Exosomes: bridge metabolic regulation in cardiac repair

Abstract

Cardiac repair following cardiovascular diseases relies heavily on coordinated metabolism across different cells. Exosomes, or small extracellular vesicles secreted by cells, have emerged as pivotal regulators of the metabolic process. This review offers an introductory exploration of the intricate role played by exosomes in cardiac repair and regeneration. Specific metabolism regulation, including metabolism and immune response alterations, is emphasized and analyzed. Additionally, we explore some innovative engineering strategies for improving the therapeutic potential of exosomes in this field. This article aims to provide an integrated framework of comprehension toward exosomes and metabolism in cardiac repair and pave the way for novel therapy designs for cardiovascular diseases by outlining future directions for clinical translation.

Introduction

Cardiovascular disease (CVD) has long threatened public health due to its high morbidity and mortality, making it the leading cause of death worldwide^1–3. Statistics suggest that clinical CVD will affect more than 45 million adults by 2050⁴. Most cardiac disorders with devastating prognoses, such as Myocardial infarction (MI), share the similarities of massive loss of cardiomyocytes (CMs) and enormous alterations at cellular and molecular levels^5,6. These indicate the importance of a thorough comprehension of underlying metabolism mechanisms. As depicted in Fig. 1, current CVD management relies on a stepwise progression from pharmacological agents^7–9 to mechanical support devices as disease severity increases^10–12.

Fig. 1. Clinical management strategies for cardiovascular disease (CVD) based on heart failure severity and treatment progression.

For mild to moderate heart failure, medications are used to manage symptoms, prevent hospitalization, and target key complications, including myocardial infarction (MI), thrombosis, stroke, and atherosclerosis. In case of severe heart failure where medications fail to stabilize the condition, mechanical or surgical interventions are employed. ICD Implantable Cardioverter Defibrillators, used to correct life-threatening arrhythmias. LVAD Left Ventricular Assist Devices, supporting mechanical blood flow. CABG Coronary Artery Bypass Grafting, restoring blood flow by rerouting blocked coronary arteries.

To better address CVD problems, more and more attention has been placed on the regeneration of the myocardium^13,14. A huge dilemma for CVD regenerative therapies is that most adult CMs exit the cell cycle and lose regeneration capacity along with differentiation and maturation¹⁵. The CM proliferation rate in human hearts is around 1% at age 20 and descends with aging¹⁶. In response to their characteristic of low regeneration ability, emerging regenerative strategies, including stem cell and gene therapies¹⁷, tend to restore or improve the regeneration ability of CM, holding great therapeutic potential. Novel delivery systems, including Lipid nanoparticles (LNPs), adeno-associated viruses (AAVs), and exosomes (EXOs), are sought to fill the gap and ameliorate the diseased condition by improving the regeneration of functional heart tissue. EXO is a naturally secreted, membrane-bound lipid bilayer vesicle ranging from 40 to 180 nm¹⁸. Cells wrap particular molecules in EXO to achieve signal specificity and targeted delivery. Filopodia, bulk micropinocytosis, and receptor-mediated endocytosis take part in the EXO uptake in the recipient cells¹⁹. Currently, therapies implicating EXOs are proven to bypass the hurdle of immunogenicity and limited resources, expecting more potential for improved efficacy and safety profiles. They are widely involved in biological processes such as intercellular communication, protein trafficking, as well as tissue remodeling²⁰. Various types of cells secrete EXOs into the circulation and communicate with surrounding cells and the microenvironment²¹. Therefore, EXOs have been discovered as essential mediators of communicative metabolism that influence CVD progression and treatment²². In the context of CVD, major cell types that secrete EXOs in the heart are CMs, endothelial cells (ECs), cardiac fibroblasts (FBs), cardiac progenitor cells (CPCs), mesenchymal stem cells (MSCs), and platelets^23,24. For instance, EXOs generated from MSCs utilize miR-144 to target the PTEN/AKT pathway and reduce CM death in hypoxic environments²⁵. The functions and composites of EXOs largely reflected the reparative properties of their parental cells. EXOs extracted from heart failure patients have a reduced level of miRNA-21-5p and show impaired ability in CM proliferation and cardiac remodeling compared to normal ones²⁶. Circulating EXOs could detect the real-time microenvironment and potentially disclose the undiscovered pathophysiology noninvasively. Over the past decades, EXOs in cell metabolism have received much attention in physiological and pathological settings²⁷. Owing to the characteristic of selective packaging molecules and the ability to regulate specific signaling pathways through certain cargos, EXOs are considered novel therapeutic vehicles for bioactive substance delivery. Exosome-regulated cellular metabolism emerges as a pivotal axis linking energy balance, survival, and regenerative capacity.

