KEY FIGURE

Highlights

• EVs are key modulators in various physiological and pathological processes.

• EV-mediated interorgan crosstalk contributes to cardiometabolic disease progression.

• EV-based biomarkers offer non-invasive tools for early disease prediction.

• Therapeutic EVs enable targeted delivery of cargos for disease treatment.

INTRODUCTION

Extracellular vesicles (EVs) are non-self-replicating, lipid bilayer-enclosed particles that contain bioactive substances [1]. EVs have gained increasing attention in biomedical research due to their pivotal roles in interorgan and intercellular crosstalk, which are important components of metabolic homeostasis and the development of various diseases [2-5]. Initially identified as platelet-derived microparticles and reticulocyte-released vesicles [6,7], EVs are now recognized as a diverse group of membranous vesicles released into the extracellular space by virtually all cell types. They carry cargo of bioactive molecules, including proteins, lipids, and nucleic acids, capable of modulating recipient cell function and phenotype. Over the past few years, the study of EVs has expanded rapidly, highlighting their role in diverse physiological and pathological processes. In addition to traditional mediators such as hormones and metabolites, EVs have emerged as key mediators in a wide range of biological processes, including immune regulation, tissue repair, angiogenesis, and metabolic control. Dysregulation of EV biogenesis, release, or cargo content has been implicated in numerous diseases, notably cancer, neurodegenerative disorders, and cardiometabolic diseases [5]. In the context of metabolic disorders, EVs derived from metabolically stressed tissues such as adipose tissue, liver, skeletal muscle, and pancreas have been shown to carry inflammatory signals, lipotoxic mediators, and regulatory RNAs that propagate systemic insulin resistance, endothelial dysfunction, and organ fibrosis [4]. Therefore, we provide a comprehensive overview of the current understanding of the role of EVs in cardiometabolic diseases. Understanding the EV-mediated network in the pathophysiological context of cardiometabolic diseases holds immense potential for identifying novel biomarkers and therapeutic targets.

NOMENCLATURE, SUBTYPES, AND BIOLOGICAL FEATURES OF EVs

The nomenclature surrounding EVs has evolved over time, reflecting advances in our understanding of their biogenesis and function. Traditionally, EVs were widely categorized into three subtypes based on their size, biogenesis, and molecular composition: exosomes, microvesicles (also known as microparticles or ectosomes), and apoptotic bodies [8]. The smallest subtype, exosomes, are derived from the endosomal pathway and have a diameter ranging from 30 to 150 nanometers. Exosome formation begins with the inward budding of the endosomal membrane, leading to the formation of multivesicular bodies containing intraluminal vesicles. These multivesicular bodies can either fuse with lysosomes for degradation or travel to the cell surface, where they integrate to the plasma membrane and release exosomes into the extracellular milieu under the regulation of several Rab-GTPases [9]. Microvesicles, with diameters ranging from 100 to 1,000 nanometers, originate through direct outward budding and shedding from the plasma membrane. Apoptotic bodies, the largest subtype, are formed during programmed cell death and typically range from 500 to 2,000 nanometers in size (Fig. 1). The molecular composition of EVs is not random but reflects selective sorting mechanisms. Several pathways have been implicated in cargo loading, including the endosomal sorting complex required for transport (ESCRT)-dependent machinery, tetraspanins, and lipid raft-associated mechanisms [10]. Recent insights have revealed that certain microRNAs (miRs) contain specific sequence motifs that direct their preferential secretion into EVs or retention within the parent cell. RNA-binding proteins such as Alyref and Fus recognize these motifs and mediate the selective packaging of miRs into EVs, influencing intercellular gene regulation at distant sites. Because different cell types use specific sorting sequences, this miR code provides information on the tissues of origin of circulating small EVs [11]. Upon release, EVs interact with recipient cells through diverse mechanisms, including receptor-ligand interactions, membrane fusion, and different forms of endocytosis such as clathrin-mediated endocytosis, macropinocytosis, or phagocytosis (Fig. 1). Surface molecules on EVs, such as integrins, tetraspanins, and lectins, play crucial roles in determining target cell specificity and uptake efficiency. Following internalization, EV cargo can modulate cellular signaling pathways, gene expression, and metabolic functions of recipient cells, thereby contributing to homeostasis or disease progression.

EVs carry a diverse range of cytosolic proteins originating from their parent cells. They are notably enriched with proteins such as integrins, major histocompatibility complex molecules and components of the cytoskeleton [5]. In addition, EVs display certain proteins that are relatively specific to vesicles, including tetraspanins like tumor susceptibility gene 101 (TSG101) and CD63, which are typically associated with exosomes and used as representative markers. Technological advances have significantly enhanced the ability to isolate, characterize, and analyze EVs. Techniques such as differential ultracentrifugation, size-exclusion chromatography, immunoaffinity capture, and nanoparticle tracking analysis, combined with omics approaches have allowed a more detailed understating of EV heterogeneity and function [12]. However, the ‘minimal information for studies of extracellular vesicles’ produced by the International Society for Extracellular Vesicles recommends using the generic term EV and discourages using exosomes or ectosomes unless subcellular origin can be demonstrated [1]. Exosomes and ectosomes are biogenesis-related terms indicating origin from the endosomal system and plasma membrane, respectively, which are difficult to characterize with most EV separation techniques. Furthermore, universal molecular markers of exosomes, ectosomes, or other EV subtypes are unknown. Although most earlier research studied a broad population of EVs, the terms EV and exosome are both used without exact distinction. In this article, we followed the terminology of the reference paper to avoid any confusion.

THE ROLE OF EVs IN THE PATHOGENESIS OF OBESITY AND INSULIN RESISTANCE

Insulin resistance is the pivotal pathogenic component of metabolic syndrome and related diseases, although its underlying mechanisms are not fully understood [13]. Excess adiposity and the accompanying disruption in insulin signaling, inflammation, and endoplasmic reticulum (ER) stress are suggested to be the main drivers of insulin resistance. Recent research has demonstrated that EVs may contribute to these processes (Table 1).

EVs in adipose tissue: mediators of metabolic communication and insulin sensitivity

Adipose tissue depots are composed of heterogeneous cells that mediate key functions of metabolism, including energy storage and release, adipokine secretion, non-shivering thermogenesis, and immune responses [27,28]. Beyond mature adipocytes and their progenitors, various immune and endothelial cells orchestrate the function of adipose tissue as an endocrine organ. Adipocyte-secreted exosomes transport miR-34a into macrophages and suppress M2 polarization by repressing Krüppel-like factor 4 (KLF4) expression in a paracrine manner. Adipose-specific miR-34a knockout mice were protected from obesity-induced metabolic impairment [14]. Adipose tissue macrophages (ATMs) also secrete and transfer exosomes to insulin sensitive cells. Ying et al. [15] showed that the treatment of lean mice with obese ATM exosomes caused glucose intolerance and insulin resistance, whereas treatment of obese mice with lean ATM exosomes restored glucose tolerance and insulin sensitivity. miR-155 was overexpressed in obese ATM exosomes and impaired cellular insulin action by targeting peroxisome proliferator-activated receptor gamma (PPARγ) [15]. Similarly, when the exosome-like vesicles from obese adipose tissue were injected intravenously (IV), peripheral blood monocytes differentiated into activated macrophages by taking up these vesicles and secreted inflammatory cytokines. This caused insulin resistance in wild-type mice, although the effect was significantly reduced in toll-like receptor 4 (TLR4) knockout mice [29]. Alternatively activated, anti-inflammatory M2 macrophages are important in maintaining metabolic homeostasis opposed to inflammatory M1 macrophages. M2 polarized bone marrow-derived macrophages produced exosomes enriched with miR-690, which improved glucose tolerance and insulin sensitivity. Nadk, a gene encoding NAD+ kinase, was a target mRNA of miR-690 and regulated cellular insulin activity [16]. Small EVs derived from ATMs of rosiglitazone-treated mice improved glucose intolerance and insulin sensitivity in obese mice, with miR-690 identified as a key mediator of these beneficial effects. Notably, common adverse effects associated with thiazolidinedione therapy, such as weight gain and hemodilution, were not observed following EV treatment, in contrast to rosiglitazone administration via diet [30]. In individuals with prediabetes or early type 2 diabetes mellitus (T2DM), insulin secretion is increased to cope with insulin resistance. Adipocyte-derived EVs from diet-induced obese mice conveying insulinotropic protein cargo enhanced first phase glucose-stimulated insulin secretion, which was not observed by EVs from lean mice. Therefore, the status of insulin resistance in adipose tissue is communicated to pancreatic beta-cells by EVs to meet the increased insulin demand [17]. Similarly, hepatocytes produce different exosomes depending on the duration of obesity to control insulin sensitivity. In early obesity, miR-3075 is enriched in exosomes and increases insulin sensitivity by down-regulating fatty-acid 2-hydroxylase in adipocytes, myocytes, and hepatocytes. However, this compensatory action is lost in chronic obesity and insulin resistance is aggravated by proinflammatory macrophage activation [18]. Liver-derived EV secretion is also increased in response to hyperglycemia, enhancing glucose effectiveness in skeletal muscle and insulin secretion from pancreas through endocrine signaling [31].

