Mesenchymal Stem Cell-Derived Exosomes: A Tool for Heart Failure Repair — From Molecular Mechanisms to Clinical Potential

Abstract

Exosomes are nanoscale vesicles abundantly distributed across biological fluids, serving as crucial mediators of intercellular communication by carrying bioactive molecules such as proteins, nucleic acids, and lipids. They exert pivotal functions in various physiological and pathological processes. Mesenchymal stem cell-derived exosomes (MSC-exos) exhibit low immunogenicity, minimal tumorigenic risk, abundant sources, and amenability to engineering modifications. Through the targeted delivery of bioactive molecules, MSC-exos exert multifaceted therapeutic effects in heart failure (HF) repair. They not only protect cardiomyocytes, thereby maintaining structural integrity, but also modulate immune and inflammatory responses, thereby improving the myocardial microenvironment. Additionally, they inhibit fibrosis, promote angiogenesis, and optimize myocardial metabolism, offering novel strategies and tools for the treatment of HF. This review aims to systematically elucidate the biological characteristics of MSC-exos, provide an in-depth analysis of their molecular mechanisms in HF therapy, summarize optimization strategies, and explore their potential in drug delivery and clinical applications. Furthermore, it discusses the challenges and future directions for clinical translation, thereby offering a comprehensive reference for both basic research and clinical practice regarding MSC-exos as a therapeutic tool for HF repair.

Introduction

Heart failure (HF) represents a major global public health burden, with continuously rising morbidity and mortality rates, making it a critical challenge in the field of cardiovascular disease.^1,2 According to the Global Burden of Disease Study, the number of HF patients worldwide has exceeded 64 million, and this figure continues to increase annually due to factors such as population aging, improved treatments for ischemic heart disease, and enhanced survival rates.³ Current clinical management strategies primarily rely on pharmacological interventions, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta-blockers, mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNI), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, as well as device-based therapies such as cardiac resynchronization therapy.^4,5 However, despite these therapeutic options, complete reversal of myocardial injury and full restoration of cardiac function remain elusive, as disease progression may continue and challenges such as drug intolerance and surgical risks persist.^6,7 Exosomes are nanoscale vesicles present in nearly all bodily fluids. As essential mediators of intercellular communication, they carry bioactive molecules, including proteins, nucleic acids (eg, mRNA, miRNA, lncRNA), lipids, and metabolites. Exosomes play key regulatory roles in diverse physiological and pathological processes, including cell proliferation, differentiation, apoptosis, and immune modulation.^8,9

In contrast to conventional cell-based therapies, extensive research has demonstrated that mesenchymal stem cell-derived exosomes (MSC-exos) offer unique advantages, including low immunogenicity, minimal tumorigenic risk, ease of storage and transportation, and the potential for engineering enhanced targeting specificity. These properties position MSC-exos as a promising tool in regenerative therapies for cardiovascular diseases.^10–13 In this review, the biological characteristics of MSC-exos are systematically elucidated, their molecular mechanisms in HF treatment, including cardiomyocyte protection, immunomodulation, anti-fibrotic effects, angiogenesis promotion, and metabolic improvement are analyzed in depth, current optimization strategies are summarized, and their application potential in drug delivery and clinical therapeutics is evaluated. Furthermore, the challenges and future directions for clinical translation are discussed, offering a comprehensive reference for both basic research and clinical applications of MSC-exos as a therapeutic agent for HF repair.

Biological Characteristics of Exosomes

Nomenclature Statement

In current research, exosomes are generally characterized as vesicles with a diameter of 30–150 nm, and their identification is operationally based on this size range, isolation methods such as ultracentrifugation or precipitation, and the presence of conventional exosomal markers.^14,15 However, according to the current guidelines of the International Society for Extracellular Vesicles (MISEV2023),¹⁶ the term “exosome” should ideally be reserved for vesicles with demonstrated endosomal origin, ie, formed as intraluminal vesicles within multivesicular bodies and released upon fusion with the plasma membrane. In many of the studies cited in this review, definitive evidence of endosomal biogenesis was not provided. Consequently, some preparations described as “exosomes” may more appropriately be classified as small extracellular vesicles (sEVs). To maintain consistency with the terminology used in the primary literature, this review retains the original authors’ designation of “MSC-exos” when discussing specific studies. This term is used here as an operational definition referring to small extracellular vesicles isolated from mesenchymal stem cell-conditioned medium by methods commonly employed in the exosome field, rather than as a claim of demonstrated endosomal origin for every preparation discussed.

The biological characteristics of exosomes are central to their role in mediating intercellular communication and to their potential for clinical application. These features are primarily reflected in three key dimensions: biogenesis and release, compositional profile, and uptake and function. The specific processes and key mechanisms are schematically illustrated in Figure 1. The biogenesis of exosomes begins with early endosomes, which mature into MVBs through ESCRT-dependent or ESCRT-independent mechanisms. These MVBs subsequently fuse with the plasma membrane, releasing intraluminal vesicles as exosomes. Exosomes carry a diverse array of functional molecules, including proteins, nucleic acids, lipids, and metabolites. Following their release, exosomes can be taken up by recipient cells via membrane fusion or endocytic pathways. Through the delivery of their bioactive cargo, exosomes modulate target cell functions and play important roles in various physiological and pathological processes, including immune regulation and tissue repair.

Figure 1.

Schematic illustration of the biogenesis, composition, uptake, and function of exosomes.

Biogenesis and Release of Exosomes

The biogenesis of exosomes begins with endocytosis, during which the plasma membrane buds inward to form early endosomes. These early endosomes are responsible for the initial sorting and fate determination of cargo. Cargo destined for recycling is transported back to the plasma membrane or Golgi apparatus via the tubular peripheries of the endosome, whereas remaining cargo within the central luminal compartment facilitates the maturation of early endosomes into late endosomes.^17,18 Late endosomes subsequently generate intraluminal vesicles (ILVs) through inward membrane budding, resulting in the formation of multivesicular bodies (MVBs). The generation of ILVs is regulated by two primary mechanisms: the ESCRT-dependent pathway and the ESCRT-independent pathway. In the ESCRT-dependent pathway, the ESCRT-0, -I, -II, and -III complexes collaborate with Vps4. Polymerization of SNF7/CHMP4 induces negative membrane curvature, facilitating ILV formation, while apoptosis-linked gene 2-interacting protein X (ALIX) may participate in cargo sorting via alternative mechanisms. In the ESCRT-independent pathway, mechanisms such as the syndecan-syntenin-ALIX axis, lipid rafts, tetraspanins, and Rab GTPases collectively promote membrane deformation and ILV generation.^19–22 The fusion of MVBs with the plasma membrane, which results in the release of ILVs as exosomes, is mediated by the vesicle docking and fusion machinery. This process relies primarily on the coordinated actions of v-SNAREs, t-SNAREs, Rab GTPases, and tethering proteins.^23,24 Rab GTPases ensure membrane targeting through the recruitment of tethering proteins and interaction with soluble NSF attachment protein receptors (SNAREs). SNARE proteins form complexes that mediate the fusion between endosomal and plasma membranes, with vesicle-associated membrane protein 7 (VAMP7) and SNAP-23 playing ubiquitous roles in this process.²⁵ Additionally, post-translational modifications of SNAREs can modulate their interactions and regulate secretion efficiency. Cytoskeletal remodeling provides structural support for MVB transport and fusion, ultimately ensuring the precise and efficient release of exosomes into the extracellular space, where they participate in intercellular communication.²²