Emerging evidence suggests that, beyond classical pharmacodynamic effects as outlined in Fig. 1, certain cardiovascular drugs can fix the heart by regulating exosomal secretion profiles. First-line drugs include ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, antiplatelets, anticoagulants, statins, and nitrates, targeting complications such as MI, thrombosis, stroke, and atherosclerosis. However, novel drugs focus more on modulating EXO mechanisms. Ticagrelor is an antiplatelet drug commonly administered following acute coronary syndrome. It has been shown to increase the release of protective EXOs from both cardiomyocytes and cardiac progenitor cells^28,29. These EXOs carry pro-survival miRNAs, potentially enhancing cell viability, reducing inflammation, and promoting neovascularization in the ischemic myocardium. Also, ticagrelor suppresses the secretion of procoagulant EXOs from activated platelets, suggesting a dual role in both thromboinflammatory regulation and myocardial tissue remodeling³⁰. Sacubitril/valsartan offers another example of pharmacologically driven exosomal modulation³¹. This treatment utilizes a neprilysin inhibitor combined with an angiotensin receptor blocker. The compound can effectively lower the circulating levels of exosomal miR-181a, which is implicated in promoting cardiac fibrosis and pathological hypertrophy. Reduced levels of miR-181a are linked to less myocardial fibrosis and better ventricular compliance. Spironolactone, a mineralocorticoid receptor antagonist, is used in heart failure management and influences the exosomal landscape³² as well. Studies indicated that it can reduce the release of detrimental pro-inflammatory EXOs in the cardiac microenvironment, contributing to a more reparative extracellular signaling milieu, mitigating post-infarction fibrosis, and enhancing tissue integrity. These findings expand the therapeutic profile of existing drugs, indicating that part of the therapeutic benefit may derive from EXO biology.

Metabolism in the heart

As cardiac function is intimately associated with the metabolic state, targeting metabolic pathways has emerged as a promising therapeutic strategy to mitigate ischemic injury and restore myocardial function in CVD. Metabolic interventions primarily aim to restrict the accumulation of detrimental metabolic byproducts, enhance mitochondrial bioenergetics, minimize oxidative stress, and optimize substrate utilization. Among various biological regulators, exosome-mediated metabolism plays a pivotal role in governing cardiac cell survival, proliferation, and migration, influencing the adaptive response to injury. Metabolic dysregulation can significantly delay cardiac functional recovery, whereas appropriate metabolic reprogramming facilitates enhanced tissue regeneration. Embryonic stem cell-derived EXOs enriched in miR-294 have been shown to improve endothelial cell proliferation and survival by modulating the cell cycle and endothelial metabolism³³. Furthermore, EXOs provide instructions for cell activities. It delivers regulatory microRNAs, such as miR-21 and miR-146a, to direct cell apoptosis (via AKT, PDCD4, FasL) and inflammation (via NF-κB, IRAK1, TRAF6)³⁴. Over the past decades, considerable attention has been directed toward therapeutic strategies that leverage exosome-mediated metabolic regulation to attenuate fibrosis and augment cardiac function. Dynamic modulation of key metabolic nodes by EXO cargo thus represents a highly promising avenue for targeted intervention in CVD.

ATP production pattern

Although the heart is the most energy-demanding organ in the body, it processes relatively limited intrinsic energy reserves³⁵. An adequate supply of appropriate metabolic substrates is essential to sustain ATP production and maintain the dynamic equilibrium of the cardiac metabolic network. Different responses and adaptations toward various stimuli characterize cardiac metabolic flexibility³⁶. Throughout development and in response to alterations in nutrient availability, the heart actively remodels its metabolic pathways to meet evolving energy demands (Fig. 2). This modeling reshapes CM metabolism and affects its proliferation capacity ultimately³⁷. Current evidence suggests that the highly proliferative neonatal heart predominantly relies on glucose and lactate for rapid ATP production³⁸. As cardiac maturation progresses, there is a metabolic transition toward primary utilization of fatty acids (FAs), which accounts for ~60% of ATP production, while glucose oxidation contributes around 30%, and the remainder derives from ketone bodies and amino acids³⁹. At this phase, oxidative phosphorylation becomes the dominant mode of energy production, replacing glycolysis observed in the fetal stage. More efficient fatty acid oxidation (FAO) is more efficient and enables the fully developed heart while maintaining metabolic flexibility concurrently. This metabolic shift reflects the heart’s adaptation to increasing energy demands and changing physiological conditions as it matures. Notably, the different regeneration capacities of the heart at different developmental stages correspond closely to the different underlying differences in metabolic programming.