Among various adipokines, oligomeric forms of adiponectin were enriched in adipose tissue-derived small EVs and were mainly distributed at the external surface of EVs. The transfer of these EVs to high-fat diet (HFD)-fed mice prevented obesity, insulin resistance, and tissue inflammation [19]. Additionally, adiponectin is known to regulate exosome biogenesis and secretion through binding with T-cadherin [32]. In adipose tissue, EVs carrying proteins and lipids are transferred between cell types to influence cellular signaling pathways, a process regulated by fasting, refeeding, and obesity. This indicates that EVs play a role in the tissue response to shifts in systemic nutrient status [33].

EVs from thermogenic adipocytes: roles in energy homeostasis

Brown and beige adipocytes are thermogenic fat cells involved in the regulation of systemic energy metabolism and glucose homeostasis [34]. Biomodulation of these thermogenic fat cells can be a promising approach to improve energy homeostasis, and various inducers have been identified. Brown adipocytes release exosomes and this is increased by brown adipose tissue (BAT) activation. Serum concentrations of exosomal miR-92a were inversely correlated with human BAT activity in cohorts of healthy individuals [35]. EVs isolated from human adipose-derived stem cells during beige-adipogenic differentiation attenuated diet-induced obesity, hepatic steatosis, and glucose intolerance through adipose tissue browning. miR-193b, miR-328, and miR-378a enriched in EVs were responsible for the observed effect and suggest a role of EVs in cellular reprogramming [20]. In another study, exosomes secreted from adipose-derived stem cells were transferred into macrophages to induce M2 polarization, inflammation alleviation, and white adipose tissue browning in diet-induced obese mice. Arginase-1 was activated by exosome-carried phosphorylated signal transducer and activator of transcription 3 (STAT3) resulting in the alternative activation of macrophages [21]. Interestingly, cellular components can be loaded in EVs. Oxidatively damaged components of mitochondria were ejected via EVs from thermogenically stressed brown adipocytes. Clearance of extracellular mitochondria by BAT-resident macrophages was instrumental in maintaining the thermogenic program [36]. Similarly, small EVs from stressed adipocytes carried respiration-competent, but oxidatively damaged mitochondria to cardiomyocytes, triggering a burst of reactive oxygen species (ROS). This pro-oxidant signal stimulates compensatory antioxidant signaling and protects cardiomyocytes from ischemia/reperfusion injury showing an example of interorgan mitohormesis [37].

EV-mediated brain-adipose tissue crosstalk: implications of cognition and obesity

The brain is an insulin-responsive organ, and brain insulin resistance is linked to memory impairment and cognitive dysfunction [38]. EVs and their cargo miRNAs have been shown to regulate adipose tissue-brain interorgan communication, resulting in cognitive impairment related to insulin resistance. miR-9-3p in adipose tissue-derived EVs from HFD-fed mice suppressed brain-derived neurotrophic factor and induced remarkable synaptic damage, especially in the hippocampus [39]. The loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons within the ventromedial nucleus of the hypothalamus leads to resistance to obesity. Central delivery or IV injection of small EVs carrying a plasmid encoding a dominant-negative mutant of AMPKα1, targeted to SF1 neurons, resulted in sympathetic nerve activation and uncoupling protein 1 (UCP1)-dependent thermogenesis in BAT [40,41]. These findings highlight the potential of small EV-based technologies to selectively modulate brain-adipose tissue crosstalk as a therapeutic approach against obesity.

EVs in skeletal muscle and intestine: regulators of insulin sensitivity

Skeletal muscle cells also secrete EVs and their contents are altered in various conditions such as aging, neuromuscular disorders, HFD, diabetes, and acute or chronic exercise [42,43]. When exosome-like vesicles from quadriceps muscle of palmitate-enriched diet-fed mice were isolated and injected in vivo, the size of the islet was increased suggesting that EVs may mediate beta-cell adaptation during insulin resistance [44]. Adipocyte-derived serum exosomal miR-27a was suggested as a biomarker of obesity and insulin resistance. Overexpression of miR-27a in C2C12 skeletal muscle cells induced insulin resistance via repression of PPARγ and downstream genes [22]. Similarly, circulating exosomal miR-20b-5p, which was highly abundant in individuals with T2DM compared to those with normal glucose tolerance, modulated insulin-stimulated glucose metabolism via protein kinase B (AKT) signaling in primary human skeletal muscle cells [23]. Intestinal epithelial cells were also shown to participate in the regulation of systemic metabolism. The composition of lipids in exosomes isolated from feces was changed from phosphatidylethanolamine to phosphatidylcholine by HFD. These intestinal exosomes were taken up by insulin sensitive tissues and induced insulin resistance via aryl hydrocarbon receptor (AhR)-activation and inhibition of the insulin signaling pathway including insulin receptor substrate 2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt [24]. Therefore, EV-mediated intercellular or interorgan crosstalk is a fundamental component of insulin sensitivity and energy metabolism.

EVs IN DIABETES MELLITUS: BIOMARKERS, PATHOGENIC MEDIATORS, AND THERAPEUTIC OPPORTUNITIES

Chronic disturbances in glucose homeostasis and metabolic perturbations caused by diabetes mellitus (DM) lead to multiple organ dysfunction and premature mortality [45]. Emerging evidence suggests that EVs may play a key role in the development and progression of DM (Table 2) [46,47].

EVs in type 1 diabetes mellitus: early indicators and mediators of autoimmunity

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by the destruction of pancreatic β-cells by T-cells. Current insights suggest the involvement of EVs in the early stages of T1DM development. A study showed that cytokine treatment to mimic the inflammatory milieu in T1DM increased miR-21-5p expression in EVs from rodent and human islets (MIN6 cells, EndoC-βH1 cells, and human islets). Moreover, serum EV miR-21-5p was elevated in newly diagnosed T1DM patients compared to that in healthy controls and in non-obese diabetic (NOD) mice prior to the onset of diabetes [48]. Interferon (IFN)-α and IFN-γ are pivotal cytokines involved in the pathogenesis of T1DM, and islet IFN signaling is known to enhance programmed death-ligand 1 (PD-L1) expression in β-cell. Exposure to IFN also increased PD-L1 on the surface of β-cell-derived EVs, which bind to programmed death protein 1 (PD1) and suppress CD8+ T-cell proliferation and cytotoxicity. Thus, EVs carrying PD-L1 may represent a potential strategy to inhibit immune-mediated β-cell destruction [49]. A study by Guay et al. [50] demonstrated that T-lymphocytes derived EVs can induce chemokine expression in pancreatic β-cells, potentially leading to apoptosis. These EVs were enriched in miR-142-3p, miR-142-5p, and miR-155. Furthermore, inhibiting these miRNAs in NOD mice reduced β-cell destruction and diabetes development [50]. In the initiation of autoimmunity in T1DM, protein-loaded exosomes originating from islets were taken up by dendritic cells and boosted antigen presentation and T-cell activation. Intracellular β-cell autoantigens (glutamate decarboxylase 65 [GAD65], islet antigen 2 [IA-2], and proinsulin) and immunostimulatory chaperones (calreticulin, Gp96, and 150-kDa oxygen-regulated protein [ORP150]) were the main cargos of these exosomes [51].