Composition of Exosomes

As nanoscale vesicles secreted by cells, exosomes exhibit a complex and cell-type-specific composition, primarily consisting of proteins, nucleic acids, lipids, and small-molecule metabolites. These components collectively confer diverse biological functions to exosomes.^26,27 Transmembrane proteins and annexins (eg, CD9, CD63, CD81) play key roles in maintaining exosomal structural stability and mediating intercellular recognition. Heat shock proteins (eg, HSP70, HSP90), cytoskeletal proteins (eg, actin, tubulin), signal transduction molecules (eg, PI3K, Akt), and enzymes are primarily involved in exosome biogenesis, targeted transport, and the functional regulation of recipient cells.^28–31 Nucleic acids, including miRNAs, mRNAs, lncRNAs, circRNAs, and DNA fragments, are encapsulated within exosomes and enable intercellular transfer. Once delivered to recipient cells, these nucleic acids regulate gene expression and modulate cellular physiological functions.³² The lipid composition of the exosomal membrane is similar to but distinct from that of the plasma membrane, being enriched in cholesterol, sphingomyelin, ceramide, and phosphatidylserine. Cholesterol and sphingomyelin contribute to the stable membrane structure of exosomes. Ceramide plays an important regulatory role in the formation of MVBs and the release of exosomes, while phosphatidylserine can act as a signaling molecule involved in the recognition and uptake of exosomes by target cells.³³ Exosomes also contain trace amounts of small-molecule metabolites and lipid mediators, which may participate in modulating the metabolic state of target cells and the local microenvironment.

Uptake and Function of Exosomes

Exosomes must be taken up by target cells via specific mechanisms to exert their biological effects. Their uptake pathways are diverse, and upon internalization, the bioactive molecules they carry can regulate target cell functions.^34,35 The main uptake mechanisms include membrane fusion and endocytosis. Membrane fusion occurs through the direct merging of the exosomal lipid bilayer with the target cell membrane, resulting in the release of exosomal contents into the cytoplasm.^36,37 Endocytosis includes clathrin-mediated endocytosis, caveolin-mediated endocytosis, macropinocytosis, and phagocytosis. Receptor-ligand interactions can confer specificity to the uptake process, a feature which is essential for the precise regulatory functions of exosomes.¹³ After the exosomes are taken up by the target cells, bioactive molecules such as nucleic acids, proteins, and lipids carried by exosomes can modulate target cell function through multiple mechanisms. At the nucleic acid level, exosomal miRNAs and other nucleic acids can regulate gene expression and influence various physiological processes in recipient cells.^38,39 At the protein level, exosome-derived proteins can directly modulate signaling pathways or participate in processes such as cellular metabolism.⁴⁰ At the lipid level, bioactive lipids can engage in signal transduction and regulate the physiological state of the cell. Furthermore, exosomes can participate in various physiological and pathological processes such as immune regulation and tissue repair by regulating immune cell function and affecting cell proliferation.^41,42 Therefore, the mechanisms of exosome uptake and their functional regulation of target cells constitute the fundamental basis for their use as therapeutic tools in HF. A thorough understanding of these processes is essential for providing theoretical support for the clinical translation of MSC-exos.

Key Regulatory Roles of MSC-Exos in HF

The pathogenesis of HF is driven by multiple pathological factors, with core triggers including coronary artery disease, hypertensive heart disease, and dilated cardiomyopathy. These factors contribute to prolonged cardiomyocyte injury, disruption of myocardial structural integrity, induction of myocardial fibrosis, and eventual cardiac decompensation, ultimately leading to diminished pumping capacity and progression to HF.^43–46 Therefore, inhibiting cardiomyocyte death, regulating immune-inflammatory balance, reversing ventricular fibrosis, improving myocardial blood perfusion, and optimizing myocardial energy metabolism have become key therapeutic directions for delaying the progression of HF and improving patient prognosis. To provide a comprehensive understanding of the role of MSC-exos in HF, the core mechanisms through which they exert therapeutic effects are illustrated in Figure 2, and specific molecular targets, signaling pathways, and experimental evidence are summarized in Table 1. As summarized in Table 1, the available evidence is dominated by preclinical studies using bone marrow-, adipose-, and umbilical cord-derived MSC-exos. Mechanistic investigations focus on miRNA cargo that regulates apoptosis, inflammation, fibrosis, and angiogenesis, with PTEN/AKT, NF-κB, TGF-β/Smad, and JNK-related signaling pathways appearing repeatedly across studies. However, notable heterogeneity among different MSC sources and experimental models may affect translational outcomes, largely because the miRNA profiles loaded into exosomes play a decisive role in their efficacy.

Figure 2.

Schematic illustration of the multidimensional therapeutic effects of MSC-exos in ameliorating HF.

Table 1.

Mechanisms of MSC-Exos in Regulating Cardiomyocyte Protection and Programmed Cell Death, Immune Response and Inflammation, Myocardial Fibrosis and Ventricular Remodeling via miRNAs