Fig. 2. Exosome-regulated metabolic reprogramming of the heart during development, maturity, and disease.

In the neonatal heart, glycolysis predominated. Exosomal miRNAs such as miR-17, miR-21, and miR-210 promote glycolysis and glucose oxidation via GLUT1-mediated uptake, supporting early growth and regeneration. In the adult heart, FAO is dominant, with upregulated GLUT4 and CD36 expression on the membrane. EXOs containing miR-1, miR-126, and miR-133 maintain mitochondrial integrity and metabolic balance. In CVD-affected cases, hypoxia and inflammation trigger a suppression of FAO and elevation of glycolysis, contributing to mitochondrial dysfunction and reduced ATP production. Exosomal miRNAs such as miR-21, miR-155, and miR-294 exacerbate inflammatory and fibrotic pathways. CPC Cardiac Progenitor Cell, CM Cardiomyocyte, FAO Fatty Acids Oxidation, TCA Tricarboxylic Acid Cycle, α-KG Alpha-Ketoglutarate, ATP Adenosine Triphosphate, GLUT Glucose Transporter.

Under pathological conditions, cardiac metabolism undergoes substantial remodeling, and the situation is overturned. In chronic pathophysiological states, the heart actively reprograms the metabolic pathways, causing changes in myocardial energetics and contractile performance³⁶. In response to reduced oxygen availability and the increased burden of neovascularization, the body activates compensatory mechanisms, notably involving EXO secretion. Studies have demonstrated that the overexpression of hypoxia-inducible factor-1α (HIF-1α) in EXOs promotes cardioprotection in the ischemic myocardium, characterized by enhanced cell survival and angiogenesis⁴⁰. As the central regulator of cellular adaptation to hypoxia, HIF-1α is stabilized under oxygen-deprived conditions and induces the upregulation of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), promoting neovascularization⁴¹. The adaptive response drives cells to adopt more oxygen-efficient strategies during ischemia, shifting energy production away from FAO toward anaerobic glycolysis and favoring heart performance under ischemia and hypertrophy stress. This transition is orchestrated by multiple pathways, including the action of MSC-derived EXO carrying miR-21 and miR-210, which upregulate the expression of glucose transporter 1 (GLUT1) and pyruvate dehydrogenase 1 (PDK1), to increase the glycolysis flux and suppress pyruvate dehydrogenase activity^42,43. Concurrently, the HIF-1α-VEGF signaling pathway, modulated by miR-210, miR-21, and miR-126⁴⁴, further promotes angiogenesis under ischemic conditions. Collectively, they support the metabolic switch and cell survival in hypoxic myocardium.

EXOs contribute to cardiac regeneration by modulating key metabolic pathways, including FAO, glycolysis, ketone body metabolism, and the mammalian target of rapamycin (mTOR) signaling pathway⁴⁵. EXO cargoes have been shown to target critical regulators such as CPT1, ACSL1, LPL, PPARα/γ/δ (FAO)^46–49; GLUT1/GLUT4, AMPK, PFK2, PFK1, MPC1 (glucose metabolism)^50–55; BDH1, SCOT (ketone metabolism)^56–58, bridging metabolic reprogramming with cardiac repair³⁵. For example, platelet-derived EXOs downregulate ACSL1 expression to reduce acyl-CoA production, impairing FAO, and prioritizing glucose and pyruvate oxidation^39,59. It is associated with downstream mTORC1 activation and leads to cardiac hypertrophy. Another remarkable regulation involves MSC-derived EXOs carrying miR-100, which suppress CD36 expression, a gene critical for oxidative phosphorylation⁶⁰. Downregulation of CD36 increases glycolytic enzymes and lactate secretion, reinforcing the metabolic shift from FAO to glycolysis in the myocardium. Along with the validation of down-regulated CD36 myocardial infarct regions, the exosome-mediated cardioprotective functions of miR-100 have been proven in the regeneration models⁶⁰. Similarly, miR-21-5p, enriched in EXOs under pathological conditions, has been found to activate the PI3K/Akt pathway by silencing PTEN, promoting CM survival and viability²⁶.

