Extracellular vesicle-mediated bidirectional communication between the liver and other organs: mechanistic exploration and prospects for clinical applications

Abstract

The liver, functioning as an endocrine organ, secretes a variety of substances that influence the activities of other body organs. Conversely, molecules generated by organs such as bone, the gut, and adipose tissue can also impact liver function. Accumulating evidence suggests bidirectional communication between the liver and other organs. However, research on how extracellular vesicles (EVs), which transport active molecular mediators, contribute to this interorgan communication is still in its nascent stages. EVs are capable of transporting functional molecules, including lipids, nucleic acids, and proteins, thereby affecting recipient cells across different organs at the biological level. This review examines the role of EVs in facilitating bidirectional communication between the liver and other organs such as bone, the cardiovascular system, the gut, the pancreas, the brain, the lungs, the kidneys, and adipose tissue. It explores their potential in disease treatment and highlights the challenges in understanding EV-mediated interorgan interactions. The contribution of mediator-carrying EVs to two-way communication between the liver and other organs remains an area of ongoing investigation. Future research will provide a more comprehensive theoretical foundation to clarify the precise mechanisms governing communication between the liver and other organs, pinpoint medical targets, and expand the application of EVs within the realm of precision medicine.

Graphical Abstract

Introduction

Through the secretion of substances including hormones, cytokines, and extracellular vesicles (EVs), inter-organs often create a complex regulatory network that maintains physiological homeostasis and enhances adaptability to disease [1]. Increasing attention has been drawn to the growing body of evidence indicating that EVs play a critical function in the interorgan communication network [2, 3]. EVs are highly heterogeneous lipid bilayer vesicles derived from the plasma membrane, which encapsulate cargo including lipids, nucleic acids, and proteins. They transmit signals from donor cells to recipient cells, thereby influencing the function and state of distant organs [4].

As the largest solid organ, the liver is essential for maintaining homeostasis since it is involved in many physiological functions, such as immunological control, synthesis of proteins, metabolism, and detoxifying [5]. Moreover, the liver sustains systemic homeostasis through bidirectional communication with other organs. For example, Akkermansia muciniphila and its EVs have been shown to mitigate liver injury [6, 7], while liver-derived EVs can interact with adipose tissue [8] and the pancreas [9] to regulate glucose homeostasis. Conversely, under pathological conditions, EVs secreted by ischemia-reperfused kidneys can cause liver injury [10],and EVs originating from fatty liver can drive the progression of atherosclerosis [11, 12]. Therefore, exploring EV-mediated communication between the liver and other organs is essential for a deeper understanding of organismal health and disease.

The function of EVs in facilitating communication between the liver and the bone, cardiovascular system, gut, pancreas, brain, lungs, kidneys, and adipose tissue is the main emphasis of this review, which also provides perspectives on the therapeutic potential of EVs for extrahepatic and liver-related disorders. Furthermore, a brief discussion is given of the difficulties and restrictions related to EVs in interorgan communication. It is essential to comprehend these intricate relationships in order to guide future research paths as well as to uncover possible treatment methods for systemic and liver-related disorders.

Biological characteristics of EVs

Overview of EVs

In both healthy and pathological processes, EVs—lipid bilayer-enclosed vesicles—are produced by cells of various types and function as messengers to mediate and control intercellular communication [13]. The International Society for Extracellular Vesicles characterizes EVs as particles secreted by cells, enveloped in a lipid bilayer, and devoid of functional nuclei [14]. Based on the origin, EVs are often divided into three types: exosomes, microvesicles, and apoptotic bodies [15]. After fusing with the plasma membrane, intraluminal vesicles (ILVs) stored in multivesicular bodies (MVBs) within cells release to produce exosomes, which are around 40 to 160 nm in size [16]. Direct secretion of microvesicles (50–1000 nm) occurs when the plasma membrane buds outward [13]. Usually ranging from 1 to 5 μm in size, apoptotic bodies are created during programmed cell death [17]. EVs contribute to numerous biological processes. Acting as natural carriers of antigens, EVs are involved in antigen presentation and immune response regulation [18]. They also promote cell proliferation [19, 20], induce the differentiation of neural stem progenitor cells [21], and facilitate neurogenesis and neurite remodeling [22]. Moreover, EVs are crucial for the processes of cell motility [23, 24] and cellular reprogramming [25, 26].

Biology of EVs

Various types of cells release exosomes. The formation of early sorting endosomes (ESEs) begins with the inward budding of the plasma membrane. Later, these ESEs develop into late sorting endosomes, which in turn produce MVBs that contain ILVs [16]. The generation of ILVs is mediated by the endosomal sorting complex required for transport (ESCRT), which consists of four distinct protein complexes: ESCRT-0 through ESCRT-III [27]. ESCRT-0 identifies ubiquitinated proteins through its subunits, hepatocyte growth factor-regulated tyrosine kinase substrate and signal transducing adaptor molecule 1/2 [28, 29]. The sorting domain that ESCRT-0, ESCRT-I, and ESCRT-II create has a high affinity for ubiquitinated cargo [30]. The protein complex ESCRT-III, on the other hand, promotes budding processes [27] and facilitates the formation of ILVs through membrane scission [31]. Finally, the class I AAA ATPase Vps4 supplies the energy required for the ESCRT-III complex to dissociate from the MVB membrane [29]. In addition to being produced via the ESCRT-dependent pathway, exosomes can also be produced via an ESCRT-independent pathway. This alternative pathway may involve raft-like microdomains enriched in sphingomyelin within the endosomal membrane, where ceramide is generated by the hydrolytic removal of phosphocholine moiety [32]. The conical shape of ceramide is believed to cause the endosomal membrane to spontaneously curve negatively, which facilitates domain-induced budding [27]. Moreover, a pathway that is not dependent on ceramide or ESCRT complexes can induce melanogenesis through the tetraspanin family protein CD63 [33]. Ultimately, MVBs can either merge with the plasma membrane to release ILVs, which turn into exosomes, or they can fuse with lysosomes for destruction [16].

