end-diastolic and systolic diameter of the left ventricle (LVEDD and LVESD), and the reduction in the infarct area size and fibrosis.14-18,22,24,26,28,29,37,38,42,46,48,50-52,58,63,68,69 Exosomal miRNAs derived from various MSC sources have been shown to play beneficial roles in targeting dysregulated signaling in CAD. These roles include anti-apoptotic effects,26,28,35,39,47,48,52,56,58,66,69 anti-inflammatory actions,16,19,20,26,31,37,46,47,51,52,56,63,66 promotion of differentiation, anti-fibrotic activity,15,27,31,55,56 pro-angiogenic effects.15,18,21,27,29,31,32,36,54,56,57 To a lesser extent, MSC-exos-miRs were involved in reducing calcification,65 suppressing autophagy,24,40,43 and enhancing cell viability. The detailed results of each study are summarized in Table 1 and Fig. 2.

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Fig. 2.

The effect of exosomal miRs derived from mesenchymal stromal cells on coronary artery disease.Exosomal miRs derived fromMesenchymal stromal cells (MSCs) could have anti-inflammatory, anti-apoptotic, pro-angiogenesis, and anti-fibrotic effects on patients with coronary artery disease. Besides, some miRs could have immunomodulatory effects, and reduce ischemia-reperfusion (I/R) injury, vascular calcification, atherosclerosis, infarct size, and immune cell infiltration.


Quality and risk of bias assessment

According to the ARRIVE guidelines 2.0 evaluations, the selected studies have had an appropriate quality to be included in the review. The main risk of bias in the included studies was the lack of clear information about the blinding and randomization process in the performance and detection phases. However, due to the small sample size of most of these animal studies, researchers assessed all the target animals instead of randomization. There was no significant risk of bias in the included studies regarding the SYRCLE's risk of bias tool (Figs. 3 and 4).

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Fig. 3.

Risk of bias chart based on the SYRCLE tool.


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Fig. 4.

Risk of Bias in the included studies.



Discussion

Recent studies support that MSC-exosomal miRs are the most functional factors regulating the regeneration of the cardiovascular, offering a multifaceted strategy to combat CAD by addressing cellular dysfunction, apoptosis, and inflammation while promoting angiogenesis and tissue repair and suppressing fibrosis.

Both MI and I/R injury are downstream effects of CAD. Myocardial ischemia occurs when the coronary artery is partially or totally occluded, resulting in the functional loss of cardiomyocytes. After an MI and performing reperfusion treatments by fibrinolytic or angioplasty, the re-establishment of blood supply causes cell damage, called I/R injury. Although reperfusion is crucial to preventing more damage, it leads to further injury due to oxidative stress, inflammation, and an overload of calcium. The pathophysiology of maladaptive cardiac remodeling after MI is the early inflammatory response, apoptosis, and the succeeding longer-term scar alteration.

Inflammation plays a central role in the development and progression of CAD by contributing to immune cell recruitment, endothelial dysfunction, and atherosclerotic plaque formation and destabilization. The result of this review indicated that MSC-exos-miRs can decrease inflammation in MI,19,20,23,26,31,34 I/R,47,52,56 and sepsis63 models. MSCs exosomes carrying miR-25-3p,20 miR-125b,19 miR-200b-3p,26 and miR-22331 have anti-inflammatory and cardioprotective effects after MI. Moreover, in I/R models, miR-126,56 miR-182-3p,47 and miR-30252 could diminish inflammation. Surprisingly, as an effective agent, miRs can target the inflammatory signaling pathways through several mechanisms, such as the TLR/NF‐ĸB pathway, NLRP334 inflammasome, PI3K/AKT pathway, and JAK/STAT pathway. Reducing macrophage infiltration and promoting the M2 macrophage phenotype is another anti-inflammatory role of MSC-exos-miRs.62 Likewise, BM-MSCs-Exos diminish the inflammatory response by miR-302d and controling the BCL6/MD2/NF-κB signaling pathway in cardiac regeneration after AMI.70

The main features of acute MI include elevated oxidative stress, loss of NADH and ATP, and cell death, all connected directly to cellular bioenergetics. MSC-exosomal miRs can preserve cardiac cells by suppressing oxidative stress and cell apoptosis and promoting cardiac regeneration and repair. In this review, an important group of MSC-exo-miRNAs was identified in CAD models that present antiapoptotic effects by targeting different pathways. This antiapoptotic miRNA group includes let-7i-5p,35 miR-21-5p,33 miR-101a-3p,59 miR-129-5p,69 miR-143-3p,40 miR-149,45 miR-150-5p,48 miR-182,47 miR-183-5p,39 miR-200b-3p,26 miR-205,15 miR-210-3p,32 miR-221 and miR-222,53 miR-302,52 miR-338,28 miR-455-3p,41 miR-512-3p,66 and miR-4732-3p.56