EVs in T2DM: modulators of β-cell function and systemic insulin resistance

The pathophysiology of T2DM involves an interplay among multiple organs [45]. Enhanced adiposity leads to increased free fatty acid uptake in muscles and liver, resulting in peripheral insulin resistance [52]. This drives hepatic gluconeogenesis and increases systemic insulin demand. In the face of failing compensatory responses from β-cells, progression towards β-cell failure begins. Reduced functional β-cell mass combined with increased hepatic gluconeogenesis contributes to hyperglycemia and T2DM. A growing body of literature suggests the potential role of EVs in this pathophysiological cascade. EV characteristics differ between T2DM and T1DM patients [53]. Earlier studies illustrated T2DM distinct EVs which play a role in T2DM pathogenesis. For example, serum EV miR-26a levels were decreased in overweight individuals and were inversely associated with T2DM characteristics in humans. In a rodent model, miR-26a was demonstrated to modulate insulin secretion and β-cell replication in an autocrine manner, as well as to alleviate insulin resistance in hepatocytes [54]. Lipotoxicity is one of the important metabolic stimuli that can cause β-cells failure. The level of circular Gli-similar 3 (circGlis3), a circular RNA, was elevated in EVs from MIN6 cells under lipotoxic conditions which was further validated in the serum of HFD-fed mice and T2DM patients. CircGlis3 was suggested to mediate lipotoxicity-induced β-cell dysfunction and trigger islet endothelial dysfunction through the glucocorticoid modulatory element-binding protein 1 (GMEB1)/mindbomb E3 ubiquitin protein ligase 2 (MIB2)/heat shock protein 27 (HSP27) pathway [55]. Pancreatic islets of mice fed with a HFD are enriched with M1 macrophages, whose exosomes impaired glucose-stimulated insulin secretion in β-cells. miR-212-5p was the main contributor in this process which is thought to be driven by targeting sirtuin 2 (SIRT2) and inhibiting the Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway [56]. Similarly, β-cell-macrophage crosstalk mediated by miR-29/TNF-receptor-associated factor 3 (TRAF3) axis aggravates systemic inflammation and glucose intolerance in the process of developing diabetes from prediabetes [57]. Islet amyloid polypeptide (IAPP) is a hormone co-secreted with insulin in β-cells, and its deposition in the islet contributes to β-cell dysfunction in patients with T2DM [58]. One study demonstrated that EVs from healthy donor pancreatic islets attenuated IAPP amyloid deposition by peptide scavenging while this function was impaired in EVs from T2DM donors [59]. β-cells release exosomal miR-29s in conditions of high free fatty acid levels, which target insulin signaling in the liver and blunt hepatic insulin sensitivity [60]. This finding suggests pancreas-liver crosstalk mediated by EVs in controlling glucose homeostasis. As such, EVs participate in the pathophysiologic process of T2DM by modulating β-cell function and peripheral insulin resistance in an endocrine and paracrine manner.

EVs in gestational diabetes mellitus and latent autoimmune diabetes in adults

Gestational diabetes mellitus (GDM) is an important metabolic disorder during pregnancy, significantly raising the risk of perinatal complications and contributing to a higher chance of obesity, T2DM, and cardiovascular risk in both mothers and their offspring [61]. Exosomes from women with GDM were enriched in miR-423-5p, while miR-122-5p, miR-148a-3p, miR192-5p, and miR-99a-5p were downregulated compared to those from normal glucose tolerant (NGT) pregnant women. These miRNAs were associated with insulin and AMPK signaling and were useful in the early prediction of GDM [62]. Furthermore, placenta-derived exosome concentrations were more markedly elevated in patients with GDM than those from NGT pregnant women, suggesting their potential role in the proinflammatory process [63]. EVs could serve as early diagnostic biomarkers for GDM and as mediators of metabolic physiology in pregnant women. Latent autoimmune diabetes in adults (LADA) is a unique subgroup of the disease with patients who develop autoimmune destruction of β-cells within a few years after their initial clinical manifestation of T2DM. A small study suggested that miR-146a-5p, miR-223-3p, and miR-21-5p were upregulated in plasma-derived exosomes from the LADA group compared with those in the T2DM group [64].

EVs in pancreatic cancer-associated diabetes

Pancreatic cancer is linked to an elevated risk of diabetes, although the mechanisms remain unclear. Studies suggest the involvement of EVs in pancreatic cancer-related diabetes. Exosomes from pancreatic cancer cell lines (MIA PaCa-2 cells) decreased glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) production in neuroendocrine cells (STC-1 cells). miR-6796-3p, miR-6763-5p, miR-4750-3p, and miR-197-3p were highly expressed in MIA PaCa2 cell-derived exosomes, which downregulated proprotein convertase subtilisin/kexin (PCSK) type 1/3 in STC-1 cells and reduced GIP and GLP-1 production [65]. Another study demonstrated that exosomes from pancreatic cancer patients reduced glucose-stimulated INS-1 cells and human islets. Adrenomedullin was suggested to mediate exosome induced β-cell dysfunction in pancreatic cancer patients by increasing ER stress and reactive oxygen/nitrogen species [66].

Therapeutic potential of EVs in diabetes management: preclinical insights

As described above, EVs participate in various processes of diabetes pathogenesis and offer potential therapeutic promise. IV delivery of human mesenchymal stem cell-derived exosomes alleviated hyperglycemia by decreasing glycogen storage in the liver, increasing glucose transporter 4 (GLUT4) translocation in muscle, and decreasing streptozotocin (STZ) mediated β-cell apoptosis in a T2DM rat model [67]. Similarly, IV delivery of miR-106b-5p and miR-222-3p improved hyperglycemia by promoting post-injury β-cell proliferation mediated by downregulation of the CDK interacting protein/kinase inhibitory protein (Cip/Kip) family proteins [68]. As these studies were primarily validated in rodent models, the clinical applicability remains limited. Nevertheless, the results are promising and strongly indicate encouraging prospects for leveraging EVs in future diabetes treatments.

EVs IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE: KEY MEDIATORS OF LIPID METABOLISM, INFLAMMATION, AND FIBROSIS

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases globally, affecting over 30% of the population [69-71]. MASLD not only impacts liver health leading to liver fibrosis, cirrhosis, and carcinoma but also contributes to systemic complications, including cardiovascular diseases (CVD), T2DM, and mortality [69, 72-74]. Resulting from toxic lipid accumulation, damaged cells drive the formation and release of EVs/exosomes, which have pivotal roles in advancing MASLD. EVs from metabolically stressed cells carry a diverse cargo, disseminating it through autocrine, paracrine, and systemic pathways. Of note, intrahepatic and extrahepatic cellular components communicating via EVs are emerging as critical factors in the pathogenesis of MASLD [75,76].