Microvesicles (MVs), in contrast to exosomes, are created by molecular rearrangements brought on by changes in the composition of protein and lipid in the plasma membrane, which results in membrane budding [34]. Changes in Ca²⁺ levels recruit and activate calcium-dependent enzymes, altering the lipid composition of the plasma membrane and inducing asymmetric phospholipid rearrangement [35], which leads to the externalization of phosphatidylserine [36]. Plasma membrane lipids are key to MV formation. The depletion of cholesterol can significantly reduce MV production [37]. The conical structure of ceramide also promotes membrane curvature, thereby regulating MV formation [38]. Additionally, actin dynamics are essential in MV formation [34]. Members of the small GTPase family, including RhoA and its downstream targets Rho-associated protein kinase (ROCK) and LIM domain kinase (LIMK), regulate actin cytoskeletal remodeling during MV formation [39]. ADP-ribosylation factor 6, a member of the ARF family that belongs to the Ras superfamily of small GTPases, also regulates actin dynamics [40]. Its downstream effectors, extracellular signal-regulated kinase (ERK) and myosin light chain kinase, are essential for regulating actin polymerization and myosin activity, thus playing significant roles in MV release [41]. Additionally, the core ESCRT component, tumor susceptibility gene 101 (TSG101), interacts with arrestin domain-containing protein 1 to facilitate MV release [42].

Apoptosis is characterized by the development of apoptotic bodies [43]. The first step in apoptosis is chromatin condensation in the nucleus, which is followed by membrane blebbing. Eventually, the cellular contents are fragmented and enclosed within independent membrane-bound vesicles, forming characteristic apoptotic bodies [44]. Apoptosis is usually accompanied by the externalization of phosphatidylserine, which acts as an “eat me” signal to aid phagocyte detection and absorption [45]. Additionally, calreticulin, another “eat me” ligand, is expressed on apoptotic cells when the “don’t eat me” signal CD47 is downregulated [46]. Actin and myosin play roles in membrane blebbing [47], which is regulated by many kinases, including the ROCK1 and LIMK1 [48]. ROCK1 is an important modulator of membrane blebbing during apoptosis [49]. Caspase-3 cleaves ROCK1, removing its inhibitory C-terminal domain to generate an active fragment that induces myosin light chain phosphorylation, leading to membrane blebbing [50]. LIMK1 supports apoptotic membrane blebbing by phosphorylating cofilin and promoting actin polymerization [51, 52]. Additionally linked to membrane blebbing, the apoptotic volume reduction (AVD) is essential for the production of apoptotic bodies [53]. Early AVD typically occurs within 0.5 to 2 h of apoptosis induction and is unrelated to mitochondrial dysfunction or initial caspase activation [54]. After membrane blebbing, apoptotic membrane protrusions form [55]. According to research, pannexin 1 (PANX1) is a crucial negative regulator of T cell and thymocyte apoptopodia production. PANX1 suppression encourages the development of apoptopodia and apoptotic bodies [56]. The “find me” signal is released into the extracellular space when the PANX1 C-terminus is cleaved by caspase, which attracts phagocytes and promotes apoptosis [57]. Finally, nuclear fragments condense and compact into half-moon shapes, resulting in apoptotic bodies that are subsequently engulfed by macrophages [58].(Table 1).

Table 1 Characteristics of EV subtypes

When EVs are released, they can be internalized by the recipient cells through several types of endocytosis, including phagocytosis, macropinocytosis, clathrin-mediated endocytosis, caveolin-dependent pathways, and lipid raft-mediated endocytosis. Direct fusing of the EV membrane with the plasma membrane is an additional potential entry pathway [62]. They can also trigger intracellular signaling in target cells via direct receptor‒ligand interactions [15]. EVs may either fuse with preexisting ESEs or be broken down in lysosomes after being internalized by recipient cells, releasing their cargo into the cytoplasm [16] (Fig. 1).

Fig. 1

Classification, biogenesis, and uptake of EVs. EVs exist in several forms, including exosomes, microvesicles, and apoptotic bodies. Early endosomes generated through endocytosis can mature into late endosomes and ultimately form MVBs containing multiple ILVs, which serve as precursors to exosomes. Exosomes are released when MVBs fuse with the plasma membrane. Apoptotic bodies are produced by the outward budding of apoptotic cell membranes, while microvesicles are directly released via the outward budding of the plasma membrane. A wide range of cargo, such as proteins, lipids, and nucleic acids, can be transported by EVs. EVs can be internalized by the target cells through mechanisms such as membrane fusion, phagocytosis, macropinocytosis, and direct binding. Abbreviation: ER: endoplasmic reticulum

It is important to note that the classification and definition of EVs based on biogenesis pathways are not entirely accurate. The biogenesis of EVs can be influenced by various factors, while current isolation techniques lack the specificity to enrich EVs generated by different mechanisms. Additionally, there are no universal markers for distinguishing subtypes of EVs, leading to uncertainty in accurately categorizing isolated EVs into specific biogenesis pathways. Therefore, caution should be exercised when using terms based on biogenesis pathways [14]. In light of this, we will consistently use the generic term “EV” in subsequent descriptions to avoid confusion.

Bidirectional communication of EVs in the liver and other organs

Interorgan communication depends on the exchange of information between cells across different organs [1]. EVs released into the circulatory system mediate crosstalk between organs by facilitating cell-cell interactions through the delivery of cargo [63]. The liver, characterized by its complex and diverse hemodynamic properties [64], secretes EVs from hepatocytes that are transported via the bloodstream to various distant organs or tissues, where they exert their biological effects. Conversely, other organs transmit their physiological or pathological information to the liver in the form of EVs through systemic circulation [63]. Cellular environmental conditions, such as temperature, pH, and oxidative/hypoxic states, influence EV-cell interactions to varying degrees. Additionally, the composition of the EV membrane, including proteins, lipids, and glycans, affects the binding of EVs to target cells [15]. Moreover, the cargo carried by EVs is influenced by the type of donor cell, metabolic state, and disease context [65]. Overall, EVs serve as key mediators of intercellular communication, playing an indispensable role in facilitating information transfer between the liver and other organs. By carrying diverse substances, EVs finely regulate physiological processes and pathological progression [63]. A comprehensive understanding of the effects of specific substances carried by EVs from different sources has the potential to offer novel insights for diagnosing and treating a wide range of diseases, with significant implications for clinical practice and research.(Fig. 2).