Beyond metabolic substrate switching, EXOs mediate the energy supply more directly by regulating mitochondrial function. Mitochondrial damage has recently become a pathophysiological hallmark of cardiac dysfunction, with a lack of available drugs^61,62. The disturbance of mitochondrial hemostasis can lead to redox imbalance, especially after ischemia or reperfusion injury. Multiple cargos in EXOs can promote mitochondrial biogenesis, increasing their number as well as boosting their functions in CMs. Apart from mitochondrial DNA (mtDNA), several miRNAs can regulate mitochondrial functions. Exosomal miRNAs such as miR-9, miR-29b, miR-320, miR-455, miR-495, miR-599, and miR-122 all impact and regulate mitochondrial functions^63–70. Specifically speaking, miR-9 targets Drp1 in the fission and fusion of mitochondria⁶³, while miR-29b inhibits pro-fibrotic signaling and supports mitochondrial integrity through enhancing PGC-1α protein^46,65. miR-320 and miR-455 influence the oxidative and redox balance through controlling SOD expression, which protects against mitochondrial ROS^66,67. The enhanced mitochondrial capacity meets the higher energy requirement for CM repair, survival, and growth. Extraordinarily, EXOs containing dysregulated mitochondria and their enzymes may be concerned with intercellular communication and affect other mitochondria⁶².

Lipid homeostasis

Due to the shift between FAO and glucose metabolism, an essential aspect being directly influenced is lipid homeostasis. It refers to the balance of lipid synthesis, degradation, and transport within the system. Interacting with energy production and redox signaling, lipid homeostasis is precarious in the heart but crucial for maintaining normal or enhanced cellular function and retaining metabolic health⁷¹. The substrate for both FAO and TCA is synthesized from non-lipid precursors, which is the de novo lipid genesis. This is the source of the whole lipid circulation, replenishing cellular membranes and energy storage. After being manufactured, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) transport lipids through the blood circulation. In this process of delivering lipids to tissue, proteins in the cardiac muscle play a crucial role in regulating the uptake of FA, as well as determining whether it goes to energy production or membrane synthesis. Downstream lipid catabolism represents their breakdown through oxidation or other pathways, which prevails after cardiac injury on account of the increased energy demand. The dysfunctional metabolism system is highly bound to the collapse of lipid homeostasis.

During the dynamic course, phospholipids, cholesterol, and FA are carried by EXOs and transferred between cells. This firsthand transportation refills lipid pools in impaired cardiac cells, guaranteeing the proper regulation of integral homeostasis. Since the nature of EXOs is lipid vesicles, their component is based on the cellular origin and the pathological conditions, which also affect the lipid composition of target cells. In obese conditions, adipose tissue loads the EXOs with more lipids and pro-inflammatory miRNAs, suppressing FAO, increasing cytotoxicity, and promoting fibrosis. This indicates that adipocyte-derived EXOs not only affect the cargo inside but also influence the membrane integrity of recipient cardiac cells. It is noticeable that excess lipids from damaged cells could contribute to lipotoxicity, which is detrimental to cells. The accumulation of free FA forms diacylglycerols (DAGs)^71,72, activating protein kinase C (PKC) pathways, and significantly impacting cellular function and viability. The following add-on of insufficient energy supply forms a negative feedback in metabolism, intensifying the toxic effects. Despite the regulation of FAO, EXOs also deliver factors that modulate lipid synthesis and storage, possibly by changing the expression of the activity of lipogenic enzymes. Excess adiposity results in excessive fatty acids, glycerol, and proinflammatory and profibrotic cytokines in the circulating systems, exacerbating the imbalance of metabolism and affecting the heart⁷³. To be more specific, perivascular adipose tissue (PVAT) produces miR-382-5p-enriched EXOs to reduce the formation of macrophage foam cells, regulating vascular homeostasis⁷⁴. Conversely, EXOs facilitate cholesterol transport to the liver by removing unnecessary cholesterol from damaged cardiac tissues, aiding heart regeneration. Healthier cardiac lipid profiles in CMs are critical for the restoration and maintenance of cardiac function post-injury. Some special lipids act as signaling molecules and influence inflammation, which directly interferes with the repair process of cardiac tissue. Anti-inflammatory lipid mediators carried by EXOs can regulate inflammation of the tissue and thereby promote cardiac healing⁷⁵. Eventually, the disruption of lipid homeostasis leads to an elevated risk of developing cardiometabolic disorders.