miRNA cargo in EVs: key regulators of MASLD progression and pathogenesis

EVs harboring miRNA are internalized by hepatocytes, hepatic stellate cells (HSCs) and macrophages, orchestrating a regulatory role in the development and progression of MASLD. In obese mice with metabolic dysfunction-associated steatohepatitis (MASH), neutrophils infiltrate around lipotoxic hepatocytes communicating with each other. The elevated levels of miR-223 in hepatocytes result from the selective absorption of miR-223-enriched EVs originating from neutrophils in an apolipoprotein E/low-density lipoprotein receptor (LDLR)-dependent manner. miR-223 inhibits inflammatory and fibrotic gene expression, and augmentation of EV transfer by upregulated LDLR with PCSK9 inhibitor ameliorated MASH in mice [77]. Another study also elucidated the antifibrotic effect of exosomal miR-223 transferred from macrophages to hepatocyte under interleukin 6 (IL-6) signaling [78]. miR-199a-5p expression was abundant in the adipose tissue of HFD-fed mice. Exosomal miR-199a-5p aggravated hepatic lipid accumulation through its interaction with mammalian sterile 20-like kinase 1 (MST1) and modulation of the downstream pathway of lipogenesis and lipolysis [79]. In the context of lipotoxicity, several miRNAs act as messengers between hepatocytes and HSCs to accelerate the progression of MASLD. Exosomal miR-1297 promoted HSC activation and proliferation through the PTEN/PI3K/AKT signaling pathway [80]. Furthermore, hepatocytes damaged by lipotoxicity release exosomes that carry and transmit miR-27a to HSCs, thereby triggering liver fibrosis associated with MASLD through inhibition of PTEN-induced kinase 1 (PINK1)-mediated mitophagy. Serum exosomal miR-27a levels were positively associated with the degree of hepatic fibrosis in both mice and humans [81]. In similar conditions, EVs originating from lipotoxic hepatocytes shuttled miR-128-3p to HSCs and induced profibrogenic activation by inhibiting the expression of PPARγ [82]. miR-122 has undergone extensive study and is recognized for its significant role in orchestrating gene expression within the liver. In the context of MASLD, miR-122 exhibited a close association with the development and progression of the disease [83]. Furthermore, it garnered attention as a prospective biomarker for MASLD. In mice subjected to methionine choline-deficient diet, the transference of proinflammatory miR-122 from hepatocytes to resident liver macrophage cells was demonstrated to hinge on matrix metalloprotease 2 (MMP2) [84]. Lipotoxic hepatocytes release exosomal miR-192-5p, which triggers M1 macrophage activation and induce hepatic inflammation through the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor)/Akt/forkhead box O1 (FoxO1) signaling pathway [85].

Protein cargo in EVs: drivers of lipid accumulation and inflammation in MASLD

Proteins are also loaded in the EVs to mediate interorgan or intercellular crosstalk in the progression of MASLD. Aldo-keto-reductase 1b7 (Akr1b7) and scavenger receptor class B (CD36) are protein cargos in the adipocyte-derived exosomes inducing lipid accumulation in hepatocytes. Obesity-triggered ER stress within adipose tissue facilitated the secretion of exosomes from adipocytes containing Akr1b7, contributing to the development of hepatic steatosis, inflammation, and fibrosis [86]. In addition, obesity-associated inactivation of AMPKα1 in white adipose tissue contributed to increased exosome biogenesis and release by elevating TSG101 and facilitating CD36 sorting into exosomes. This led to hepatic lipid accumulation and inflammation, which was mitigated by metformin-induced AMPK activation [87]. Hepatocytes exposed to lipotoxicity also transfer EVs containing protein cargos to macrophages or monocytes initiating chemotaxis. Integrin β1 (ITGβ1)-enriched EVs intensify the adherence of monocytes to liver sinusoidal endothelial cells, consequently initiating hepatic inflammation. Of note, ITGβ1 antibody treatment significantly ameliorated liver injury and fibrosis [88]. Hepatocyte-derived EVs induced by palmitate or lysophosphatidylcholine were discovered to encompass both C-X-C motif chemokine 10 (CXCL10) and tumor necrosis factor-like apoptosis-inducing ligand (TRAIL), which induce chemotaxis and proinflammatory cascade in macrophages [89]. The death receptor 5 signaling cascade activated rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and promoted the release of TRAIL-bearing EVs, which subsequently activated macrophages via the receptor interacting protein kinase 1 (RIP1)-nuclear factor kappa-B (NF-κB) signaling pathway. Thereby, treatment of ROCK1 inhibitor fasudil effectively decreased liver inflammation and fibrosis [90].

Lipid cargo in EVs: mediators of liver injury and fibrosis in MASLD

EVs containing lipids can potentially induce liver injury by directly affecting macrophages and endothelial cells. Hepatocytes damaged by lipotoxic ER stress stimulate inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1), leading to the release of ceramide-enriched EVs, some of which contain sphingosine-1-phosphate, a ceramide metabolite. These EVs recruit monocyte-derived macrophages to the liver, causing inflammation and injury [91,92]. Lipotoxic stress triggers hepatocytes to release small EVs enriched in palmitic (C16:0) and stearic (C18:0) saturated fatty acids. These small EVs target Kupffer cells and induce inflammation via TLR4. Treatment of conditioned media from macrophages/Kupffer cells loaded with lipotoxic small EVs impaired hepatocyte insulin signaling making a hepatocyte-macrophage-hepatocyte crosstalk in a paracrine manner [93]. Iron homeostasis in the liver is also associated with steatosis and fibrosis. Hepatocyte-secreted iron-containing EVs lead to hepatocyte iron deficiency and HSC iron overload. Iron accumulation promotes ROS overproduction and fibrogenic activation of HSCs, and this effect is mitigated by blocking EV secretion or depleting EV iron cargo [94]. In summary, EVs originating from various cells under metabolic stress contribute to various facets of MASLD pathogenesis, including hepatic inflammation, angiogenesis, and fibrosis, through the transfer of various cargos within the complex network (Table 3).

EVs IN ATHEROSCLEROSIS: LOCAL AND SYSTEMIC CROSSTALK DRIVING CVD

In the process of atherosclerosis development and progression, EVs from various cells are emerging as key players and have both favorable and detrimental effects by controlling endothelial dysfunction, vascular calcification, plaque stability and thrombus formation [95,96]. An analysis of plaque microparticles from carotid endarterectomy samples revealed that EVs involved in atherogenesis originated from leukocytes, macrophages, granulocytes, erythrocytes, smooth muscle cells, and endothelial cells [97].

Local crosstalk by EVs among diverse cells in the atherogenic milieu

A complex network between diverse immune cells and endothelial cells mediated by EVs has been identified in the atherogenic milieu. Exosomes from immune-activated monocytes carry inflammatory miRNA cargo and upregulate intercellular adhesion molecule-1 (ICAM-1), chemokine ligand 2 (CCL-2), and IL-6 via TLR4 and NF-κB pathways in endothelial cells [98]. Plaque EVs also promote inflammatory cell recruitment by transferring ICAM-1 to endothelial cells which contributes to plaque instability [99]. Enrichment of several miRNAs, particularly miR-146a, was found in EVs from oxidized low-density lipoprotein-treated atherogenic macrophages. These EVs are delivered to naïve recipient macrophages and reduce migratory capacity promoting macrophage entrapment in the vessel wall and the development of atherosclerosis [100]. Vascular smooth muscle cell (VSMC)-derived exosomes from diabetic sources induce vascular inflammation, proinflammatory polarization of monocytes, and atherosclerotic plaque formation by a paracrine signaling of transferring miR-221/222 [101]. EVs isolated from the red blood cells of patients with T2DM impair endothelial function by delivering arginase-1 and inducing oxidative stress [102].

Perivascular adipose tissue also plays a role in vascular homeostasis. Perivascular adipose tissue-derived exosomes from patients with coronary atherosclerotic heart disease showed a lower miR-382-5p expression level than those from healthy individuals. miR-382-5p reduces macrophage foam cell formation through the upregulation of the cholesterol efflux transporters adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) [103]. Exosomes from adipose-derived mesenchymal stem cells transfer miR-324-5p to endothelial cells, which protects endothelial cells against atherosclerosis by inhibiting protein phosphatase 1 regulatory subunit 12B (PPP1R12B)-mediated apoptosis [104]. Exosomes secreted from dendritic cells containing miR-203-3p target cathepsin S in bone marrow-derived macrophages attenuating atherosclerosis at both the cellular and mouse levels [105]. These examples reveal local crosstalk among various components in the vessel.