Fig. 2

Liver‒organ axis: bidirectional crosstalk. EVs carry different cargo that facilitate communication between the liver and other organs, which are essential for the physiological or pathological state of the organism. Abbreviation: LRG1: leucine-rich alpha-2-glycoprotein 1; HSP70: heat shock protein 70; Fasn: fatty acid synthase; HMGB1: high-mobility group box protein 1; ApoE4: apolipoprotein E4

Liver and bone

The anatomical separation between the liver and bone prohibits the direct interaction. Instead, the liver influences bone metabolism by secreting proteins, enzymes, and cytokines, whereas bone secretes osteokines that regulate liver metabolism. The liver‒bone axis maintains homeostasis through hepatokines, osteokines, and biochemical signaling [66].

In recent years, there has been a growing focus on the role of EVs in liver-bone communication [67,68,69,70,71]. Maintaining liver‒bone axis homeostasis is crucial for understanding osteoporosis progression [66]. Leucine-rich α-2-glycoprotein 1 (LRG1)-enriched small extracellular vesicles (sEVs) from SIRT2-deficient hepatocytes can prevent osteoclast differentiation by lowering the nuclear translocation of nuclear factor κB (NF-κB) p65. Additionally, a positive association has been observed between the plasma level of sEV-LRG1 and bone mineral density. These results indicate the potential therapeutic value of LRG1-containing sEVs in osteoporosis treatment [67]. Moreover, EVs from patients’ liver tissue with type 2 diabetes can carry fatty acid synthase (Fasn) to periodontal inflammation sites, which causes ectopic fatty acid synthesis in periodontal ligament cells (PDLCs), activating the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and the cleavage of gasdermin D (GSDMD). The activation of pyroptosis in PDLCs, driven by these factors, contributes to bone loss observed in individuals with diabetes [68]. In addition, it has been demonstrated that EVs produced from liver tissue increase osteogenic gene expression in mandibular mesenchymal stem cells, which improves the repair of mandibular defects [69].

EVs originating in the bone can also affect liver function. The balance between Tregs and Th17 cells is also modulated by the EVs generated by bone marrow-derived dendritic cells, which transport heat shock protein 70 (HSP70) to naïve T cells. This stimulates the PI3K/mTOR axis, favoring regulatory T-cell (Treg) maturation and suppressing T helper 17 cell (Th17) differentiation. The results of the study showed that hepatic ischemia-reperfusion (I/R)-injured (HIRI) mice injected with these EVs had higher amounts of anti-inflammatory factors and lower levels of inflammatory factors, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in their blood, which attenuated liver injury [70]. Notably, EVs derived from human periodontal ligament fibroblasts promote hepatic lipogenesis by increasing SCD-1 expression and inhibiting the AMPK pathway, suggesting that managing periodontal disease could help prevent fatty liver [71].

In conclusion, EVs have a significant impact on bone health and contribute to the etiology of liver illnesses, which regulate liver-bone axis homeostasis. Research on exploring the operational mechanisms of EVs along the complex axis should be conducted in the future.

Liver and cardiovascular system

The liver and cardiovascular system have a complex relationship [72]. Emerging evidence underscores the role of liver-secreted EVs in modulating cardiovascular health [73].

EVs derived from fatty hepatocytes deliver miR-1, which inhibits Kruppel-like factor 4 (KLF4) and activates NF-κB, promoting endothelial inflammation and thus contributing to atherosclerosis [11]. Another study revealed that sEVs from fatty hepatocytes inhibit ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux via miR-30a-3p, promoting foam cell formation and accelerating atherosclerosis [12]. Furthermore, lysosome-associated membrane protein 1 (LAMP1) is specifically targeted by novel-miR-7 in liver-derived EVs from non-alcoholic fatty liver disease(NAFLD) patients, which increases lysosomal permeability and aids in cathepsin B leakage. These lead to NLRP3 inflammasome activation, which causes microvascular endothelial cells to become hyperpermeable [74]. These findings reveal novel mechanisms underlying cardiovascular disease in NAFLD patients, suggesting that inhibiting EVs secreted by fatty liver or targeting their miRNAs could serve as potential therapeutic strategies for atherosclerosis.

ADP-ribosylation factor-like protein 2 (Arl2) is a key regulator of mitochondrial ATP production, and silencing Arl2 reduces mitochondrial activity in cardiomyocytes [75]. One study reported that EVs from the livers of high-fat diet (HFD)-fed mice contain miR-122, which impairs cardiac mitochondrial function by inhibiting Arl2, promoting the development of obesity-related cardiomyopathy. In both primary cardiomyocytes and obese mouse models, blocking liver-derived miR-122 has been demonstrated to enhance cardiac remodeling and metabolic profiles, suggesting that miR-122 and Arl2 are potential therapeutic targets for obesity-related cardiomyopathy [76].

Physical exercise is well-established as a preventive and therapeutic intervention for multiple diseases [77]. Exercise has been shown to increase levels of miR-122-5p in the bloodstream, which is transported by liver-derived EVs. These EVs enhance fatty acid oxidation in endothelial cells by downregulating 1-acyl-sn-glycerol-3-phosphate acyltransferase(AGPAT1), leading to increased capillary density in perilesional skin tissue and promoting wound healing. This highlights a mechanism by which exercise improves cardiovascular health [78].

Although EVs produced by the liver exhibit important functions in the cardiovascular system, relatively little is known about how cardiovascular-derived EVs influence liver function. Therefore, further investigation is warranted to thoroughly elucidate the bidirectional roles of EVs within the liver-cardiovascular system axis.

Liver and gut

The gut and liver are connected by the portal vein system, and the maintenance of general physiological balance depends heavily on the reciprocal communication [79]. The liver’s produced bile acids are crucial signaling molecules that influence the gut microbiota’s makeup and preserve intestinal integrity to regulate liver metabolism while liver functions are regulated by the gut microbiota, its metabolites, and gut hormones [80].

Growing interest has been shown in the function of gut-derived EVs in the gut-liver axis [81]. Akkermansia muciniphila and its EVs can inhibit hepatic stellate cells(HSCs) activation and suppress fibrosis marker gene expression [6]. These EVs also exhibit anti-inflammatory effects by inhibiting Toll-like receptor (TLR) expression and upregulating peroxisome proliferator-activated receptor (PPAR) expression [7], thereby preventing HFD/CCL4-induced liver injury.