Function	Extracellular Vesicle Source	Key miRNAs	Target Genes or Protein	Mechanisms	References
Exerting cardiomyocyte protective effects and regulating programmed cell death	Human endometrial mesenchymal stem cells	miR-21	PTEN ↓	miR-21 targets PTEN, regulates Akt phosphorylation, and inhibits apoptosis of human ischemic cardiomyocytes	[47,48]
	Rat bone marrow mesenchymal stem cells	miR-21-5p	YAP1 ↓	miR-21-5p directly targets YAP1 and inhibits hypoxia-induced inflammation and apoptosis in H9c2 cardiomyocytes	[49]
	Rat bone marrow mesenchymal stem cells	miR-144	PTEN ↓	miR-144 targets the PTEN/AKT pathway to inhibit H9c2 myocardial cell injury and apoptosis in rats under hypoxic conditions	[50]
	Rat bone marrow mesenchymal stem cells	miR-183-5p	FOXO1 ↓	miR-183-5p inhibits FOXO1 expression and reduces myocardial cell apoptosis in ischemia-reperfusion rats	[51]
	Rat bone marrow mesenchymal stem cells	miR-338	MEKK2 ↓, JNK ↓	miR-338 targets MEKK2/JNK pathway to alleviate apoptosis of H9c2 cardiomyocytes in MI rats	[52]
	Rat bone marrow mesenchymal stem cells	miR-455-3p	MEKK1 ↓, MKK4 ↓, JNK ↓	miR-455-3p inhibits the MEKK1-MKK4-JNK signaling pathway to reduce apoptosis of H9c2 cardiomyocytes in MI rats	[53]
	Rat adipose mesenchymal stem cells	miR-146a	EGR1 ↓, TLR4 ↓, NF-κB ↓	miR-146a downregulates EGR1, reverses hypoxia-induced TLR4/NF-κB signaling activation, and alleviates myocardial cell death in AMI rats	[54]
	Human umbilical cord mesenchymal stem cells	miR-125b-5p	Smad7 ↑	miR-125b-5p, when inhibited, upregulates Smad7 expression and reduces myocardial cell damage and apoptosis in AMI mice	[55]
	Human umbilical cord mesenchymal stem cells	miR-100-5p	FOXO3 ↓, NLRP3 ↓	miR-100-5p downregulates FOXO3, inhibits NLRP3 inflammasome activation, and reduces inflammation-mediated pyroptosis and injury in human cardiomyocytes	[56]
	Human induced pluripotent stem cell-derived mesenchymal stem cells	miR-202-5p	TRAF3IP2 ↓, JNK ↓	miR-202-5p targets TRAF3IP2 to inhibit JNK signaling, thereby suppressing NLRP3-mediated cardiomyocyte pyroptosis and improving cardiac function in mouse myocardial infarction models	[57]
	Human umbilical cord mesenchymal stem cells	miR-3152-5p	FKBP4 ↓	miR-3152-5p directly targets FKBP4, inhibits pyroptosis and fibrosis in TGF-β-treated H9c2 cells, and improves cardiac function in isoproterenol-induced heart failure mice	[58]
Regulating immune response and reducing inflammation	Mouse adipose-derived mesenchymal stem cells	miR-671	TGFBR2 ↓, Smad2 ↓	miR-671 inhibits TGFBR2 expression and Smad2 phosphorylation, reducing the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α	[59]
	Human adipose mesenchymal stem cells	miR-34a, miR-124, miR-135b	IL-10 ↑, TNF-α ↓, IL-6 ↓	miR-34a, miR-124, and miR-135b increase IL-10 secretion under melatonin stimulation, inhibit TNF-α and IL-6 expression, and exert anti-inflammatory effects	[60]
	Rat adipose mesenchymal stem cells	miR-146a	IL-6 ↓, IL-1β ↓, TNF-α ↓	miR-146a inhibits the release of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, reducing local inflammation	[54]
	Mouse bone marrow mesenchymal stem cells	miR-182-5p	GSDMD ↓, TLR4 ↓, NF-κB ↓	miR-182-5p inhibits the apoptosis-related proteins GSDMD and TLR4, as well as the TLR4/NF-κB signaling pathway, exerting anti-inflammatory effects	[61]
Inhibiting fibrosis and reversing ventricular remodeling	Rat umbilical cord mesenchymal stem cells	miR-24	Bim ↓	miR-24 targets Bim via the miR-24/Bim pathway to inhibit cardiac fibrosis and restore cardiac function	[62]
	Mouse bone marrow mesenchymal stem cells	miR-210	EGR1 ↓	miR-210 downregulates EGR1, reduces myocardial cell death, inhibits fibrosis, and increases vascular density in AMI mice	[63]
	Mouse bone marrow mesenchymal stem cells	miR-129-5p	TRAF3 ↓, NF-κB ↓	miR-129-5p targets TRAF3 to inhibit NF-κB signaling, thereby alleviating oxidative stress, apoptosis, inflammation, and fibrosis in HL-1 cardiomyocytes and mice with heart failure	[64]
Promoting angiogenesis and improving perfusion	Rat bone marrow mesenchymal stem cells	miR-143-3p	CHK2 ↓, Beclin2 ↓	miR-143-3p inhibits the CHK2-Beclin2 pathway to regulate autophagy and suppresses myocardial ischemia-reperfusion injury in rats	[65]
	Human adipose mesenchymal stem cells	miR-342-5p	PPP1R12B ↓	miR-342-5p targets PPP1R12B in a human umbilical vein endothelial cell model under H2O2 attack, protecting endothelial cells and improving endothelial dysfunction	[66]
	Human adipose mesenchymal stem cells	miR-125a	DLL4 ↓	miR-125a inhibits angiogenesis inhibitor delta-like 4, stimulates endothelial cell proliferation and migration, and regulates endothelial cell angiogenesis	[67]

Notes: The arrows (↑ and ↓) used in the tables indicate the direction of change in the levels, activity, or content of molecules, metabolites, or indicators. Specifically, (↑) denotes increase and (↓) denotes decrease.

Exerting Cardiomyocyte Protective Effects and Regulating Programmed Cell Death

Cardiomyocyte apoptosis is a major contributor to myocardial injury and functional deterioration in HF. MSC-exos mitigate apoptosis by delivering anti-apoptotic molecules and activating pro-survival signaling pathways. Specifically, exosomal miR-21 derived from induced pluripotent stem cells targets phosphatase and tensin homolog (PTEN) to regulate Akt phosphorylation, thereby inhibiting ischemic cardiomyocyte apoptosis and stimulating angiogenesis. Similarly, upregulation or knockdown of miR-21 in human endometrial mesenchymal stem cell-derived exosomes (ENMSC-exos) correspondingly modulates PTEN expression and Akt phosphorylation in target cells, indicating that the miR-21/PTEN/Akt pathway is a crucial mechanism underlying the cardioprotective effects of ENMSC-exos.^47,48 Rat bone marrow mesenchymal stem cell-derived exosomal miR-21-5p directly targets Yes-associated protein 1 (YAP1) in H9c2 cardiomyocytes, thereby attenuating hypoxia-induced inflammation and apoptosis.⁴⁶ Moreover, rat bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) deliver miR-144 to cardiomyocytes, targeting the PTEN/Akt pathway to suppress apoptosis under hypoxic conditions.⁵⁰ Rat BMSC-exos carrying miR-183-5p inhibit forkhead box O1 (FOXO1) expression, thereby reducing cardiomyocyte apoptosis.⁵¹ Rat MSC-derived exosomal miR-338 alleviates cardiomyocyte apoptosis by targeting the MEKK2/JNK pathway, while rat BMSC-derived exosomal miR-455-3p inhibits the MEKK1-MKK4-JNK signaling cascade to attenuate apoptosis.^52,53 Rat adipose-derived mesenchymal stem cell exosomes (ADMSC-exos) modified with miR-146a protect cardiomyocytes by downregulating early growth response factor 1 (EGR1) to prevent cell death.⁵⁴ Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-exos) miRNAs regulate apoptosis-related molecules; for instance, inhibition of miR-125b-5p promotes Smad7 expression, reducing cardiomyocyte injury and apoptosis in damaged myocardium.⁵⁵ Human UCMSC-exos containing miR-100-5p downregulate FOXO3, inhibit NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and mitigate inflammation-mediated pyroptosis and injury in cardiomyocytes.⁵⁶ Human induced pluripotent stem cell-derived mesenchymal stem cell exosomes (iPSC-MSC-exos) deliver miR-202-5p to inhibit cardiomyocyte pyroptosis by downregulating the TRAF3IP2/JNK axis, showing superior cardioprotective effects compared to BMSC-exos.⁵⁷ Additionally, rat BMSC-exos pretreated with leonurine, which are enriched in miR-3152-5p, alleviate cardiomyocyte pyroptosis and apoptosis, reduce fibrosis and collagen deposition, and exert beneficial effects on improving cardiac function by directly targeting FKBP4.⁵⁸