Distant organ-derived EV signals driving atherosclerosis and CVD

Signals from distant organs also drive atherosclerosis and CVD. Epidemiologic studies demonstrated MASLD as an independent risk factor for CVD, although underlying molecular mechanisms are not fully understood [69]. Recent studies suggest that EVs may play a role in mediating this association. EVs derived from steatotic hepatocytes showed inducing of endothelial inflammation and promoting atherosclerosis. miR-1 was identified as a key cargo within these EVs, contributing to this effect through the suppression of KLF4 and activation of NF-κB. miR-1 inhibition attenuated atherogenesis in ApoE^−/− mice [106]. Similarly, miR-30a-3p from steatotic hepatocyte-derived small EVs inhibits ABCA1-mediated cholesterol efflux, thereby promoting foam cell formation in atherosclerosis. Treatment of antagomir-30a-3p attenuated diet-induced atherosclerosis in ApoE^−/− mice [107]. Liver-specific deletion of the acid ceramidase gene N-acylsphingosine amidohydrolase 1 (Asah1) enhanced ceramide levels and liver lipid deposition in HFD-fed mice accompanied by increased EV release. This led to Nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation and neointimal hyperplasia explaining the mechanism of MASLD-associated vascular endothelial dysfunction [108]. Exosomal miR-27b-3p transferred from the visceral adipocytes to vascular endothelial cells also activates NF-κB pathway by degrading PPARα mRNA which eventually induces endothelial inflammation and atherogenesis. Administration of miR-27b-3p mimic accelerated atherosclerotic plaque formation in ApoE^−/− mice [109]. Another study showed that exosomes from visceral adipose tissue of HFD-fed mice facilitated macrophage foam cell formation, M1 polarization, and proinflammatory cytokine secretion. These findings were accompanied by the downregulation of ATP-binding cassette transporter-mediated cholesterol efflux and increased phosphorylation of NF-κB-p65. Systemic injection of these exosomes for 6 weeks exacerbated atherosclerosis in HFD-fed ApoE^−/− mice [110].

Insufficient or disrupted sleep is also associated with cardiovascular disease risk. Melatonin plays important roles in sleep, circadian rhythms, and cardiovascular systems. Melatonin treatment attenuated osteogenic differentiation and senescence of VSMCs, and therefore delaying vascular calcification and aging. These effects were mediated by miR-204 and miR-211 from VSMC-derived exosomes through paracrine mechanism [111]. Circulating exosomes from sleep-deprived human and mice were a potent inducer of atherogenesis and endothelial inflammation. In this condition, exosomal miR-182-5p secreted from small intestinal epithelium was decreased, upregulating myeloid differentiation factor 88 (MYD88)—NF-κB/NLRP3 pathway in endothelial cells [112]. Collectively, complex interplay among various cells and organs via EVs mediate atherogenesis and CVD (Table 4).

THERAPEUTIC POTENTIALS OF EV

EVs have potential as a drug-delivery platform or as therapeutics to target specific cells and transfer functional molecules. Incorporation of cargos into or onto isolated EVs (exogenous loading) by manipulations including co-incubation, electroporation, and sonication can utilize EVs as natural delivery vectors. Alternatively, the parental cell can be genetically modified to overexpress desired RNA or protein of interest, which will be loaded during the EV biogenesis (endogenous loading) [113]. According to a literature review by Fusco et al. [114], 40 studies examining EVs as human therapeutics were published up to the end of 2023. Most of these studies were small-sized non-randomized trials without control group. Treated diseases varied including malignant tumor, coronavirus disease-19 infection, skin diseases, neurologic diseases, graft versus host disease, ulcers and delayed wound healing, skin aging, hair loss, etc. Approximately two thirds used mesenchymal stem cells as an EV source, and all were non-engineered EVs. Based on these observations, it seems that the application of EV formulations for human therapeutics is still in the early stage and multiple challenges remain. Defining optimal cellular sources for specific diseases, standardization of methods for isolation, characterization and large-scale production of EVs, development of efficient storing procedure, establishment of appropriate dosing and route of administration for efficacy and safety, and evaluation of biodistribution, clearance, and the long-term risks of EVs are important aspects that need to be further clarified [113-115].

CONCLUSIONS AND FUTURE PERSPECTIVES

Cardiometabolic diseases are systemic disorders with complex interorgan networks in their pathophysiology. Despite rapid expansion and meaningful progress in EV research, it is still underrepresented in the field of cardiovascular or metabolic diseases. However, emerging evidence suggests that EVs play a significant role in these processes as described in this study (Fig. 2). Therefore, research into EVs holds immense promise for advancing our understanding of cardiovascular and metabolic diseases. Advances in EV isolation methods and characterization techniques may enable better disease prediction and monitoring by utilizing EVs as early and non-invasive biomarkers. Novel techniques for profiling EV surface markers, such as the proximity-dependent barcoding assay or immunomagnetic bead-based methods, are being applied to separate EVs originating from specific cells in mixed samples [116,117]. In addition, EVs have therapeutic potential with their ability to serve as targeted delivery systems for drugs, RNAs, and other bioactive compounds. Engineering EVs for loading specific cargo and targeting specific receptor cells could lead to breakthroughs in treating diseases by modulating pathological signaling pathways. However, many challenges remain, including standardization of EV isolation methods, understanding the heterogeneity of EV populations, establishing accurate differentiation and separation techniques, and elucidating the precise mechanisms through which EVs contribute to disease progression. The efficacy, safety, and scalability of EVs also need to be addressed because of potential immunogenicity, unintended off-target effects, and variability in EV production during large-scale manufacturing. Regulatory guidelines for EV-based therapies need to evolve to ensure clinical applicability. Addressing these challenges will require interdisciplinary collaboration and innovative technologies, ultimately opening the way for EV-based diagnostics and therapies in cardiometabolic disease management.

NOTES

CONFLICTS OF INTEREST

Seung-Hwan Lee has been an associate editor of the Diabetes & Metabolism Journal since 2022. He was not involved in the review process of this article. The authors declare that they have no competing interests.

FUNDING

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2023R1A2C2004341 to Seung-Hwan Lee and RS-2025-00555223 to Joonyub Lee) and the research fund of Seoul St. Mary’s Hospital, The Catholic University of Korea (to Seung-Hwan Lee).

Acknowledgements

None

Fig. 1.

Biogenesis, secretion, and action of extracellular vesicles. Exosomes are extracellular vesicles generated by virtually all cells, carrying nucleic acids, proteins, lipids, and metabolites as cargo. They originate through the inward budding of endosomal membranes, incorporating various molecules. Their formation occurs within multivesicular bodies, which eventually fuse with the plasma membrane, releasing exosomes into the extracellular environment. In contrast, microvesicles and apoptotic bodies are shed directly from the plasma membrane. Exosomes function in an autocrine, paracrine, or endocrine manner. They are taken up by nearby or distant cells through phagocytosis/macropinocytosis, direct membrane fusion, receptor-ligand interactions, or clathrin-mediated endocytosis. TSG101, tumor susceptibility gene 101; HSP70, heat shock protein 70; ER, endoplasmic reticulum.

Fig. 2.

Extracellular vesicle (EV)-mediated network in the pathogenesis of cardiometabolic diseases. EVs carry miRNAs, proteins, and lipids that mediate intercellular or interorgan communication, contributing to the development of obesity, insulin resistance, diabetes mellitus, metabolic dysfunction-associated liver disease, and cardiovascular disease. Blue characters indicate EV cargos with beneficial effects, while red characters indicate EV cargos with detrimental effects. Dashed lines represent intraorgan crosstalk, and solid lines denote interorgan or distant crosstalk. CXCL10, C-X-C motif chemokine 10; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; SFA, saturated fatty acid; ATM, adipose tissue macrophage; ADSC, adipose-derived stem cell; STAT3, signal transducer and activator of transcription 3; VSMC, vascular smooth muscle cell; ICAM-1, intercellular adhesion molecule-1; GAD65, glutamate decarboxylase 65; IA-2, islet antigen 2.