However, under pathological conditions, gut-derived EVs may exert adverse effects on the liver. EVs derived from the gut of mice subjected to intestinal I/R promote Kupffer cell polarization toward the M1 phenotype and increase proinflammatory cytokine expression, thereby inducing liver injury following intestinal I/R [82]. Additionally, a study revealed that gut microbial DNA-containing EVs from obese hosts impair insulin sensitivity and activate the cGAS/STING pathway in hepatocytes, enhancing inflammatory reactions [83]. It has also been demonstrated that fecal-derived EVs from nonalcoholic steatohepatitis(NASH) patients activate HSCs and disrupt hepatocyte integrity, exacerbating liver damage [84]. Furthermore, diet-induced obese (DIO) mice’s portal venous blood was discovered to include higher levels of bacterial-derived EVs, which accumulated in the liver and may have a role in promoting liver inflammation through TLR4-mediated signaling [85]. High-mobility group box protein 1 (HMGB1) is expressed in HFD-induced NAFLD models [86]. Research indicates that the upregulation and release of HMGB1 are linked to hepatic steatosis and that EVs produced from the dysbiotic gut microbiota of HFD-fed mice carry HMGB1 from the gut to the liver, contributing to the development of hepatic steatosis [87]. Understanding the communication between the liver and gut through EVs provides novel insights into disease risk prediction and potential therapy strategies (Fig. 3).

Fig. 3

Overview of the communication network between the liver, bone, cardiovascular system, and gut mediated by EVs. (a) Within the liver-bone axis, EVs carry different substances to maintain bone health and influence hepatic metabolism. (b) The liver-cardiovascular axis focuses on revealing the effects of liver-derived EVs on the vascular endothelium and the heart, ranging from atherosclerosis and neovascularisation to cardiomyopathy. (c) The liver-gut axis unravels the role that gut microbiota-derived EVs play in the regulation of hepatic injury. Each axis represents a distinct spectrum of organ-liver interactions and provides a thorough understanding of the liver’s pivotal function in systemic physiology and pathology. Abbreviation: SIRT2: sirtuin 2; NF-κB: nuclear factor κB; LRG1: leucine-rich alpha-2-glycoprotein 1; HSP70: heat shock protein 70; HIRI: hepatic ischemia‒reperfusion injury; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; PDLCs: periodontal ligament cells; Fasn: fatty acid synthase; SCD-1: stearoyl-CoA desaturase 1; AMPK: adenosine monophosphate (AMP)-activated protein kinase; KLF4: kruppel-like factor 4; ABCA1: ATP-binding cassette transporter A1; LAMP1: lysosomal-associated membrane protein 1; NLRP3: NOD-like receptor pyrin domain-containing protein 3; AGPAT1: 1-acyl-sn-glycerol-3-phosphate acyltransferase; Arl2: ADP-ribosylation factor-like protein 2; TLR: toll-like receptor; PPAR: peroxisome proliferator-activated receptor; HSC: hepatic stellate cell; HFD: high-fat diet; cGAS: cyclic GMP–AMP synthase; STING: stimulator of interferon genes; NASH: nonalcoholic steatohepatitis; DIO: diet-induced obese; HMGB1: high-mobility group box protein 1

Liver and pancreas

The liver and pancreas are integral to the body’s energy metabolism, together forming a crucial regulatory network for maintaining energy balance. In addition to secreting insulin, which is essential for glucose homeostasis, pancreatic β-cells also release EVs to communicate with other organs, fulfilling their biological functions [88].

EVs from pancreatic β-cells deliver members of the miR-29 family (miR-29s), which have been shown to enter the liver and decrease insulin-stimulated AKT phosphorylation. The elevated level of miR-29s in the liver indicates that this miRNA primarily acts in the liver, ultimately inducing systemic insulin resistance [89].

Pancreatic β-cells can also take up liver-derived EVs. Under insulin-resistant conditions, liver-derived EVs increase the expression of insulin-related genes in pancreatic β-cells and increase the phosphorylation of the AKT downstream target FoxO1. These results point to elevated AKT phosphorylation, suggesting that some factors governing glucose homeostasis may be present in liver-derived EVs [9].

However, EVs produced from the liver may potentially negatively impact the pancreas. For example, miR-126a-3p is upregulated in EVs from fatty hepatocytes, and overexpression of miR-126a-3p may exacerbate the diabetic process by promoting β-cell apoptosis through inhibition of insulin receptor substrate-2 (IRS2) expression [90]. Insulin resistance is strongly linked to NAFLD, and the liver and pancreas play a crucial role in maintaining metabolic balance. Clarifying these illnesses and improving preventative and treatment methods require a better grasp of the dynamic interactions between these two organs [91].

Liver and brain

Complex communication exists between the liver and the brain through various hormones, hepatokines, metabolites, and other substances [92], and the role of EV in the liver-brain axis is gradually being discovered [93,94,95,96].

Hepatic encephalopathy is a serious brain function disorder, frequently observed in patients with acute liver failure or chronic liver disease, and is commonly associated with hyperammonemia [97]. In hyperammonemic mice, elevated levels of tumor necrosis factor-alpha (TNF-α) in plasma EVs reach the cerebellum, where they activate microglia and astrocytes and engage the TNFR1/CCL2/BDNF/TrkB/KCC2 and TNFR1/NF-κB/glutaminase/GAT3 pathways. These increase cerebellar GABAergic neurotransmission and cause motor incoordination [93]. In addition, age-related thyroid deficiency promotes the accumulation of apolipoprotein E4 (ApoE4)-laden EVs from the liver to the brain, leading to neuronal cholesterol accumulation and triggering elevated reactive oxygen species (ROS), which activate the NLRP3 inflammasome and trigger neuronal pyroptosis, ultimately resulting in cognitive, motor, and emotional impairments [94].