Regulating Immune Response and Reducing Inflammation

MSC-exos have shown potential to protect against HF by regulating immune and inflammatory responses.⁶⁸ Their core mechanism involves remodeling the myocardial immune microenvironment to reduce inflammatory damage. Studies indicate that mouse ADMSC-exos carrying miR-671 suppress the expression of transforming growth factor beta receptor 2 (TGFBR2) and the phosphorylation of Smad2 in oxygen-glucose deprivation (OGD)-treated cardiomyocytes. Knockdown of miR-671 attenuates this inhibition, while further TGFBR2 knockdown significantly reduces the secretion of pro-inflammatory factors such as IL-6 and TNF-α, thereby mitigating inflammation. Additionally, exosomal miR-671 reduces cardiomyocyte apoptosis and inhibits α-SMA expression to attenuate fibrosis, further demonstrating its comprehensive protective role in HF-related pathological processes.⁵⁹ Human ADMSC-exos also modulate immune cells via paracrine activity, upregulating M2 macrophage-associated anti-inflammatory genes such as IL-10 to suppress excessive inflammation. Notably, human ADMSC-exos stimulated by melatonin enhance anti-inflammatory effects, which are mediated through miRNAs such as miR-34a, miR-124, and miR-135b, presenting a potential tool for treating inflammatory conditions in HF.⁶⁰ Rat ADMSC-exos modified with miR-146a further reduce local inflammation by inhibiting the release of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α.⁵⁴ Xu et al found that rat BMSC-exos preconditioned with low-dose lipopolysaccharide (LPS) promote M2 macrophage polarization, inhibit M1 polarization and NF-κB signaling, and partially activate AKT1/AKT2 signaling, thereby exerting anti-inflammatory and anti-apoptotic effects. This suggests a promising cell-free therapeutic strategy for HF.⁶⁹ Moreover, mouse BMSC-exos carrying miR-182-5p inhibit pyroptosis-related proteins including GSDMD and TLR4, as well as the TLR4/NF-κB pathway, to exert anti-inflammatory effects.^61,70 Furthermore, treatment with FNDC5 enhances the ability of mouse BMSC-exos to promote macrophage polarization, indirectly reducing inflammatory responses.⁷¹ In an angiotensin II (Ang II)-induced hypertrophic H9c2 cardiomyocyte model, rat BMSC-exos ameliorate hypertrophy, downregulate apoptosis-related proteins such as Bax and caspase 3, upregulate Bcl-2, reduce levels of inflammatory factors (eg, IL-1β, IL-4, IL-6, TNF-α) and BNP, and inhibit the Hippo-YAP pathway by downregulating p-YAP and upregulating TAZ, thereby attenuating apoptosis and inflammation.⁷² Finally, human UCMSC-exos promote the differentiation of cardiac fibroblasts (CFs) into myofibroblasts and stimulate the secretion of anti-inflammatory cytokines, which collectively reduce inflammation and protect cardiac tissue.⁷³

Inhibiting Fibrosis and Reversing Ventricular Remodeling

Excessive myocardial fibrosis is a key driver of progressive cardiac dysfunction and the development of HF.^74,75 MSC-exos alleviate ventricular remodeling and impede fibrotic progression through the delivery of specific miRNAs and direct intervention in fibrotic signaling pathways, offering significant experimental evidence and therapeutic potential for delaying HF progression. Shao et al reported that rat UCMSC-exos are enriched with miR-24, which bioinformatic and experimental analyses identified as targeting Bim. These exosomes subsequently inhibit cardiac fibrosis and restore cardiac function via the miR-24/Bim pathway.⁶² Furthermore, human UCMSC-exos carrying TIMP2 attenuate post-myocardial infarction (MI) cardiac remodeling by inhibiting ECM remodeling and collagen deposition via suppression of TGFβ-induced MMP2, MMP9, and α-SMA in cardiac fibroblasts, while also reducing oxidative stress and cardiomyocyte apoptosis through modulation of Bcl-2/Bax/caspase-9 and the Akt/Sfrp2 pathway.⁷⁶ Studies also demonstrate that hypoxia-preconditioned mouse BMSC-exos exhibit elevated expression of miR-210. This elevation correlates with reduced cardiomyocyte death, inhibited fibrosis, increased vascular density, improved cardiac function in murine MI models, and amelioration of post-MI HF.⁶³ Mouse BMSC-derived exosomal miR-129-5p ameliorates oxidative stress, cell apoptosis, inflammation, and fibrosis in cardiomyocytes of mice with HF by inhibiting the TRAF3/NF-κB signaling pathway, thereby alleviating ventricular dysfunction.⁶⁴ Additionally, research by Chen et al confirmed that mouse BMSC-exos attenuate cardiac hypertrophy and fibrosis during pressure overload-induced cardiac remodeling, highlighting their promising therapeutic potential for HF.⁷⁷ Human ADMSC-exos transfer miR-125a to endothelial cells, where it inhibits the angiogenesis suppressor delta-like 4 (DLL4).⁶⁷ Moreover, mouse ADMSC exosomal miR-671 inactivates the TGFBR2/Smad2 axis, blocks TGF-β1/Smad2 signaling, reduces fibroblast-to-myofibroblast transition, and thereby alleviates myocardial fibrosis and inflammation.⁵⁹