However, diet may help protect the heart by influencing the composition and tropism of EXOs in the blood. Long-term intake of sulforaphane, a bioactive compound from cruciferous vegetables, has been shown to enhance the release of FB-derived EXOs that inhibit adverse remodeling⁷⁶. Counterintuitively, some studies showed that omega-3 PUFA do not reduces thrombotic risk through small vesicles in elder patients who have suffered from MI⁷⁷. However, adherence to a Mediterranean diet reduces the levels of prothrombotic EVs, possibly contributing to improved vascular homeostasis⁷⁸. These findings underscore the regulatory role of nutrition in EXO-mediated signaling, bridging dietary habits and myocardial resilience.

Redox balance

The redox balance refers to the equilibrium between oxidants and antioxidants in the cardiac salvage. A balanced redox state provides favorable conditions for cell survival, especially in stress conditions. Comparing the proliferative human induced pluripotent stem cell-derived CMs (hPSC-CMs) and mature CMs in normal adults, their cellular structure, mitochondrial function, and metabolism have displayed strong differences³⁸. In pathological cardiac settings, thrombus removal leaves excessive reactive oxygen species (ROS), including hydrogen peroxide (H2O2), superoxide anion (O²⁻), and hydroxyl radicals, which exacerbate ischemia-reperfusion (I/R) injury²¹. Breaking the redox balance burdens oxidative stress (OS), promotes apoptosis, and disrupts endothelial functions. Mitochondria are both major sources and targets of ROS, and mitochondrial dysfunction can impair the metabolic system at the molecular level. EXOs secreted by stressed cells carry regulatory molecules that modulate signal transduction, enhance cellular defense, and increase endurance to OS⁷⁹. CPC-EXOs have been shown to improve cardiac function after MI and reduce OS²⁴. Activated CD4+ T cell-derived EXOs upregulate the expression of both pro-oxidative (NOX2, NOX4) and antioxidant (SOD1, SOD2) genes in endothelial cells, highlighting the role of EXOs in balancing endogenous redox^80,81. Given the fact that exogenous antioxidants are ineffective against OS²¹, the exosomal delivery strategy offers promising alternatives. Specific miRNAs, such as miR-21, miR-100, miR-29a, and miR-210^82–85, prominently reduce ROS and stabilize local homeostasis. Moreover, emerging evidence highlights the role of Ca²⁺ as a key regulator for cardiac redox balance, involved in tricarboxylic acid cycle (TCA) cycle activation and ROS detoxification. Nevertheless, excessive Ca²⁺ can trigger mitochondrial permeability transition and complicate therapeutic applications. Exosomal therapies potentially offer a means to deliver Ca²⁺ transporter-regulating molecules, such as miR-25 targeting the mitochondrial calcium uniporter (MCU)⁸⁶. Altogether, EXOs modulate antioxidant delivery, preserve redox homeostasis, and promote cardiomyocyte survival and cardiac repair.

Immune response, fibrosis, and angiogenesis

To maintain cardiac function following injury, the body engages intricate acute and chronic adaptations (Fig. 3), especially immune and inflammatory responses^87,88. In the diseased cardiac microenvironment, inflammation is essential for clearing dead cells and initiating repair, though the capacity of immune cells is constrained by ischemia and nutrient deprivation⁸⁹. Anti-inflammation, anti-fibrosis, and pro-angiogenesis are interdependent processes orchestrated in cardiac repair. Among various immune cells, cardiac macrophages (cMPs) play a pivotal role, with their metabolism tightly linked to inflammatory outcomes^89,90. Cardiac macrophages are increasingly recognized as modulators of myocardial homeostasis and metabolism, with macrophage phenotype switching closely associated with CVD types and severity, including coronary artery disease, myocarditis, heart failure, and atherosclerosis⁸⁸. Early post-injury, macrophages predominantly adopt a detrimental M1 phenotype⁹¹. However, EXOs secreted by MSCs, cardiac progenitor cells (CPCs), and Tregs can reprogram macrophages toward a reparative M2 phenotype via delivery of anti-inflammatory miRNAs⁹². For instance, EXOs carrying miR-125a-5p modulate macrophage function by targeting Klf13, Tgfbr1, and Daam1, skewing the M0 differentiation balance towards the anti-inflammatory M2 phenotype⁹³. Similarly, endothelial cell-derived EXOs transfer miR-10a to suppress NF-κB signaling, while miR-126 and miR-294 carried by EXOs enhance stem cell homing, endothelial repair, and myocardial regeneration, respectively²³. Moreover, exosome uptake by MHC-II⁺ antigen-presenting cells in cardiac-draining lymph nodes activates PP2A/p-Akt/Foxo3 axis, establishing a Treg-inducing niche that promotes inflammation resolution and cardiac repair⁹². Together, these findings underscore the strong potential of immune-modulating EXOs and miRNAs for cardiac regeneration.