Conversely, brain-derived EVs can also impact liver function. In the case of traumatic brain injury, EVs released from the brain induce liver damage, resulting in elevated serum AST and ALT levels, excessive inflammatory exudation, sinusoidal congestion, hepatocyte swelling and degeneration, and disordered cellular structures, ultimately leading to hepatocyte apoptosis [95]. Furthermore, insulin-like growth factor-binding protein 5 (IGFBP5) is downregulated by pituitary-derived sEVs containing miR-143-3p, which therefore increases the production of insulin-like growth factor 1 (IGF-1), ultimately triggers the Wnt/β-catenin pathway to encourage hepatocyte proliferation [96].

In conclusion, the liver and brain exhibit a variety of complex interactions in both healthy and diseased states, encompassing metabolism, neuronal control, and disease initiation. A deeper understanding of the mechanisms underlying liver-brain interactions will enhance our comprehensive view of physiological processes and pathological alterations. This knowledge will also provide new insights and potential therapeutic targets for the identification, management, and prevention of associated diseases.

Liver and lungs

The pathological manifestations of hepatopulmonary syndrome (HPS) underscore the intimate connection between the liver and lungs [98]. The most markedly elevated miRNA in a mouse model of HPS was found to be miR-194. Hepatocyte-derived EVs transport miR-194 to pulmonary microvascular endothelial cells (PMVECs), where it directly suppresses the expression of THBS1, STAT1, and LIF. This suppression may enhance PMVEC migration, proliferation, and angiogenesis, thereby exacerbating the progression of HPS [99]. By lowering p65 expression, suppressor of cytokine signaling 1 (SOCS-1) is known to limit NF-κB activation [100]. According to prior research, HIRI-derived EVs deliver miR-122-5p to alveolar macrophages, where it targets and inhibits SOCS-1. This activates the NF-κB signaling pathway, which in turn promotes inflammation and M1 macrophage polarization, eventually resulting in acute lung injury [101]. Furthermore, a rise in the quantity of EVs in circulation during acute pancreatitis, mostly from the liver, dramatically raises the expression of proinflammatory proteins, causing pulmonary inflammation and a contributing cause to the lung inflammation linked to acute pancreatitis [102]. The bidirectional connection between the liver and lungs is still a relatively new area of study. Future research is necessary to comprehensively elucidate the physiological and pathological mechanisms underlying the critical role of EVs in the lung-liver axis.

Liver and kidneys

The precise communication pathways between the liver and kidneys are still not fully understood, even under normal physiological conditions. In disease states, such as hepatorenal syndrome, a fatal complication arising from acute liver failure (ALF), cirrhosis, and other severe liver conditions, rapid renal failure can occur, posing a significant threat to life [103]. Additionally, liver diseases like viral hepatitis and autoimmune hepatitis (AIH) can lead to kidney injury [104], indicating a close interaction between these two organs. EVs carrying miR-687 are secreted by ischemic renal cells during renal I/R and are deposited in the liver, which leads to elevated ALT and AST values, along with increased caspase-3 and inflammatory markers such as vascular cell adhesion molecule-1, myeloperoxidase, monocyte chemotactic protein-1 (MCP-1), and NF-κB in liver tissue. These changes, which are associated with liver inflammation and apoptosis, may contribute to distal liver injury following acute renal I/R [10]. Currently, a comprehensive understanding of the detailed communication network between the liver and kidneys requires substantial in-depth research that fully elucidates the complex interplay between the organs (Fig. 4).

Fig. 4

Overview of the communication network between the liver, brain, lungs, and kidneys mediated by EVs. (a) The liver-pancreas axis mainly reflects the effects of EVs on insulin function, which is essential for regulating energy metabolism. (b) The liver-brain/pituitary axis reveals that EVs carrying different substances shuttle between the liver and brain/pituitary, supporting motor and cognitive functions as well as liver health. (c) The liver-lung axis reveals the pathological effects of liver-derived EVs on the lungs, contributing to the understanding of lung disease progression. (d) The liver-kidney axis research focuses on the impact of kidney disease on hepatic function, and this axis of interaction has yet to be studied in depth. Overall, these axes reflect the impact of interactions between the liver and other organs on physiological or disease states. They are important in maintaining overall homeostasis. Abbreviation: AKT: protein kinase B; TNFR1: tumor necrosis factor receptor-1; CCL2: C-C motif chemokine 2; BDNF: brain-derived neurotrophic factor; TrkB: tropomyosin-related kinase B; KCC2: K-Cl cotransporter 2; GAT3: GABA transporter type 3; ApoE4: apolipoprotein E 4; sEVs: small extracellular vesicles; Wnt: wingless-related integration site; HPS: hepatopulmonary syndrome; PMVEC: pulmonary microvascular endothelial cell

Liver and adipose tissue

As a complex and extremely dynamic component of the organism, adipose tissue plays a critical role in physiological functions like insulin sensitivity, energy balance, and metabolism [105]. Recent studies show that EVs are crucial for the adipose tissue-liver axis, which together controls the balance of energy metabolism [79].

Brown adipose tissue (BAT) is of great importance in gluconeogenesis. During cold exposure, activated BAT secretes EVs containing miR-378a-3p, which reduces the protein level of p110α, a key regulator of glucose metabolism, thereby diminishing insulin-induced AKT phosphorylation, increasing hepatic gluconeogenic gene expression, and regulating gluconeogenesis [106]. Furthermore, EV miR-132-3p produced from BAT suppresses the expression of hepatic Srebf1 and lowers the expression of lipogenic genes that control hepatic lipogenesis during cold adaptation [107]. These findings demonstrate the endocrine function of BAT in mitigating cold stress.

Adipose tissue is essential for energy homeostasis. For example, miR-141-3p reduces the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN), enhancing AKT phosphorylation and insulin signaling. However, miR-141-3p of EVs is secreted at lower levels from adipose tissue in obese individuals than in healthy individuals. Consequently, when hepatocytes take up EVs with low miR-141-3p levels, insulin sensitivity and glucose uptake capacity are significantly impaired [108]. Moreover, compared with those in obese individuals with a normal intrahepatic triglyceride content, EVs derived from subcutaneous abdominal adipose tissue in obese individuals with NAFLD downregulate AKT phosphorylation in hepatocytes, leading to impaired insulin signaling and insulin resistance [109]. miR-155 affects adipocyte metabolism by inhibiting PPARγ [110]. Adipose tissue macrophages (ATMs) secrete EVs (ATM-EVs) loaded with miR-155, and in obese mice, the miR-155 content in ATM-EVs is increased, which reduces PPARγ expression and contributes to insulin resistance [111]. Additionally, under HFD conditions, AMPK activity in white adipose tissue (WAT) decreases, leading to increased TSG101 expression [112]. An essential part of the ESCRT pathway, TSG101, is involved in the biogenesis of MVBs [113]. TSG101 facilitates CD36 sorting into WAT-derived EVs, which exacerbate NAFLD by causing lipid buildup and inflammation following hepatocyte endocytosis [112]. Besides, adipocyte-derived EVs deliver miR-122, which targets Sirt1 and suppresses its expression, thus increasing blood lipid levels, causing hepatocyte injury, and accelerating the progression of NAFLD [114]. Moreover, EVs derived from adipose tissue carry miR-103, which interacts with PTEN to inhibit hepatocyte autophagy, exacerbating liver injury, thereby promoting the development of NASH [115].