Promoting Angiogenesis and Improving Perfusion

In the pathological process of HF, MSC-exos not only promote angiogenesis and improve myocardial blood perfusion by delivering pro-angiogenic factors and regulating endothelial cell function, but also mitigate myocardial injury induced by ischemia-reperfusion through specific mechanisms, thereby preventing the onset of HF. Komaki et al demonstrated that exosomes derived from human term placenta-derived mesenchymal stem cells (PMSC-exos) promote endothelial tube formation and migration in vitro, while upregulating the expression of angiogenesis-related genes such as Tie-2 and Ang-2, and enhance angiogenesis and blood perfusion in a murine auricular ischemia model in vivo. Although these findings are derived from a peripheral ischemia model, the potent pro-angiogenic and perfusion-enhancing effects of PMSC-exos suggest that they may serve as a potential novel therapeutic strategy for HF.⁷⁸ Rat BMSC-derived exosomal miR-143-3p attenuates myocardial ischemia-reperfusion injury (IRI) by directly targeting CHK2 and inhibiting autophagy through the CHK2-Beclin2 pathway, thereby reducing cardiomyocyte apoptosis.⁶⁵ Furthermore, Wang et al demonstrated that rat BMSC-exos dynamically modulate PDGFR-β signaling. Early upregulation promotes microvascular regeneration, increasing MVD and CD34 while reducing vWF. Late suppression limits fibrosis by decreasing TGF-β1 and collagen, thereby preserving cardiac function.⁷⁹ Notably, human ADMSC-exos carrying miR-342-5p have been demonstrated to protect endothelial cells by targeting PPP1R12B in an H2O2-challenged human umbilical vein endothelial cell (HUVEC) model. This mechanism provides novel insights into improving vascular endothelial dysfunction, helping maintain vascular patency and reducing myocardial ischemia-induced HF caused by vascular stenosis.⁶⁶ Meanwhile, human ADMSC-exos can transfer miR-125a to endothelial cells, inhibit the angiogenesis suppressor DLL4, stimulate endothelial cell proliferation and migration, and regulate endothelial cell-mediated angiogenesis, thereby delaying the progression of HF.⁶⁷ Human UCMSC-exos activate platelet-derived growth factor D (PDGF-D) to improve angiogenesis and cardiac function, addressing insufficient capillary formation in HF and delaying the transition from compensatory hypertrophy to decompensation.⁸⁰

Improving Myocardial Metabolism and Mitochondrial Function

Myocardial metabolic disorders, autophagy dysregulation, and mitochondrial dysfunction significantly exacerbate the deficiency in energy supply and impair the function of cardiomyocytes.⁸¹ MSC-exos ameliorate these pathological states by regulating related molecular mechanisms, thereby providing critical energy support and maintaining cellular homeostasis. At the metabolic level, studies demonstrate that BMSC-derived exosomal lncRNA GAS5 mitigates heart failure by inhibiting UL3/Hippo pathway-mediated ferroptosis, thereby reducing oxidative stress and improving mitochondrial function in cardiomyocytes.⁸² Zhuang et al demonstrated that rat BMSC-exos limit MIRI by activating the AMPK/PGC-1α signaling pathway, thereby reducing oxidative stress and mitochondrial dysfunction in cardiomyocytes.⁸³ Feng et al proposed that MSC-exos modulate glucose-6-phosphate dehydrogenase (G6PD)-dependent metabolic remodeling in heart failure through specific phospholipid cargoes that allosterically regulate G6PD to enhance pentose-phosphate pathway activity and sustain NADPH-dependent redox balance, linking exosomal paracrine signaling to redox-driven myocardial regeneration.⁸⁴ The synergistic effects of these mechanisms translate into significant functional improvements in animal models. Studies in rats show that rat ADMSC-exos improve key hemodynamic and metabolic indicators, such as left ventricular ejection fraction, left ventricular fractional shortening, stroke volume, and ATP content in cardiac tissue, optimizing myocardial energy metabolism while reducing serum levels of brain natriuretic peptide and atrial natriuretic peptide, demonstrating cardioprotective effects and offering a novel potential strategy for HF treatment.⁸⁵ These studies suggest that MSC-exos provide multi-targeted interventions for HF by coordinately regulating myocardial metabolism and mitochondrial function.

Development of MSC-Exos from Functional Optimization to Clinical Application

Strategies for Constructing Functionally Enhanced MSC-Exos

Active intervention strategies for constructing functionally enhanced MSC-exos represent a core approach for improving their therapeutic specificity and efficacy. This process involves not only the regulation of MSCs themselves but also the modulation of exosome biogenesis and cargo sorting, facilitating the transition from natural exosomes to high-performance therapeutic agents, thereby laying the foundation for subsequent applications as drug carriers or direct therapeutics. Specific strategies for engineering functional MSC-exos are illustrated in Figure 3.

Figure 3.

Engineering strategies for functional enhancement of MSC-exos. (A) Preconditioning optimization, (B) Genetic engineering modification, (C) Microenvironment modulation and pathway intervention.

Preconditioning Optimization of Parent MSCs

Pretreatment optimization of MSCs offers a straightforward and effective method to enhance exosome function. For instance, hypoxia-preconditioned ADMSC-exos are enriched with pro-angiogenic proteins and their receptors, such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF). These exosomes modulate VEGF/VEGFR signaling in human umbilical vein endothelial cells (HUVECs) and transplanted tissues. This modulation promotes HUVEC proliferation, migration, and tube formation. In vivo, the exosomes further enhance neovascularization around fat grafts in nude mice and increase the expression of angiogenesis-related molecules in the transplanted tissues.⁸⁶ Similarly, MSC-exos preconditioned under ischemic conditions are rich in miR-22. These exosomes can directly target cardiomyocytes and exert anti-apoptotic effects by suppressing methyl-CpG-binding protein 2 (Mecp2), thereby reducing ischemia-induced cardiomyocyte apoptosis. In vivo experiments have demonstrated that the delivery of ExoIPC significantly attenuates cardiac fibrosis.⁸⁷ Additionally, ADMSC-exos pretreated with macrophage migration inhibitory factor (MIF) can protect cardiomyocytes from H₂O₂-induced apoptosis by regulating oxidative stress and modulating the lncRNA-NEAT1/miR-142-3p/FOXO1 pathway, wherein lncRNA-NEAT1 acts as a competitive endogenous RNA to exert anti-apoptotic effects.⁸⁸