REFERENCES

• 1. Welsh JA, Goberdhan DC, O’Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles 2024;13:e12404.PubMedPMC
• 2. Isaac R, Reis FCG, Ying W, Olefsky JM. Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metab 2021;33:1744-62.ArticlePubMedPMC
• 3. Jeppesen DK, Zhang Q, Franklin JL, Coffey RJ. Extracellular vesicles and nanoparticles: emerging complexities. Trends Cell Biol 2023;33:667-81.ArticlePubMedPMC
• 4. Hu S, Hu Y, Yan W. Extracellular vesicle-mediated interorgan communication in metabolic diseases. Trends Endocrinol Metab 2023;34:571-82.ArticlePubMed
• 5. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020;367:eaau6977.PubMedPMC
• 6. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967;13:269-88.ArticlePubMed
• 7. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation: association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987;262:9412-20.ArticlePubMed
• 8. Lawson C, Vicencio JM, Yellon DM, Davidson SM. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol 2016;228:R57-71.ArticlePubMed
• 9. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002;2:569-79.ArticlePubMedPDF
• 10. Huang-Doran I, Zhang CY, Vidal-Puig A. Extracellular vesicles: novel mediators of cell communication in metabolic disease. Trends Endocrinol Metab 2017;28:3-18.ArticlePubMed
• 11. Garcia-Martin R, Wang G, Brandao BB, Zanotto TM, Shah S, Kumar Patel S, et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 2022;601:446-51.ArticlePubMedPDF
• 12. Coumans FA, Brisson AR, Buzas EI, Dignat-George F, Drees EE, El-Andaloussi S, et al. Methodological guidelines to study extracellular vesicles. Circ Res 2017;120:1632-48.ArticlePubMed
• 13. Lee SH, Park SY, Choi CS. Insulin resistance: from mechanisms to therapeutic strategies. Diabetes Metab J 2022;46:15-37.ArticlePubMedPDF
• 14. Pan Y, Hui X, Hoo RL, Ye D, Chan CY, Feng T, et al. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest 2019;129:834-49.ArticlePubMedPMC
• 15. Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 2017;171:372-84.ArticlePubMed
• 16. Ying W, Gao H, Dos Reis FC, Bandyopadhyay G, Ofrecio JM, Luo Z, et al. MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice. Cell Metab 2021;33:781-90.ArticlePubMedPMC
• 17. Kulaj K, Harger A, Bauer M, Caliskan OS, Gupta TK, Chiang DM, et al. Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo. Nat Commun 2023;14:709.ArticlePubMedPMCPDF
• 18. Ji Y, Luo Z, Gao H, Dos Reis FC, Bandyopadhyay G, Jin Z, et al. Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075. Nat Metab 2021;3:1163-74.ArticlePubMedPMCPDF
• 19. Blandin A, Amosse J, Froger J, Hilairet G, Durcin M, Fizanne L, et al. Extracellular vesicles are carriers of adiponectin with insulin-sensitizing and anti-inflammatory properties. Cell Rep 2023;42:112866.ArticlePubMed
• 20. Jung YJ, Kim HK, Cho Y, Choi JS, Woo CH, Lee KS, et al. Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes. Sci Adv 2020;6:eaay6721.ArticlePubMedPMC
• 21. Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes 2018;67:235-47.ArticlePubMedPDF
• 22. Yu Y, Du H, Wei S, Feng L, Li J, Yao F, et al. Adipocyte-derived exosomal MiR-27a induces insulin resistance in skeletal muscle through repression of PPARγ. Theranostics 2018;8:2171-88.ArticlePubMedPMC
• 23. Katayama M, Wiklander OP, Fritz T, Caidahl K, El-Andaloussi S, Zierath JR, et al. Circulating exosomal miR-20b-5p is elevated in type 2 diabetes and could impair insulin action in human skeletal muscle. Diabetes 2019;68:515-26.ArticlePubMedPDF
• 24. Kumar A, Sundaram K, Mu J, Dryden GW, Sriwastva MK, Lei C, et al. High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance. Nat Commun 2021;12:213.ArticlePubMedPMCPDF
• 25. Di W, Amdanee N, Zhang W, Zhou Y. Long-term exercise-secreted extracellular vesicles promote browning of white adipocytes by suppressing miR-191a-5p. Life Sci 2020;263:118464.ArticlePubMed
• 26. Phu TA, Ng M, Vu NK, Bouchareychas L, Raffai RL. IL-4 polarized human macrophage exosomes control cardiometabolic inflammation and diabetes in obesity. Mol Ther 2022;30:2274-97.ArticlePubMedPMC
• 27. Corvera S. Cellular heterogeneity in adipose tissues. Annu Rev Physiol 2021;83:257-78.ArticlePubMedPMC
• 28. An SM, Cho SH, Yoon JC. Adipose tissue and metabolic health. Diabetes Metab J 2023;47:595-611.ArticlePubMedPMCPDF
• 29. Deng ZB, Poliakov A, Hardy RW, Clements R, Liu C, Liu Y, et al. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes 2009;58:2498-505.ArticlePubMedPMCPDF
• 30. Rohm TV, Castellani Gomes Dos Reis F, Isaac R, Murphy C, Cunha E Rocha K, Bandyopadhyay G, et al. Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization. Nat Metab 2024;6:880-98.ArticlePubMedPMCPDF
• 31. Miotto PM, Yang CH, Keenan SN, De Nardo W, Beddows CA, Fidelito G, et al. Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication. Nat Metab 2024;6:254-72.ArticlePubMedPDF
• 32. Kita S, Maeda N, Shimomura I. Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome. J Clin Invest 2019;129:4041-9.ArticlePubMedPMC
• 33. Crewe C, Joffin N, Rutkowski JM, Kim M, Zhang F, Towler DA, et al. An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state. Cell 2018;175:695-708.ArticlePubMedPMC
• 34. Ikeda K, Maretich P, Kajimura S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab 2018;29:191-200.ArticlePubMedPMC
• 35. Chen Y, Buyel JJ, Hanssen MJ, Siegel F, Pan R, Naumann J, et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat Commun 2016;7:11420.ArticlePubMedPMCPDF
• 36. Rosina M, Ceci V, Turchi R, Chuan L, Borcherding N, Sciarretta F, et al. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue. Cell Metab 2022;34:533-48.ArticlePubMedPMC
• 37. Crewe C, Funcke JB, Li S, Joffin N, Gliniak CM, Ghaben AL, et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab 2021;33:1853-68.ArticlePubMedPMC
• 38. Lee SH, Zabolotny JM, Huang H, Lee H, Kim YB. Insulin in the nervous system and the mind: functions in metabolism, memory, and mood. Mol Metab 2016;5:589-601.ArticlePubMedPMC
• 39. Wang J, Li L, Zhang Z, Zhang X, Zhu Y, Zhang C, et al. Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance. Cell Metab 2022;34:1264-79.ArticlePubMed
• 40. Milbank E, Dragano NR, Gonzalez-Garcia I, Garcia MR, Rivas-Limeres V, Perdomo L, et al. Small extracellular vesiclemediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation. Nat Metab 2021;3:1415-31.ArticlePubMedPDF
• 41. Milbank E, Dragano N, Vidal-Gomez X, Rivas-Limeres V, Garrido-Gil P, Wertheimer M, et al. Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice. Metabolism 2023;139:155350.ArticlePubMed
• 42. Aoi W, Tanimura Y. Roles of skeletal muscle-derived exosomes in organ metabolic and immunological communication. Front Endocrinol (Lausanne) 2021;12:697204.ArticlePubMedPMC
• 43. Safdar A, Saleem A, Tarnopolsky MA. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol 2016;12:504-17.ArticlePubMedPDF
• 44. Jalabert A, Vial G, Guay C, Wiklander OP, Nordin JZ, Aswad H, et al. Exosome-like vesicles released from lipid-induced insulin-resistant muscles modulate gene expression and proliferation of beta recipient cells in mice. Diabetologia 2016;59:1049-58.ArticlePubMedPDF
• 45. Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet 2022;400:1803-20.ArticlePubMed
• 46. Lee J, Lee SH. New mediators in diabetes pathogenesis: exosomes and metabolites. J Diabetes Investig 2021;12:1931-3.ArticlePubMedPMCPDF