Fig. 3. Exosome-mediated metabolic reprogramming of macrophage polarization during cardiac injury and repair.

M0 macrophages differentiate into pro-inflammatory M1 and anti-inflammatory M2 phenotypes with the interference of EXOs. EXOs from injured cardiomyocytes and FBs carrying miR-155, miR-33, HIF-1α, IL-1β, and TNF-α, leading to activation of NF-κB signaling. M1 macrophages release IFN-γ, TNF-α, and IL-6, promoting ROS generation, tissue damage, and fibrosis. EXOs from CPCs, MSCs, and Tregs carrying miR-146a, miR-21, miR-125b, miR-223, and the let-7 family. M2 polarization is regulated through STAT3/STAT6, with IL-10, IL-4, IL-13, and TGF-β promoting angiogenesis, FB remodeling, and cardiac repair. Together, they mediate the fibrosis and repair of the heart through metabolic pathways. MSC Mesenchymal Stem Cell, OXPHOS Oxidative Phosphorylation.

During early cardiac injury, cardiac FBs differentiate into myofibroblasts (myoFbs), contributing to scar formation through extracellular matrix (ECM) synthesis, which initially supports structural stability³⁷ but later results in maladaptive fibrosis and impaired cardiac function^94,95. Immune responses regulate this biphasic fibrotic remodeling. miR-21, notably downregulated in diseased tissues, drives FB activation, and exosomal delivery of miR-21 represents a promising strategy for controlled fibrosis mediation. In addition to its intracellular regulatory roles, circulating exosomal miR-21-5p may serve as a predictive biomarker for functional recovery following structural cardiac interventions⁹⁶. Elevated miR-21-5p levels have been associated with successful reverse remodeling after mitral valve repair. This suggests that miR-21-5p may influence intrinsic myocardial plasticity and regenerative readiness, offering non-invasive insight into patient-specific repair potential. Conversely, miR-146a-5p and miR-29a, delivered via EXOs, have been shown to attenuate fibrosis by reducing ECM deposition and collagen gene expression^97,98. Thus, fibrosis is intricately regulated by metabolic and immunologic exosome-mediated signaling.

Angiogenesis is equally critical for cardiac repair, ensuring oxygen supply, nutrient delivery, and waste clearance in ischemic myocardium. Endothelial cells orchestrate neovascularization but are highly susceptible to dysfunction, often exacerbated by inflammation. CM-derived EXOs carrying HSP60 activate TLR4 signaling in endothelial cells and promote monocyte activation through IL-6, CCL2, and CCL7 contained within EXOs²³. In parallel, exosomal miRNAs, including miR-24, miR-126, miR-200b, and miR-210, regulate endothelial function and angiogenesis. Transplanted stem cells also secrete proangiogenic miRNAs via EXOs. Moreover, EXOs derived from macrophage migration inhibitory factor (MIF)-overexpressing umbilical cord MSCs (ucMSCs) exhibit superior cardioprotection, mediated by miR-133a-3p regulation of the AKT signaling pathway, leading to reduced CM apoptosis, increased VDGF levels, and stimulated endothelial cell proliferation and migration⁹⁹. Importantly, angiogenesis mitigates hypoxia-induced inflammation, generating positive feedback for immune response and halting fibrosis. EXOs thus act as central coordinators, integrating immune resolution, structural remodeling, and vascular regeneration into a unified reparative response. Understanding the immune-exosomal axis in cardiac repair provides critical insight into endogenous healing mechanisms and offers promising avenues for the development of next-generation regenerative therapies.