Genetic Engineering for Cargo Manipulation

Compared with pretreatment, genetic engineering enables precise control over the cargo of MSC-exos. Rat BMSCs were genetically engineered to overexpress miR-30e, and the secreted exosomes were harvested for functional evaluation. Studies showed that these exosomes negatively regulate LOX1 expression, downregulate NF-κB p65/Caspase-9 signaling activity, reduce cardiomyocyte apoptosis and fibrosis, and improve cardiac function in post-myocardial infarction HF rats, providing experimental evidence for targeted miRNA modification in constructing functionally enhanced rat BMSC-exos.⁸⁹ Yu et al genetically engineered MSCs to overexpress GATA-4, generating functionally enhanced exosomes (ExoGATA-4). Functional validation revealed that ExoGATA-4 increases the survival of cardiomyocytes (CMs) under hypoxic conditions, reduces apoptosis, maintains mitochondrial membrane potential, and significantly restores cardiac contractile function and reduces infarct size after intramyocardial transplantation. At the molecular level, ExoGATA-4 was found to be enriched with anti-apoptotic miRNAs such as miR-19a, which can be rapidly internalized by CMs. miR-19a downregulates the expression of target proteins PTEN and BIM, activating Akt and ERK signaling pathways to inhibit apoptosis. Additionally, ExoGATA-4 carries miR-451, miR-221, and IGF-1, which synergize with miR-19a to enhance cardioprotective effects.⁹⁰ Similarly, using H9c2 cells and Sprague-Dawley rats to model doxorubicin-induced myocardial injury, potential target proteins were identified through genetic sequencing. Studies using Kruppel-like factor 4 (KLF4) knockout cell lines and rats to examine the effects of exosomes on inflammatory factors and myocardial injury markers revealed that BMSC-exos enhance KLF4 expression in cardiomyocytes, reduce levels of BNP, high-sensitivity troponin I, and inflammatory factors such as TNF-α and IL-6, thereby mitigating HF injury. Conversely, downregulation of KLF4 expression weakens this regulatory effect.⁹¹

Microenvironmental Regulation of Exosome Biogenesis

Beyond direct manipulation in MSCs, microenvironment regulation and pathway intervention serve as important supplements for constructing functionally enhanced MSC-exos. Studies have shown that circulating adiponectin can bind to T-cadherin on the surface of human MSCs, activating the ESCRT pathway to promote exosome release. In a cardiac hypertrophy model, activation of peroxisome proliferator-activated receptor gamma (PPARγ) or adenovirus-mediated overexpression increased plasma adiponectin levels, enhancing the therapeutic effects of human MSCs via the adiponectin/T-cadherin/ESCRT axis. This effect was significantly diminished in the absence of adiponectin. Furthermore, loss of ALIX reduced human MSC exosome production and diminished its therapeutic efficacy without affecting cytokine secretion or differentiation potential, demonstrating the specificity of this regulatory mechanism. This approach, which incorporates the organismal microenvironment into regulation, provides new insights for enhancing the efficacy of MSC-exos.⁹²

Design and Advantages of MSC-Exos as Targeted Delivery Systems

Building on functional enhancement, MSC-exos have emerged as ideal drug delivery vehicles due to their exceptional biological properties, including high biocompatibility, low immunogenicity, the ability to cross biological barriers, and the capacity to co-load multiple types of molecules (proteins, nucleic acids, small-molecule drugs, etc).^93–95 Compared to traditional nanocarriers such as liposomes and polymeric nanoparticles, MSC-exos not only possess inherent intercellular communication functions but also achieve precise delivery to HF lesions through natural targeting and engineering modifications. This addresses bottlenecks in existing drug therapies, such as significant off-target effects, insufficient local concentration, and rapid clearance, further expanding their potential in HF treatment. The design and advantages of MSC-exos as targeted delivery systems are comprehensively illustrated in Figure 4. The single-vector system utilizes exosomes that, through innate tropism or surface engineering, precisely accumulate in diseased cardiac tissue to deliver therapeutics such as anti-fibrotic miRNAs and large plasmids directly to target cells like fibroblasts. Complementarily, the hybrid-vector system combines MSC-exos with liposomes to form hybrid nanoparticles, which integrate the natural targeting of exosomes with the superior loading capacity of liposomes, thereby enabling efficient delivery of large genetic constructs like CRISPR/Cas9.

Figure 4.

Engineering design and advantages of MSC-exos as a targeted drug delivery system.

MSC-Exos as Standalone Delivery Systems

When MSC-exos are used alone as delivery vehicles, their natural targeting capability stems from various adhesion molecules expressed on their surface, which can specifically recognize markers of damaged myocardial tissue and guide exosomes actively toward the lesion site. To enhance targeting precision, membrane surface modifications such as chemical conjugation or genetic engineering to incorporate myocardial-specific ligands can reduce non-target organ uptake.³⁸ For example, to address cardiac fibrosis contributing to HF after MI, human UCMSC-exos loaded with the anti-fibrotic miR-29b mimic via electroporation can be effectively internalized in cardiac fibroblasts, upregulate miR-29b expression, downregulate fibrosis-related proteins, and thereby exert anti-fibrotic effects.⁹⁶ Studies have found that exosomes, by virtue of their unique lipid bilayer structure and hydrophilic core, can simultaneously load multiple therapeutic molecules, enabling synergistic targeting of multiple aspects of the HF pathological process to amplify treatment efficacy.^97,98 Additionally, a liposome-based delivery system functionalized with a cardiac-targeting peptide has been developed to deliver exosomal miR-185-5p inhibitor for the treatment of dilated cardiomyopathy. In doxorubicin-induced DCM mice, this targeted liposomal formulation significantly improved cardiac function, attenuated myocardial apoptosis and cuproptosis, and reduced fibrosis, demonstrating that exosomal RNA cargoes retain therapeutic efficacy even when delivered via non-exosomal carriers.⁹⁹ This approach offers an alternative strategy for HF treatment, particularly when exosome production or engineering is challenging.

MSC-Exos as Hybrid Delivery Systems

Beyond standalone therapeutic applications, MSC-exos are combined with other carriers to form hybrid delivery systems, whereby the advantages of different carriers can be integrated. For instance, exosome-liposome hybrid nanoparticles constructed via simple incubation retain exosomal characteristics while leveraging the high encapsulation efficiency of liposomes for large nucleic acids. Such systems can effectively load large plasmids, such as CRISPR/Cas9 expression vectors, be endocytosed by MSCs, which are otherwise difficult to transfect with lipids alone, and achieve gene expression, offering a new avenue for combined delivery systems in HF treatment.^100,101 Lai et al developed tri-component hybrid nanovesicles integrating SIRPα-overexpressing vesicles, MSC-exos, and platelet-derived vesicles, which synergistically alleviated myocardial inflammation and improved cardiac function in mouse I/R models.¹⁰² Pan et al prepared atorvastatin-pretreated MSC-exo-like nanovesicles for HFpEF treatment, which promoted anti-inflammatory macrophage polarization and attenuated cardiac hypertrophy via enrichment of lncRNAs TARID, H19, and KLF3-AS1.¹⁰³ These hybrid systems integrate the natural targeting and biocompatibility of exosomes with the enhanced loading capacity or functional diversity of other carriers, offering versatile platforms for HF therapy.