Notably, EVs released from ex vivo human subcutaneous and omental adipose tissue explants contain varying levels of MCP-1, interleukin-6, and macrophage migration inhibitory factor, which correlate with inconsistencies in AKT phosphorylation levels in hepatocytes, indicating that the impact of adipose-derived EVs on insulin signaling depends on their adipokine content [116]. The duration of HFD exposure may also influence the role of EVs. According to a study, hepatocytes are unaffected by adipose tissue-derived EVs from HFD-fed mice after 4 weeks, but lipid synthesis, insulin resistance, inflammation, and ER stress are shown after 8 and 12 weeks, indicating that the severity of obesity affects the impact of EVs on hepatocytes [117].

Liver-derived EVs can also regulate energy metabolism in adipose tissue. Evidence shows that liver-derived EV-encapsulated miR-130a-3p can activate the AKT-AS160-GLUT4 signaling pathway in adipocytes through the inhibition of PHLPP2, thereby increasing glucose uptake and improving glucose intolerance [8]. In early-onset obese mice, hepatocyte-derived EVs enriched with miR-3075 downregulate fatty acid 2-hydroxylase (FA2H) expression, increasing insulin-stimulated AKT phosphorylation and improving insulin sensitivity and glucose uptake in adipocytes. In individuals with chronic obesity, however, this compensatory effect is lost [118]. Furthermore, transmembrane 4 L six family member 5 (TM4SF5) can bind to glucose transporter 1 to promote glucose uptake and glycolysis, and liver-derived sEVs containing TM4SF5 can target BAT for homeostatic glucose clearance [119].

In addition to regulating glucose homeostasis, liver-derived EVs may also have pathological effects on adipose tissue. Under conditions of lipid overload, the expression of geranylgeranyl diphosphate synthase in the liver is upregulated, modulating the secretion of miRNAs-containing hepatic EVs to promote lipid accumulation in adipocytes [120]. High-energy diet-induced obesity increases the triglyceride content in liver-derived EVs, promoting lipid accumulation and inflammatory gene expression in adipocytes, thereby exacerbating lipogenesis and adipocyte inflammation [121]. Numerous studies have demonstrated that EVs play significant roles in the adipose tissue-liver axis and are profoundly involved in the regulation of both the physiological and pathological states of the liver and adipose tissue (Fig. 5).

Fig. 5

Overview of the communication network between the liver and adipose tissue mediated by EVs.Adipose tissue secretes EVs that have an impact on insulin function, liver disorders, and cold acclimatization. EVs produced from the liver, in turn, have a role in controlling adipose tissue remodeling and glucose homeostasis. The relationship between EVs and metabolic balance as well as liver disorders is shown in the liver-adipose axis. Abbreviation: Srebf1: sterol regulatory element binding transcription factor 1; PTEN: phosphatase and tensin homolog deleted on chromosome 10; ATM: adipose tissue macrophage; PPARγ: peroxisome proliferator-activated receptor gamma; Sirt1: silent information regulator 1; NAFLD: nonalcoholic fatty liver disease; PHLPP2; PH domain and leucine rich repeat protein phosphatase 2; AS160: Akt substrate of 160 kDa; GLUT4: glucose transporter 4; TM4SF5: transmembrane 4 L six family member 5

Potential of EVs in disease treatment

EVs have garnered significant attention in therapeutic applications because of the favorable properties, such as stability, biocompatibility, and low immunogenicity [122]. Because of these qualities, EVs are attractive options for medication delivery systems [17]. Among the diverse types of EVs, those derived from mesenchymal stem cells (MSCs) have demonstrated significant potential in the treatment of a wide array of diseases [123]. Furthermore, potential strategies for EV-based therapies include targeting EV cargo for drug development, regulating EV secretion, and modifying their cargo and functions.

MSC-derived EVs

MSCs have demonstrated significant promise for tissue regeneration and repair, which are widely used in cell therapy. However, the limitations, such as therapeutic risks, reduced viability when stored at low temperatures, and high processing costs, have led researchers to focus on MSC-derived paracrine products, such as EVs [124]. MSC-derived EVs serve as a noninvasive, nontoxic, and low-immunogenic alternative for treating liver diseases [123]. Previously, we have found that MSC-EVs induced metabolic reprogramming of CD4⁺ T cells by transferring mitochondrial components, thereby reducing T-cell overactivation and hepatic inflammatory injury, offering new ideas for the treatment of AIH [125]. Next, we will focus on the use of bone marrow mesenchymal stem cell-derived EVs (BMSC-EVs) and adipose mesenchymal stem cell-derived EVs (ADSC-EVs) in liver disease therapy.

BMSC- EVs

Liver fibrosis, a common complication of liver disease, has been a key target for novel therapies. BMSC-EVs enriched with miR-148a-5p have been shown to significantly alleviate liver fibrosis by inhibiting Smad4, resulting in downregulation of the mRNA and protein levels of transforming growth factor β(TGF-β)1, tissue inhibitor of metalloproteinase-1, collagen I, and α-smooth muscle actin [126]. In addition, BMSC-EVs mitigate fibrosis by preventing hepatocyte pyroptosis and promoting hepatocyte proliferation [127]. Notably, BMSC-EVs also suppress the Wnt/β-catenin signaling pathway, which lowers inflammatory cytokine levels in liver fibrosis models and prevents HSC activation, resulting in antifibrotic effects [128]. Furthermore, BMSC-EVs carrying miR-192-5p can inhibit PPP2R3A expression, which effectively prevents HSC activation and fibrosis progression [129].