Engineered exosomes

Various exosome modifications

Engineered EXOs are increasingly recognized as potent therapeutic delivery vehicles, driven by diverse modification strategies aimed at enhancing targeting specificity, cargo capacity, and therapeutic efficacy. Surface modifications, including the conjugation of ligands, antibodies, and peptides, can direct EXOs toward cardiac tissues or ischemic sites¹⁰⁰. Recent studies have employed click chemistry, which refers to a set of chemical reactions that are efficient, simple, and selective for joining molecular binding blocks. For example, Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) can functionalize exosome surfaces, improving membrane stability and targeting precision¹⁰¹. Hybrid strategies, combining EXOs with hydrogels, liposomes, or plant-derived vesicles, further expand structural versatility and biological compatibility. In parallel, genetic and chemical engineering approaches enable efficient loading of nucleic acids, proteins, and therapeutic agents. Bacterial outer membrane vesicles (ONVs) also demonstrate potential by modulating inflammatory pathways relevant to CVD¹⁰², offering novel mechanistic insights for therapeutic intervention.

Efficient cargo loading remains a critical determinant of therapeutic success. Widely utilized techniques include electroporation, drug incubation, surfactants, low-frequency ultrasound, and genetic modification of donor cells^103,104. Emerging genetic and chemical engineering approaches offer improved cargo encapsulation while preserving EXO integrity. Refinements of existing methods, such as optimizing electroporation and sonication parameters, are equally vital.

A major challenge limiting EXO therapeutic efficacy is off-target effects. Targeted delivery mechanisms can guarantee that cargo is delivered specifically to the cardiac tissue, optimizing the therapeutic outcomes while minimizing off-target adverse effects. Bioengineered modifications, especially surface functionalization with homing ligands (e.g., anti-CD71 antibodies), improve targeting precision and enhance accumulation within infarcted myocardium even following intravenous (IV) administration^105,106. Genetic engineering of donor cells, such as CPCs, facilitates targeted delivery by expressing specific homing biomarkers. Beyond systemic injections, local delivery strategies, such as intramyocardial (IM) and intrapericardial (iPC) injection^92,107, achieve high local retention and sustained release. Synthetic biomaterials and well-established cellular therapy further improve the EXO therapy. The patch-like hydrogel structure, which enables self-attach and sustained release, is delivered through the iPC method, clinching the therapeutics to the targeted site¹⁰⁸. It keeps the advantages of low immunogenicity, high payload capacity, and targeting capabilities. Moreover, innovative strategies offer a controllable release of EXOs. Inhalable stem cell-derived exosome nebulization therapy (SCENT) offers a groundbreaking, non-invasive delivery route, allowing EXOs to traverse the alveolar-capillary barrier and reach ischemic cardiac tissues through pulmonary circulation, establishing EXOs as agents of endocrine-like signaling⁶⁰. Considering the dynamic nature of the cardiac microenvironment, developing metabolism-responsive EXOs offers promising advances. In ischemic myocardium, hallmarks such as acidosis, hypoxia, elevated ROS, and matrix metalloproteinase (MMP) activation present unique metabolic cues¹⁰⁹. Engineering strategies that embed pH-sensitive linkers, ROS-responsive transcriptional elements, or enzyme-degradable coatings into EXOs enable site-specific cargo release upon encountering pathological environments¹¹⁰. These intelligent EXOs can change their structure according to specific cues in the diseased heart, achieve target delivery, and minimize off-target risks.

Personalized exosome therapies harness autologous or patient-derived cells to tailor therapeutic strategies according to individual metabolic profiles. Embedding iPSC-derived CPCs or MSC-derived EXOs within hydrogels facilitates robust cardiac regeneration while leveraging endogenous compatibility¹⁰⁸. Patient-specific EXOs minimize immune rejection, permit precise cargo customization, and align therapy with individual physiological conditions. Synergistic strategies combining personalized EXOs with stem cell or gene therapies hold significant promise for optimizing comprehensive cardiac repair outcomes.