Clinical Translation Pathway and Application Scenarios of MSC-Exos for HF Treatment

Currently, translational research on MSC-exos for HF treatment remains largely confined to preclinical stages, with ongoing efforts extending to large animal studies and early-phase clinical exploration. Advancing this field requires not only rigorous validation of efficacy and safety but also solutions to key challenges such as production standardization, optimization of administration regimens, and establishment of robust efficacy evaluation systems. Based on the available preclinical evidence, MSC-exos may represent a potential therapeutic strategy for HF, and further investigation is warranted to determine their clinical applicability.

In exploratory efforts toward clinical translation, Yao et al tested a minimally invasive exosome spray based on MSC exosomes and biomaterials, demonstrating its feasibility and safety for cardiac repair and highlighting its promise as a therapeutic exosome delivery strategy, offering new ideas for future clinical applications.¹⁰⁴ Additionally, Mayourian et al combined systems biology with human engineered cardiac tissue (hECT) technology to reveal that miR-21-5p is a key molecule mediating the pro-contractile function of human MSC-exos through the PI3K signaling pathway. This study not only elucidated the mechanism of action of human MSC-exos but also provided precise molecular targets for engineering exosomes to enhance their efficacy, thereby offering precise targeting for optimizing stem cell-based cardiac therapies and improving HF treatment outcomes.¹⁰⁵

Given the unique advantages of MSC-exos, such as high biocompatibility, low immunogenicity, the capacity to carry a variety of bioactive molecules, and the ability to cross biological barriers, it is reasonable to speculate that they may show broad application prospects in future clinical treatments.^15,106–108 Theoretically, in the early stages of HF, MSC-exos could leverage their anti-inflammatory and pro-angiogenic properties to reduce cardiomyocyte necrosis and apoptosis, providing timely protection to damaged myocardium. In the middle and late stages of HF, their functions in inhibiting fibrosis and regulating metabolism could be employed to reverse ventricular remodeling and improve cardiac function.^109–113 This ability to intervene across different stages of HF offers new possibilities for comprehensive disease management and strengthens the theoretical and experimental foundation for translating related research from basic science to clinical applications, fostering optimism for effective future treatments of HF.

Engineered MSC-exos represent a potential upgrade over natural exosomes, enabling enhanced precision and efficiency, thereby injecting renewed momentum into future HF therapies. Through pretreatment strategies and genetic engineering of therapeutic MSCs, the secreted exosomes can be selectively enriched with specific therapeutic molecules. Incorporating myocardial-specific ligands via surface modification technologies allows precise targeting of HF lesion sites, significantly reducing off-target effects. Simultaneously, the efficient loading of therapeutic molecules such as miRNA mimics and small-molecule drugs enables synergistic effects between enhanced native function and precise delivery, offering a highly promising solution for more accurate and effective future approaches to overcoming the challenges of HF.^114–116

Challenges and Future Perspectives

In the field of MSC-exos research for HF treatment, several key directions demonstrate their unique advantages and translational potential: (i) Exosomes can be isolated from various types of mesenchymal stem cells found in different bodily fluids. This broad source ensures stable material availability, which is crucial for the preparation and subsequent clinical application of MSC-exos. (ii) The bioactive molecules carried by MSC-exos, such as non-coding RNAs (eg, miRNAs) and proteins, play clearly defined roles in regulating core pathways including cardiomyocyte apoptosis, immune inflammation, fibrosis, and angiogenesis. This provides new insights into the molecular mechanisms of cardiac regeneration and repair, and lays a foundation for identifying precise therapeutic targets for HF. (iii) MSC-exos exhibit low toxicity and immunogenicity, excellent biocompatibility, and tunable targeting capability, making them promising drug delivery vehicles that can overcome limitations of conventional drugs such as off-target effects and rapid clearance, thus representing a promising direction for developing novel therapeutic strategies.

Despite the broad application prospects of MSC-exos, current clinical research still faces several limitations: (i) The function of MSC-exos is influenced by cell source, microenvironment, and cargo molecules. Their regulatory networks have not been fully elucidated, and the correspondence between exosome subtypes and functions lacks unified standards, hindering a deeper understanding of their biological characteristics. (ii) Technical bottlenecks exist in the isolation and purification of MSC-exos. Current methods suffer from low purity, unstable yield, and a tendency to lose small molecular components. Moreover, it remains challenging to efficiently isolate specific MSC-exos subtypes, affecting the consistency between functional studies and clinical applications. (iii) Although one pilot study has recently explored the clinical application of MSC-exos in HF patients, the translational evidence chain remains largely incomplete, as the vast majority of current studies are still confined to animal experiments and in vitro models, with a notable absence of well-controlled clinical trials or regulatory-approved products for HF to date.¹¹⁷

To address these issues, future efforts should focus on the following key directions to accelerate the clinical translation of MSC-exos: (i) To clarify functional heterogeneity and decipher regulatory networks, studies should integrate cutting-edge technologies such as transcriptomics, proteomics, and metabolomics to deeply analyze the cargo sorting mechanisms and intercellular communication networks of MSC-exos. Clarifying the specific roles and interrelationships of different cargo molecules in each stage of myocardial repair will provide clearer targets for precise intervention, further improve the theoretical system of molecular mechanisms, and offer solid theoretical support for clinical translation. (ii) To overcome isolation and purification challenges and ensure product consistency, there is an urgent need to develop efficient and scalable isolation and purification processes. This can involve optimizing existing techniques such as ultracentrifugation and magnetic bead-based sorting, or exploring novel approaches like microfluidic chips to improve separation efficiency and purity. Simultaneously, unified quality control standards should be established, covering the physicochemical properties, bioactivity, and contaminant control of MSC-exos. Engineering strategies such as gene editing and surface modification can enhance their targeted delivery precision to damaged myocardial tissue, systematically addressing stability and safety issues during mass production. (iii) To close the translational validation chain and provide high-level evidence, priority should be given to designing multicenter, randomized controlled trials with large sample sizes. These trials should evaluate the therapeutic efficacy and long-term safety of MSC-exos in patients with HF of different etiologies and stages. Additionally, exploring combination therapies with existing drugs, cardiac resynchronization therapy, and other modalities will help clarify the advantages and optimal combinations of synergistic treatments.

Conclusion

MSC-exos demonstrate significant therapeutic potential in the treatment of heart failure, owing to their unique advantages including low immunogenicity, multi-target regulatory capacity, and amenability to engineering. Accumulating preclinical evidence suggests that MSC-exos exert cardioprotective effects through the modulation of multiple pathological pathways, including cardiomyocyte apoptosis, immune inflammation, fibrosis, angiogenesis, and myocardial metabolism. However, their clinical translation remains hindered by several critical limitations, including poorly defined functional heterogeneity, immature large-scale production and quality control systems, insufficient targeting delivery efficiency, and extremely limited clinical evidence. Future research should focus on the precise characterization of functional subtypes, the establishment of standardized production processes, and the design of rigorous large-scale randomized controlled trials, thereby facilitating the effective translation of MSC-exos from preclinical studies to clinical therapy for HF.