• 47. Prattichizzo F, Matacchione G, Giuliani A, Sabbatinelli J, Olivieri F, de Candia P, et al. Extracellular vesicle-shuttled miRNAs: a critical appraisal of their potential as nano-diagnostics and nano-therapeutics in type 2 diabetes mellitus and its cardiovascular complications. Theranostics 2021;11:1031-45.ArticlePubMedPMC
• 48. Lakhter AJ, Pratt RE, Moore RE, Doucette KK, Maier BF, DiMeglio LA, et al. Beta cell extracellular vesicle miR-21-5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes. Diabetologia 2018;61:1124-34.ArticlePubMedPMCPDF
• 49. Rao C, Cater DT, Roy S, Xu J, De Oliveira AG, Evans-Molina C, et al. Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of type 1 diabetes. Diabetologia 2025;68:382-96.ArticlePubMedPDF
• 50. Guay C, Kruit JK, Rome S, Menoud V, Mulder NL, Jurdzinski A, et al. Lymphocyte-derived exosomal microRNAs promote pancreatic β cell death and may contribute to type 1 diabetes development. Cell Metab 2019;29:348-61.ArticlePubMed
• 51. Cianciaruso C, Phelps EA, Pasquier M, Hamelin R, Demurtas D, Alibashe Ahmed M, et al. Primary human and rat β-cells release the intracellular autoantigens GAD65, IA-2, and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 2017;66:460-73.ArticlePubMedPDF
• 52. Jung I, Koo DJ, Lee WY. Insulin resistance, non-alcoholic fatty liver disease and type 2 diabetes mellitus: clinical and experimental perspective. Diabetes Metab J 2024;48:327-39.ArticlePubMedPMCPDF
• 53. Sabatier F, Darmon P, Hugel B, Combes V, Sanmarco M, Velut JG, et al. Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes 2002;51:2840-5.ArticlePubMedPDF
• 54. Xu H, Du X, Xu J, Zhang Y, Tian Y, Liu G, et al. Pancreatic β cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving β cell function. PLoS Biol 2020;18:e3000603.ArticlePubMedPMC
• 55. Xiong L, Chen L, Wu L, He W, Chen D, Peng Z, et al. Lipotoxicity-induced circGlis3 impairs beta cell function and is transmitted by exosomes to promote islet endothelial cell dysfunction. Diabetologia 2022;65:188-205.ArticlePubMedPDF
• 56. Qian B, Yang Y, Tang N, Wang J, Sun P, Yang N, et al. M1 macrophage-derived exosomes impair beta cell insulin secretion via miR-212-5p by targeting SIRT2 and inhibiting Akt/GSK3β/β-catenin pathway in mice. Diabetologia 2021;64:2037-51.ArticlePubMedPDF
• 57. Sun Y, Zhou Y, Shi Y, Zhang Y, Liu K, Liang R, et al. Expression of miRNA-29 in pancreatic β cells promotes inflammation and diabetes via TRAF3. Cell Rep 2021;34:108576.ArticlePubMed
• 58. Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, et al. β-Cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol 2011;178:2632-40.ArticlePubMedPMC
• 59. Ribeiro D, Horvath I, Heath N, Hicks R, Forslow A, Wittung-Stafshede P. Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation. Proc Natl Acad Sci U S A 2017;114:11127-32.ArticlePubMedPMC
• 60. Li J, Zhang Y, Ye Y, Li D, Liu Y, Lee E, et al. Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR-29 family. J Extracell Vesicles 2021;10:e12055.ArticlePubMedPMCPDF
• 61. Wicklow B, Retnakaran R. Gestational diabetes mellitus and its implications across the life span. Diabetes Metab J 2023;47:333-44.ArticlePubMedPMCPDF
• 62. Ye Z, Wang S, Huang X, Chen P, Deng L, Li S, et al. Plasma exosomal miRNAs associated with metabolism as early predictor of gestational diabetes mellitus. Diabetes 2022;71:2272-83.ArticlePubMedPMCPDF
• 63. Salomon C, Scholz-Romero K, Sarker S, Sweeney E, Kobayashi M, Correa P, et al. Gestational diabetes mellitus is associated with changes in the concentration and bioactivity of placenta-derived exosomes in maternal circulation across gestation. Diabetes 2016;65:598-609.PubMed
• 64. Fan W, Pang H, Li X, Xie Z, Huang G, Zhou Z. Plasma-derived exosomal miRNAs as potentially novel biomarkers for latent autoimmune diabetes in adults. Diabetes Res Clin Pract 2023;197:110570.ArticlePubMed
• 65. Zhang Y, Huang S, Li P, Chen Q, Li Y, Zhou Y, et al. Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3. Cancer Lett 2018;431:190-200.ArticlePubMed
• 66. Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, et al. Pancreatic cancer-derived exosomes cause paraneoplastic β-cell dysfunction. Clin Cancer Res 2015;21:1722-33.ArticlePubMedPDF
• 67. Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B, et al. Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction. ACS Nano 2018;12:7613-28.ArticlePubMed
• 68. Tsukita S, Yamada T, Takahashi K, Munakata Y, Hosaka S, Takahashi H, et al. MicroRNAs 106b and 222 improve hyperglycemia in a mouse model of insulin-deficient diabetes via pancreatic β-cell proliferation. EBioMedicine 2017;15:163-72.ArticlePubMed
• 69. Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol 2019;7:313-24.ArticlePubMed
• 70. Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. Metabolic dysfunction-associated steatotic liver disease: update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology 2024;79:1212-9.ArticlePubMed
• 71. Han E, Han KD, Lee YH, Kim KS, Hong S, Park JH, et al. Fatty liver & diabetes statistics in Korea: nationwide data 2009 to 2017. Diabetes Metab J 2023;47:347-55.ArticlePubMedPMCPDF
• 72. Friedman SL. Hepatic fibrosis and cancer: the silent threats of metabolic syndrome. Diabetes Metab J 2024;48:161-9.ArticlePubMedPMCPDF
• 73. Kim KS, Hong S, Ahn HY, Park CY. Metabolic dysfunction-associated fatty liver disease and mortality: a population-based cohort study. Diabetes Metab J 2023;47:220-31.ArticlePubMedPMCPDF
• 74. Bae J, Han E, Lee HW, Park CY, Chung CH, Lee DH, et al. Metabolic dysfunction-associated steatotic liver disease in type 2 diabetes mellitus: a review and position statement of the Fatty Liver Research Group of the Korean Diabetes Association. Diabetes Metab J 2024;48:1015-28.ArticlePubMedPMCPDF
• 75. Wu D, Zhu H, Wang H. Extracellular vesicles in non-alcoholic fatty liver disease and alcoholic liver disease. Front Physiol 2021;12:707429.ArticlePubMedPMC
• 76. Eguchi A, Iwasa M, Nakagawa H. Extracellular vesicles in fatty liver disease and steatohepatitis: role as biomarkers and therapeutic targets. Liver Int 2023;43:292-8.ArticlePubMedPDF
• 77. He Y, Rodrigues RM, Wang X, Seo W, Ma J, Hwang S, et al. Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis. J Clin Invest 2021;131:e141513.ArticlePubMedPMC
• 78. Hou X, Yin S, Ren R, Liu S, Yong L, Liu Y, et al. Myeloid-cell-specific IL-6 signaling promotes microRNA-223-enriched exosome production to attenuate NAFLD-associated fibrosis. Hepatology 2021;74:116-32.ArticlePubMedPDF
• 79. Li Y, Luan Y, Li J, Song H, Li Y, Qi H, et al. Exosomal miR-199a-5p promotes hepatic lipid accumulation by modulating MST1 expression and fatty acid metabolism. Hepatol Int 2020;14:1057-74.ArticlePubMedPDF
• 80. Luo X, Luo SZ, Xu ZX, Zhou C, Li ZH, Zhou XY, et al. Lipotoxic hepatocyte-derived exosomal miR-1297 promotes hepatic stellate cell activation through the PTEN signaling pathway in metabolic-associated fatty liver disease. World J Gastroenterol 2021;27:1419-34.ArticlePubMedPMC
• 81. Luo X, Xu ZX, Wu JC, Luo SZ, Xu MY. Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD. Mol Ther Nucleic Acids 2021;26:1241-54.ArticlePubMedPMC
• 82. Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo Horcel L, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol 2015;1:646-63.PubMedPMC
• 83. Hochreuter MY, Dall M, Treebak JT, Barres R. MicroRNAs in non-alcoholic fatty liver disease: progress and perspectives. Mol Metab 2022;65:101581.ArticlePubMedPMC