Non-coding RNAs in circulating exosomes and cardiac remodeling

EXOs are enriched not only with miRNAs but with other types of non-coding RNAs, including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), both of which contribute as key regulators in CVDs. CircRNAs, characterized by their covalently closed-loop structures, are highly stable in circulation and exhibit diverse regulatory functions. In patients with dilated cardiomyopathy (DCM) and chronic heart failure, distinct circRNA signatures have been identified in plasma EXOs, reflecting disease progression and myocardial remodeling¹¹¹. Functionally, circRNAs may act as miRNA sponges, transcriptional modulators, or even templates for peptide translation, thereby influencing cellular phenotypes through non-canonical regulatory networks.

Concurrently, pathological cardiac remodeling has also been linked to exosomal lncRNAs. Specific circulating lncRNAs such as ENST00000556899.1 and ENST00000575985.1 are elevated in MI patients¹¹². LIPCAR, a long intergenic non-coding RNA that has been related to adverse left ventricular remodeling following infarction, is proposed as a prognostic biomarker¹¹³. Though its level in EXOs is not significantly different between heart-failing and non-failing patients, it did exhibit higher expression in MI patients who develop left ventricular remodeling. These findings underscore the potential of exosomal non-coding RNAs as both mechanistic contributors and diagnostic indicators in heart failure and post-ischemic repair.

Standardization of EXO isolation and characterization

Robust isolation and characterization protocols are fundamental for the clinical translation of exosome therapies. The isolation procedures usually involve sample collection, initial centrifugation, and ultracentrifugation¹¹⁴. Ultracentrifugation remains the standard isolation method, but often yields low purity (10–25%)¹¹⁵. With strict FDA regulations, further improvements of efficiency, yield, concentration, and purity are required¹¹⁶. Innovative affinity-based techniques, such as ligand-capture systems, and size-based methods like tangential flow filtration (TFF), offer improved specificity and scalability¹¹⁷. Automating isolation and purification processes is critical to achieving high-throughput, reproducible EXO production. Characterization approaches, such as nanoparticle tracking analysis (NTA), western blotting, RNA profiling, and mass spectrometry, confirm EXO identity and quality¹¹⁸. Integration of multi-omics strategies, such as proteomics, genomics, and metabolomics, further advances functional characterization¹¹⁹. Given the heterogeneity in exosome sources, recipient cells, disease models, and purification methods¹²⁰, establishing standardized protocols and stringent quality controls is paramount to ensure clinical reproducibility.

Conclusion

In cardiac repair, exosomes (EXOs) offer a flexible framework for optimizing and shifting the metabolic process, influencing a wide array of biological metabolic processes in myocardial healing. Owing to their characteristics of recipient cell targeting and high biocompatibility, EXOs represent highly promising candidates for selectively delivering bioactive cargo such as miRNAs, proteins, and other therapeutic agents. EXOs modulate energy production, maintain redox balance, preserve lipid homeostasis, and control immune responses. For the metabolic cascade in cardiac regeneration and repair, EXO serves as a mediator and affiliates with different aspects. During energy supply, it enhances glycolysis and suppresses fatty acid oxidation through modulating mitochondria, benefiting lipid homeostasis and redox balance. The anti-inflammatory polarization of immune cells also contributed to a more balanced redox state and was related to other metabolic sections. The whole sophisticated mediating circle reveals the dynamic metabolism loop system in the body. Multiple unique merits, including low immunogenicity and high biocompatibility, position EXOs as promising therapeutic tools in regenerative medicine. As research continues to evolve in this field, innovative exosome-based therapy holds great promise for mediating metabolism in cardiac repair, ultimately leading to improved patient outcomes and a new era in the treatment of CVDs.

Future outlook

The therapeutic potential of naturally secreted and engineered exosomes (EXOs) sparks growing interest in metabolic regulation of cardiac diseases (CVDs) and offers promising direction for cardiac regeneration. In the short term, efforts should focus on improving standardized protocols for EXO isolation and developing stimulus-responsive EXOs that release their cargo in response to conditions like hypoxia or oxidative stress. In the long term, personalized EXO therapies could be created using patient-specific or stem-cell-derived sources. The key area is improving targeted delivery through bioengineering and biomaterials integration. Together, these approaches could help repair damaged heart tissue, improve energy balance, and support better recovery in heart failure patients. Encouraging collaboration across disciplines around EXO-based therapies will be essential to bring them into clinical use.

Author contributions

The idea of the paper came from K.C. and L.M. L.M. was a major contributor in writing the manuscript and preparing the figures, K.C., Z.Y., C.L., and D.Z. edited the manuscript. All authors reviewed the final manuscript.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare no competing interests.