In addition to the antifibrotic effects, BMSC-EVs have demonstrated therapeutic efficacy in various liver diseases. In ALF, BMSC-EVs reduce hepatocyte apoptosis by activating autophagy, decreasing the proapoptotic protein Bax, and increasing the antiapoptotic protein Bcl-2 [130]. BMSC-EVs carrying miR-136-5p alleviate chronic liver damage by promoting M2 macrophage polarization via the suppression of the GNAS-mediated PI3K/ERK/STAT3 axis [131]. Additionally, BMSC-EVs that include miR-146a-5p can activate intrinsic hepatocytic progenitor cells (HPCs) to aid in liver regeneration [132]. In AIH, BMSC-EVs containing miR-223 reduce NLRP3 and caspase-1 expression, decrease serum inflammatory cytokine levels, and ultimately ameliorate liver injury [133]. BMSC-EVs enriched with miR-25-3p inhibit PTEN expression, reduce p53 and cleaved caspase-3 levels, and lower serum ALT and AST levels, ultimately reducing apoptosis and alleviating HIRI [134].

In summary, BMSC-EVs exhibit multifunctional therapeutic potential for liver diseases, including alleviating fibrosis, improving chronic liver injury, promoting liver regeneration, and treating AIH. These findings provide new perspectives and possibilities for clinical practice.

ADSC-EVs

ADSC-EVs also exhibit promising potential in treating liver diseases. Research has demonstrated that ADSC-EVs can alleviate the process of hepatic fibrosis by inhibiting the PI3K/AKT/mTOR signaling pathway, decreasing the expression of fibrosis-related genes, and regulating choline metabolism [135]. Moreover, ADSC-EVs carrying miR-20a-5p downregulate transforming growth factor beta receptor 2 expression and suppress p38MAPK/NF‒κB pathway activation, significantly reducing fibrosis markers and effectively controlling fibrosis progression. It leads to a significant reduction in fibrosis markers and effectively curbs the progression of fibrosis [136]. Notably, fibrotic tissues are characterized by decreased miR-150-5p and elevated CXC chemokine ligand-1 (CXCL1) levels. ADSC-EVs enriched with miR-150-5p can effectively inhibit CXCL1 expression, reduce TGF-β-induced HSC activation, and ultimately alleviate fibrosis [137].

ADSC-EVs also exhibit remarkable potential in alleviating HIRI. The mechanism of action involves multiple regulatory factors, including the stimulation of the Wnt/β-catenin pathway to promote hepatocyte proliferation and inhibition of the NF-κB pathway to reduce inflammation, thus alleviating HIRI-induced liver injury [138]. ADSC-EVs can also reduce hepatic endoplasmic reticulum stress (ERS) and alleviate histopathological damage and ultrastructural alterations in the ER by downregulating ERS-related factors [139]. Additionally, ADSC-EVs significantly increase the expression of the mitochondrial fusion proteins, promoting mitochondrial function recovery, increasing ATP content, and improving the hepatocyte mitochondrial ultrastructure [140]. ADSC-EVs can provide protection against HIRI-induced apoptosis by reducing caspase activity and regulating apoptosis-related factors [141], which may be a promising approach for HIRI treatment.

In addition, ADSC-EVs enriched with miR-223-3p inhibited E2F transcription factor 1 expression and reduced lipid buildup and fibrosis to delay the advancement of NAFLD [142]. Research has demonstrated that ADSC-EVs is a novel therapy for fibrosis with marked effects by signaling pathway regulation, gene expression modulation, and inflammation suppression. Moreover, ADSC-EVs show significant therapeutic efficacy in HIRI and hold some potential for treating other liver diseases, such as NAFLD, which may be new strategies for clinical applications (Fig. 6).

Fig. 6

Therapeutic effects of MSC-EVs on liver diseases. MSC-EVs carry a variety of bioactive molecules that target different molecular mechanisms to mitigate liver injury by inhibiting fibrosis, inflammatory responses, oxidative stress, and other pathological changes in the liver. Abbreviation: Smad4: smad family member 4; PPP2R3A: protein phosphatase 2 regulatory subunit B’’alpha; GNAS: guanine nucleotide-binding protein, alpha stimulating; ERK: extracellular regulated protein kinases; STAT3: signal transducer and activator of transcription 3; VCAM-1: vascular cell adhesion molecule-1; CXCL1: CXC chemokine ligand-1; TGFBR2: transforming growth factor beta receptor 2; p38MAPK: p38 mitogen-activated protein kinase; E2F1:E2F transcription factor 1; ALF: acute liver failure; CLD: chronic liver damage; HIRI: hepatic ischemia‒reperfusion injury; AIH: autoimmune hepatitis; NAFLD: nonalcoholic fatty liver disease; HPCs: hepatocytic progenitor cells

Development of targeted drugs against EVs

EVs are intriguing therapeutic targets for disease intervention in addition to being essential for interorgan communication. For example, infliximab targets TNF-α-enriched EVs derived from hyperammonemic rats, representing an innovative approach for alleviating neuromotor coordination disorders associated with hepatic encephalopathy [93]. Targeting factors such as LRG1 [67] and Fasn [68], which influence bone metabolism, may be effective therapeutic interventions for bone loss. Antagonists of miR-1 [11] and inhibitors of miR-30a-3p [12] have shown efficacy in preventing the progression of atherosclerosis, whereas inhibitors of novel-miR-7 have significantly improved endothelial barrier integrity [74]. Notably, miR-122 sponge therapy has been demonstrated to enhance cardiac mitochondrial function, paving the way for novel treatments for obesity-related cardiomyopathy [76]. Additionally, applications utilizing miR-122-5p have shown promise in tissue repair [78]. Moreover, miR-155 [111], miR-29s [89], and miR-126a-3p [90] are identified as “harmful factors”, negatively impacting insulin function, whereas the delivery of miR-141-3p [108], miR-130a-3p [8], miR-3075 [118], and TM4SF5 [119] may present novel opportunities for treating obesity or diabetes. Therefore, EVs show promising potential in therapeutic applications for various extrahepatic disorders, including bone metabolism, cardiovascular health, and energy metabolism (the remaining detailed targets are illustrated in Figs. 3, 4 and 5 and the corresponding sections). Future research into EV-targeted therapies is still in its nascent stages. The design of antagonist strategies that either load therapeutic agents or inhibit EV-mediated pathological effects on target organs will undoubtedly expand the applications of EVs in precision medicine, bringing new vitality and potential to the field.