Funding Statement

This work was supported by the National Natural Science Foundation of China (82074378), the Project of Science & Technology Department of Sichuan Province (2026NSFSC1823), Youth Innovation Project of Sichuan Medical Association (Q20250014), Macao Young Scholars Program (AMWQ2025010), the Research Fund of Chinese Medicine Guangdong Laboratory (HQL2025SU024), the Project of Southwest Medical University (2024ZXYZX30, 2024ZKZ007, 2024ZXYZX39, 2024ZKY073), and Southwest Medical University Undergraduate Innovation and Entrepreneurship Project (2026182, 2026107). The funders had no role in the study design, data analysis, or decision to publish.

Abbreviations

AKT, Protein kinase B; ATP, Adenosine Triphosphate; α-SMA, Alpha-Smooth Muscle Actin; AMPK, AMP-activated Protein Kinase; ALIX, Apoptosis Linked Gene 2-Interacting Protein X; ARNI, Angiotensin Receptor-neprilysin Inhibitor; ADMSC-exos, Adipose Mesenchymal Stem Cell-derived Exosomes; ACEi/ARB, Angiotensin-converting Enzyme Inhibitors/Angiotensin Receptor Blockers; BNP, Brain Natriuretic Peptide; Bim, BCL2-like 11 (Bcl-2 interacting mediator of cell death); BMSC-exos, Bone Marrow Mesenchymal Stem Cell-derived Exosomes; CMs, Cardiomyocytes; CircRNAs, Circular RNAs; CHK2, Checkpoint Kinase 2; CD9, Cluster of Differentiation 9; CHMP4, Charged Multivesicular Body Protein 4; CRISPR/Cas9, Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated Protein 9; DLL4, Delta-like 4; ECM, Extracellular Matrix; EGF, Epidermal Growth Factor; EGR1, Early Growth Response 1; ERK, Extracellular Signal-regulated Kinase; ESCRT, Endosomal Sorting Complex Required for Transport; ENMSC-exos, Endometrial Mesenchymal Stem Cell-derived Exosomes; ExoIPC, Exosomes Derived from Ischemic Preconditioning-treated Cells; FOXO1, Forkhead Box O1; FKBP4, FK506-binding Protein 4 (prolyl isomerase 4); FNDC5, Fibronectin Type III Domain-containing Protein 5; GSDMD, Gasdermin D; GATA-4, GATA Binding Protein 4; G6PD, Glucose-6-phosphate Dehydrogenase; HF, Heart Failure; Hsp90, Heat Shock Protein 90; hECT, Human Engineered Cardiac Tissue; hs-TnI, High-sensitivity Troponin I; HUVEC, Human Umbilical Vein Endothelial Cells; IL-6, Interleukin-6; ILVs, Intraluminal Vesicles; IRI, Ischemia-Reperfusion Injury; IGF-1, Insulin-like Growth Factor 1; iPSC-MSC-exos, Induced Pluripotent Stem Cell-derived Mesenchymal Stem Cell Exosomes; JNK, c-Jun N-Terminal Kinase; KLF4, Kruppel-Like Factor 4; LPS, Lipopolysaccharide; lncRNA, Long non-coding RNA; LOX1, Lectin-like Oxidized Low-density Lipoprotein Receptor 1; miRNA, microRNA; MEKK2, MEK Kinase 2; MI, Myocardial Infarction; MVBs, Multivesicular Bodies; MMP2, Matrix Metalloproteinase 2; Mecp2, Methyl-CpG-binding Protein 2; MRA, Mineralocorticoid Receptor Antagonist; MIF, Macrophage Migration Inhibitory Factor; MKK4, Mitogen-Activated Protein Kinase Kinase 4; MSC-exos, Mesenchymal Stem Cell-derived Exosomes; NLRP3, NOD-Like Receptor Family Pyrin Domain Containing 3; NF-κB, Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells; OGD, Oxygen-Glucose Deprivation; OXPHOS, Oxidative Phosphorylation; PI3K, Phosphoinositide 3-Kinase; PTEN, Phosphatase and Tensin Homolog; PDGF-D, Platelet-Derived Growth Factor D; PDGFR-β, Platelet-Derived Growth Factor Receptor Beta; PMSC-exos, Placental Mesenchymal Stem Cell-Exosomes; PPP1R12B, Protein Phosphatase 1 Regulatory Subunit 12B; PPARγ, Peroxisome Proliferator-Activated Receptor Gamma; PGC-1α, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Alpha; RabGTPases, Rab GTPases; SNF7, Sucrose Nonfermenting 7; SGLT2, Sodium-glucose Cotransporter 2; SIRPα, Signal Regulatory Protein Alpha; SNAP23, Synaptosomal-Associated Protein 23; SNAREs, Soluble NSF Attachment Protein Receptors; Smad2, Mothers Against Decapentaplegic Homolog 2; TNF-α, Tumor Necrosis Factor Alpha; TGF-β1, Transforming Growth Factor Beta 1; TRAF3, TNF Receptor-associated Factor 3; TRAF3IP2, TRAF3 Interacting Protein 2; TIMP2, Tissue Inhibitor of Metalloproteinases 2; TGFBR2, Transforming Growth Factor Beta Receptor 2; TAZ, Transcriptional Coactivator with PDZ-Binding Motif; UCMSC-exos, Umbilical Cord Mesenchymal Stem Cell-derived Exosomes; Vps4, Vacuolar Protein Sorting 4; VEGF, Vascular Endothelial Growth Factor; VAMP7, Vesicle-Associated Membrane Protein 7; YAP1, Yes-associated Protein 1.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analyzed in this study.

Author Contributions

Ming-Tai Chen: Writing-original draft, Investigation, Data curation, Validation.

Zhen-Xun Wan: Writing-original draft, Investigation, Data curation, Validation.

Yuan-Yuan Li: Writing-original draft, Investigation, Data curation, Validation.

Xiao-Lin Li: Visualization, Validation, Data curation, Software, Writing-original draft.

Yang Luo: Validation, Visualization, Software, Writing-original draft.

Shi-Yun Yang: Investigation, Validation, Writing-review & editing.

Hang Jiang: Investigation, Validation, Writing-review & editing.

Qiu-Yu Liu: Investigation, Data curation, Writing-review & editing.

Rui Lyu: Investigation, Data curation, Writing-review & editing.

Yan Jiang: Writing-review & editing, Conceptualization, Methodology, Supervision.

Gang Luo: Writing-review & editing, Conceptualization, Methodology, Supervision.

Meng-Nan Liu: Writing-review & editing, Conceptualization, Methodology, Funding acquisition, Supervision, Project administration.

All authors gave final approval of the version to be published, have agreed on the journal to which the article has been submitted, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.