Shuttled miR-486-5p, miR-144, and miR-2171 from MSC-exos can prevent cardiomyocyte apoptosis by targeting the PTEN/PI3K/AKT pathway.60,72 miR-21a-5p participates in cell survival/death pathways, presenting cardioprotective effects after MI by targeting PTEN, FasL, PDCD4, and Peli1.73 Likewise, in ischemic human cardiomyocytes, it is found that human BM-MSCs-exosomal miR-21-5p could enhance cardiac tissue's calcium handling gene and contractility.74 Moreover, miR-22 (by targeting methyl CpG binding protein 2),55 miR-24,75 miR-125b-5p (by interaction with SMAD4),76 miR-221,77 and miR-451 (by targeting TLR4/NF-κB pathway) hinder apoptosis. AD-MSCs-derived exosomal miR-221/222 and miR-146a can reduce MI-induced myocardial injury by targeting PUMA and EGR1 (early growth response factor 1), respectively.78,79 Similarly, exosomal miR-25-3p alleviates MI by targeting a histone-lysine N-methyltransferase EZH2 (Enhancer of zest homolog 2) that promotes the formation of heterochromatin and thereby represses gene expression.60 Cardiomyocytes are protected after reperfusion with the help of the miR149/let-7c/Faslg pathway.45 Moreover, these exosomes can reduce myocardial cell damage through the HAND2-AS1/miR-17-5p/Mfn2 pathways.45 Some other MSCs-exosomal miRs such as miR-338,28 miR-133,80 miR-210,81 and miR-12682 could improve cardiac function, diminish infarct size, and prevent cardiomyocyte apoptosis by targeting different pathways. Other exosomal miRs, such as miR-132, miR-223, miR-19a, and miR-22 have also been reported to have cardioprotective effects.55,58,83 miR-125b-5p derived from MSC exosomes can regulate the infarct size of mice and cardiac function by reducing autophagy through the p53-BNIP3 signaling pathway.19

A plethora of reports support that the paracrine activity of ischemic preconditioning MSCs can improve their therapeutic effect on MI in primates.84 Hypoxia-conditioned BM-MSCs,76 ischemic pre-conditioned BM-MSCs,55 and GATA-4-overexpressing MSCs that were enriched in exosomal miR-125b, miR-22, and miR-19a,58 respectively, could enhance the apoptosis of cardiomyocytes, decrease cardiac fibrosis, and ease cardiac repair. Besides, MSCs, grown under hypoxic conditions, secret exosomal miR-19a, that acts as anti-apoptotic. These exosomes with a high concentration of miR-19a can reduce apoptosis and increase mitochondrial membrane stability, increasing rat cardiomyocytes' survival rate.58

One of the important complications after MI is cardiac fibrosis and scarring. Therefore, a critical principle following MI is preventing fibrosis and reducing its progression. Scar repair, which includes angiogenesis and activation of myofibroblasts (MFBs), is responsible for cardiac structural recovery at the early stages of MI. On the other hand, insufficient repair can cause thinning and eventual rupture of the heart wall. Therefore, a precise mechanism in scar repair should be established to balance maintaining the heart's function and creating resistance of the walls.85 Based on the results of this systematic review, MSC-exos carrying miR-22, miR-126, miR-205, miR-210-3p, miR-223, and miR-373 exert antifibrotic effects on CAD preclinical models.15,23,27,31,32,55,56 AD-MSC-derived exosomal miR-671 attenuates myocardial fibrosis by hindering the TGFBR2/Smad2 signaling pathway.23

After MI, the angiogenesis of the myocardium is critical for stimulating the function of the ischemic heart.86 MCSs-exosomal miRs can induce the formation of new blood vessels87 by penetrating the endothelial cells to increase cell proliferation and help re-endothelialize blood vessels.88 The proliferative and angiogenic effects of MSC-derived exosomes can be primarily attributed to specific miRs, including miR-199a and miR-130a-3p.71 miR-126 enhanced the VEGF signaling pathway by downregulating the expression of PI3KR2 and SPRED1. Moreover, miR-126 targeting VCAM1, PIK3R2, and SPRED1 presents anti-inflammatory effects.82 miR-210 found in the exosomes derived from BM-MSCs can improve the angiogenesis of the repair process by affecting the EFNA3 gene. Likewise, MSC can preserve myocytes against stress in vitro and in vivo by overexpressing exosomal miR-210. It is important to note that both exogenous and endogenous miR-210 have similar therapeutic effects.81 MiR-21 is also associated with the property of neovascularization and angiogenesis by the PTEN/Akt pathway in preventing MI complications.18,89 It should be noted that inflammatory factors (IL-6 and TNF-α) and miR-dysregulated angiogenesis-related miRs (miR-320, miR-21-3p, miR-146b-5p, miR-17-5p, and 196a-5p) impair the MSCs-exo ability to stimulate angiogenesis. Those proinflammatory cytokines also decrease VEGF, MAPK, and PI3K-AKT signaling pathways related to angiogenesis.90 Nevertheless, alternative results indicate that inflammatory mediators could enhance the capacity of MSC-derived exosomes to facilitate angiogenesis.91