• 84. Das A, Basu S, Bandyopadhyay D, Mukherjee K, Datta D, Chakraborty S, et al. Inhibition of extracellular vesicle-associated MMP2 abrogates intercellular hepatic miR-122 transfer to liver macrophages and curtails inflammation. iScience 2021;24:103428.ArticlePubMedPMC
• 85. Liu XL, Pan Q, Cao HX, Xin FZ, Zhao ZH, Yang RX, et al. Lipotoxic hepatocyte-derived exosomal microRNA 192-5p activates macrophages through Rictor/Akt/Forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease. Hepatology 2020;72:454-69.ArticlePubMedPDF
• 86. Gu H, Yang K, Shen Z, Jia K, Liu P, Pan M, et al. ER stress-induced adipocytes secrete-aldo-keto reductase 1B7-containing exosomes that cause nonalcoholic steatohepatitis in mice. Free Radic Biol Med 2021;163:220-33.ArticlePubMed
• 87. Yan C, Tian X, Li J, Liu D, Ye D, Xie Z, et al. A high-fat diet attenuates AMPK α1 in adipocytes to induce exosome shedding and nonalcoholic fatty liver development in vivo. Diabetes 2021;70:577-88.ArticlePubMedPDF
• 88. Guo Q, Furuta K, Lucien F, Gutierrez Sanchez LH, Hirsova P, Krishnan A, et al. Integrin β1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol 2019;71:1193-205.ArticlePubMedPMC
• 89. Ibrahim SH, Hirsova P, Tomita K, Bronk SF, Werneburg NW, Harrison SA, et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 2016;63:731-44.ArticlePubMedPDF
• 90. Hirsova P, Ibrahim SH, Krishnan A, Verma VK, Bronk SF, Werneburg NW, et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 2016;150:956-67.ArticlePubMed
• 91. Dasgupta D, Nakao Y, Mauer AS, Thompson JM, Sehrawat TS, Liao CY, et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology 2020;159:1487-503.ArticlePubMed
• 92. Kakazu E, Mauer AS, Yin M, Malhi H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res 2016;57:233-45.ArticlePubMedPMC
• 93. Garcia-Martinez I, Alen R, Pereira L, Povo-Retana A, Astudillo AM, Hitos AB, et al. Saturated fatty acid-enriched small extracellular vesicles mediate a crosstalk inducing liver inflammation and hepatocyte insulin resistance. JHEP Rep 2023;5:100756.ArticlePubMedPMC
• 94. Gao H, Jin Z, Bandyopadhyay G, Wang G, Zhang D, Rocha KC, et al. Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metab 2022;34:1201-13.ArticlePubMedPMC
• 95. Jansen F, Li Q, Pfeifer A, Werner N. Endothelial- and immune cell-derived extracellular vesicles in the regulation of cardiovascular health and disease. JACC Basic Transl Sci 2017;2:790-807.ArticlePubMedPMC
• 96. Zisser L, Binder CJ. Extracellular vesicles as mediators in atherosclerotic cardiovascular disease. J Lipid Atheroscler 2024;13:232-61.ArticlePubMedPMCPDF
• 97. Leroyer AS, Isobe H, Leseche G, Castier Y, Wassef M, Mallat Z, et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J Am Coll Cardiol 2007;49:772-7.ArticlePubMed
• 98. Tang N, Sun B, Gupta A, Rempel H, Pulliam L. Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-κB in endothelial cells. FASEB J 2016;30:3097-106.ArticlePubMedPMCPDF
• 99. Rautou PE, Leroyer AS, Ramkhelawon B, Devue C, Duflaut D, Vion AC, et al. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ Res 2011;108:335-43.ArticlePubMed
• 100. Nguyen MA, Karunakaran D, Geoffrion M, Cheng HS, Tandoc K, Perisic Matic L, et al. Extracellular vesicles secreted by atherogenic macrophages transfer microRNA to inhibit cell migration. Arterioscler Thromb Vasc Biol 2018;38:49-63.ArticlePubMed
• 101. Yu H, Douglas HF, Wathieu D, Braun RA, Edomwande C, Lightell DJ Jr, et al. Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells. Cardiovasc Diabetol 2023;22:112.ArticlePubMedPMCPDF
• 102. Collado A, Humoud R, Kontidou E, Eldh M, Swaich J, Zhao A, et al. Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes. J Clin Invest 2025 Mar 20 [Epub]. https://doi.org/10.1172/JCI180900.Article
• 103. Liu Y, Sun Y, Lin X, Zhang D, Hu C, Liu J, et al. Perivascular adipose-derived exosomes reduce macrophage foam cell formation through miR-382-5p and the BMP4-PPARγ-ABCA1/ ABCG1 pathways. Vascul Pharmacol 2022;143:106968.ArticlePubMed
• 104. Xing X, Li Z, Yang X, Li M, Liu C, Pang Y, et al. Adipose-derived mesenchymal stem cells-derived exosome-mediated microRNA-342-5p protects endothelial cells against atherosclerosis. Aging (Albany NY) 2020;12:3880-98.ArticlePubMedPMC
• 105. Lin B, Xie W, Zeng C, Wu X, Chen A, Li H, et al. Transfer of exosomal microRNA-203-3p from dendritic cells to bone marrow-derived macrophages reduces development of atherosclerosis by downregulating Ctss in mice. Aging (Albany NY) 2021;13:15638-58.ArticlePubMedPMC
• 106. Jiang F, Chen Q, Wang W, Ling Y, Yan Y, Xia P. Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1. J Hepatol 2020;72:156-66.ArticlePubMed
• 107. Chen X, Chen S, Pang J, Huang R, You Y, Zhang H, et al. Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle-mediated inhibition of cellular cholesterol efflux. J Hepatol 2023;79:1491-501.ArticlePubMed
• 108. Yuan X, Bhat OM, Zou Y, Zhang Y, Li PL. Contribution of hepatic steatosis-intensified extracellular vesicle release to aggravated inflammatory endothelial injury in liver-specific Asah1 gene knockout mice. Am J Pathol 2023;193:493-508.ArticlePubMedPMC
• 109. Tang Y, Yang LJ, Liu H, Song YJ, Yang QQ, Liu Y, et al. Exosomal miR-27b-3p secreted by visceral adipocytes contributes to endothelial inflammation and atherogenesis. Cell Rep 2023;42:111948.ArticlePubMed
• 110. Xie Z, Wang X, Liu X, Du H, Sun C, Shao X, et al. Adipose-derived exosomes exert proatherogenic effects by regulating macrophage foam cell formation and polarization. J Am Heart Assoc 2018;7:e007442.ArticlePubMedPMC
• 111. Xu F, Zhong JY, Lin X, Shan SK, Guo B, Zheng MH, et al. Melatonin alleviates vascular calcification and ageing through exosomal miR-204/miR-211 cluster in a paracrine manner. J Pineal Res 2020;68:e12631.ArticlePubMedPMC
• 112. Li X, Cao Y, Xu X, Wang C, Ni Q, Lv X, et al. Sleep deprivation promotes endothelial inflammation and atherogenesis by reducing exosomal miR-182-5p. Arterioscler Thromb Vasc Biol 2023;43:995-1014.ArticlePubMed
• 113. Wiklander OP, Brennan MA, Lotvall J, Breakefield XO, El Andaloussi S. Advances in therapeutic applications of extracellular vesicles. Sci Transl Med 2019;11:eaav8521.ArticlePubMedPMC
• 114. Fusco C, De Rosa G, Spatocco I, Vitiello E, Procaccini C, Frige C, et al. Extracellular vesicles as human therapeutics: a scoping review of the literature. J Extracell Vesicles 2024;13:e12433.ArticlePubMedPMC
• 115. Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol 2021;16:748-59.ArticlePubMedPDF
• 116. Wu D, Yan J, Shen X, Sun Y, Thulin M, Cai Y, et al. Profiling surface proteins on individual exosomes using a proximity barcoding assay. Nat Commun 2019;10:3854.ArticlePubMedPMCPDF
• 117. Prattichizzo F, De Nigris V, Sabbatinelli J, Giuliani A, Castano C, Parrizas M, et al. CD31+ extracellular vesicles from patients with type 2 diabetes shuttle a miRNA signature associated with cardiovascular complications. Diabetes 2021;70:240-54.ArticlePubMedPDF

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Lee J, Choi WG, Rhee M, Lee SH. Extracellular Vesicle-Mediated Network in the Pathogenesis of Obesity, Diabetes, Steatotic Liver Disease, and Cardiovascular Disease. Diabetes Metab J. 2025;49(3):348-367.

Received: Mar 06, 2025; Accepted: Apr 16, 2025

DOI: https://doi.org/10.4093/dmj.2025.0184.

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