Atherosclerosis is the underlying cause of CAD and is involved in the development of both CAD and ACS. Coronary atherosclerosis, progressively narrows the coronary arteries' lumen, leading to reduced blood flow and myocardial ischemia. Exosomes that contain miR-512-3p have a protective role against oxidized low-density lipoproteins-induced vascular damage. This miR inhibits the destructive effect of Keleh-like ECH-associated protein 1 (Keap1) to cause endothelial damage.66 Vesicles containing miR-21a-5p stimulate M2 macrophage polarization and reduce the infiltration of macrophages through ERK1/2 and KLF6 signaling pathways, thus diminishing atherosclerosis.62 In addition, macrophage accumulation is suppressed through the miR-let7/IGF2BP1/PTEN pathway. MSC-exos also exerts atherosclerosis inhibitory properties by inhibiting miR-342-5p.79 MSC-derived miR-145-rich exosomes can downregulate junction adhesion molecule A, prevent cell migration in vitro, and diminish atherosclerotic plaque.61 On the other hand, exosomes derived from BM-MSCs carrying miR-223 stabilize atherosclerotic plaques by suppressing the expression of NLRP3.92

Differential expression of epicardial adipose tissue-exos-miRs was found in CAD patients compared to patients without CAD, providing hints for further mechanisms of atherosclerosis. Among 53 uniquely identified miRs, 21 miRs were downregulated and 32 miRs were upregulated in CAD patients. Seven differentially expressed miRs (miR-485-3p, miR-382-5p, miR-429, miR-205-5p, miR-200a-5p, miR-183-5p, and miR-141-3p) were involved in cell proliferation, survival, differentiation, and apoptosis.11

Vascular calcification (VC), a common cardiovascular problem in chronic kidney disease (CKD) cases, is caused by irregular inflammation, metabolism of phosphate and calcium, and other factors. Vascular calcification is often associated with atherosclerosis and CAD. Gau et al. found that miRs derived from BM-MSCs-exosomes can diminish calcium deposition in the human aorta's vascular smooth muscle cells (VSMCs) by affecting the central pathways.93 Later, this team found that BM-MSCs-exosomes play a role in inhibiting VC by transferring miR-16/-15a/-15 and hindering nuclear factors of activated T cells 3 (NFAT-3). This target gene can prevent the osteogenic trans-differentiation of VSMCs in the aorta by downregulating the osteocalcin expression.65 Moreover, Liu et al. indicated that BM-MSCs-derived exosomes exert anti-apoptosis and anti-calcification roles in CKD by transferring miR-381. This miR directly downregulates NFAT-5, reducing VSMC apoptosis and VC.94


Conclusion

Cell-free therapy using MSC-exos-miRs demonstrates remarkable potential in cardiology, particularly through its ability to mitigate inflammation, apoptosis, and fibrosis, prevent tissue damage, promote angiogenesis, and protect against I/R injury. Exosomes derived from MSCs play a pivotal role in regulating physiological and pathological processes by transporting bioactive molecules such as miRs to recipient cells. These exosomal miRs contribute significantly to the therapeutic effects of MSCs by influencing cell proliferation, differentiation, and migration. However, challenges remain due to the heterogeneity of MSC sources, preconditioning methods, and exosome extraction protocols. These variations complicate the assessment of therapeutic efficacy and hinder clinical translation. Standardized protocols for preparing and evaluating MSC-exosomal miRs are crucial to ensuring reproducibility in clinical trials. Additionally, optimizing therapeutic parameters such as exosome extraction,95 content, concentration, administration frequency, and delivery routes are vital for enhancing their efficacy in treating CAD. Developing universally accepted methods for isolating and characterizing MSC-derived exosomes is essential to ensure homogeneity and reproducibility in clinical applications. Future studies should focus on identifying optimal therapeutic concentrations, dosing regimens, and delivery routes to maximize the cardioprotective effects of MSC-exosomal miRs.

Review Highlights

What is the current knowledge?

  • MSC-exosomal miRs have positive effects in preclinical models of cardiovascular disease.

What is new here?

  • MSC-exosomal miRs are emerging as key regulators in CAD, influencing atherosclerosis progression, plaque stability, and post-ischemic cardiac repair.

  • MSC-exosomal miRs offer dual diagnostic and therapeutic potential in CAD, modulating inflammation, apoptosis, and tissue repair.

  • The cardioprotective properties MSC-exosomal miRs could play a role in the management of CAD patients.


Competing Interests

The authors declared that there was no conflict of interest in this study.


Consent to Participate

Not applicable.


Consent for Publication

Not applicable.


Data Availability Statement

Data will be made available upon a reasonable request.


Ethical Approval

This study was ethically approved via Tabriz University of Medical Sciences (Ethical code: IR.TBZMED.VCR.REC.1402.231).


Supplementary files

Supplementary file 1 contains Table S1. (pdf)

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Submitted: 02 Feb 2025
Revised: 24 Apr 2025
Accepted: 28 May 2025
First published online: 06 Sep 2025
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