Manipulating EV secretion, function, and cargo

Through their diverse and complex functions, EVs released by various cell types in both healthy and pathological settings have a substantial impact on the host. Research on controlling the mechanics of EV release has shown promise [143]. Environmental factors such as pH fluctuations and hypoxia can considerably impact EV formation and release [144]. Additionally, changes in nutrient composition can influence EV biogenesis and functional properties [145]. For example, pretreatment with quercetin has been found to promote miR-136-5p expression in BMSC-EVs, thereby activating the GNAS/PI3K/ERK/STAT3 signaling axis, reducing M1 macrophage polarization, alleviating liver inflammation, and ultimately improving liver function [146]. Similarly, BMSC-EVs triggered by lipopolysaccharide significantly attenuate septic liver injury by inhibiting macrophage STING signaling, which possibly was related to upregulated autophagy-related protein 2 homolog B in BMSC-EVs [147]. Engineered EVs, which are designed to enhance therapeutic outcomes through surface modifications and the loading of endogenous or exogenous substances, have emerged as an innovative strategy for improving treatment efficacy [148]. Current approaches to engineering EVs include cargo loading, surface modification, and genetic engineering [149]. For example, MSCs transduced with lentivirus-mediated hepatocyte growth factor produce EVs that exert hepatoprotective effects by alleviating liver fibrosis and restoring liver function [150]. Additionally, loading quercetin and vitamin A onto ADSC-EVs has been shown to increase their therapeutic efficacy and liver-targeting ability, mitigating the rapid senescence-like response induced by acute liver injury [151].

Park JH outlined the directions and challenges of EVs as nanomedicines, covering the three dimensions of improving the targeting of therapeutic EVs, controlling pathological EVs by inhibiting EV biogenesis in disease-associated cells, removing circulating EVs, and preventing the uptake of EVs by target cells [152]. Whether they focus on the targeting strategies and effectiveness of therapeutic EVs or control them by targeting the biogenesis and action pathways of pathological EVs, the realization of these optimization measures is highly valuable for promoting the applied research of EVs in the field of disease treatment (Fig. 7).

Fig. 7

Therapeutic strategies involving EVs. For EVs, we can design specific drugs or inhibitors to block the signaling of disease-causing molecules or load components with therapeutic effects. Moreover, pretreatment of EV-producing cells can also produce unexpected results. Engineered EVs, which take three main approaches: cargo loading, surface modification, and genetic engineering to improve the targeting and efficacy of EVs, are the new solutions for optimizing therapeutic treatments nowadays. In addition, different environments can regulate the biogenesis and function of EVs, which provides new ideas for enhancing the yield and quality of therapeutic EVs and inhibiting the secretion of pathological EVs. Abbreviations: ATG2B: autophagy-related protein 2 homolog B. LPS: lipopolysaccharide

Challenges and prospects EV-Mediated interorganism communication networks

Nearly all bodily fluids include EVs, which are crucial for facilitating interorgan communication through fluid transfer [63]. However, the EV-mediated complete communication network between the liver and other organs remains unclear. CX3C-chemokine ligand 1 and CX3C-chemokine receptor 1(CX3CR1) are critical for regulating liver inflammation and fibrosis [153]. HAN C et al. found that CX3CR1 monocytes with a classical phenotype moved to the fibrotic liver from the spleen. They worsen liver fibrosis through the release of cytokines and alter the migratory patterns of hepatic endogenous CX3CR1^GFP cells [154]. Furthermore, CD11b⁺CD43^hiLy6C^lo splenic monocytes migrate to the liver and acquire macrophage phenotype, which accelerates fibrosis progression [155]. These findings highlight the close interrelationship between the liver and spleen.

Research has also suggested a link between liver function and ocular health. According to reports, retinitis pigmentosa-induced retinal stress may interfere with the melanosystem or the exit of soluble macromolecules from the retina, resulting in liver oxidative stress [156]. Patients with liver disease often experience abnormal skin conditions, including palmar erythema and spider angiomas [157]. Notably, psoriasis patients have a higher risk of developing NAFLD [158]. Moreover, AIH may be related to alopecia areata, psoriasis, and pyoderma gangrenosum [159]. The relationship between the liver and muscle has received more attention lately. A recent study has demonstrated that the expression of interferon regulatory factor 4 (IRF4) is markedly upregulated in the skeletal muscle of mice with NASH. IRF4 transcriptionally modulates follistatin-like protein 1, which could be a critical factor in the pathophysiology of NASH [160]. On the other hand, liver-derived fibroblast growth factor 21 has been shown to impair muscle regeneration by inhibiting the PI3K/AKT pathway, suggesting a new therapeutic strategy for decompensated cirrhosis-related sarcopenia [161]. In summary, it is worthwhile to investigate whether EVs, as new mediators of interorgan communication, have a significant regulatory function in the connections between the liver and other organs (such as the spleen, eye, skin, and muscle).

The role of EVs in the propagation of disease phenotypes across organ tissues and individuals is also of interest. Intravenous injection of EVs from the serum of patients with Behçet’s syndrome (BS) into healthy mice caused significant inflammatory cell infiltration at the injection site, resulting in a pathological inflammatory response similar to BS symptoms. This experimental evidence strongly underscores the vital role of EVs in the propagation and exacerbation of inflammation [162]. Similarly, healthy human hepatocytes with gut microbial EVs derived from obese hosts enhance inflammatory responses [83]. EVs from individuals with insulin resistance carry phosphotyrosine 1 phosphatase and protein phosphatase 2, which impair insulin signaling in adipose tissue, liver, and systemic tissues after injection into healthy mice [163]. It is fascinating to consider whether EVs could potentially play a critical role in transmitting disease phenotypes across individuals, organs, and tissues in a broader spectrum of diseases and organ interactions.

Current research on EVs mediating interorgan communication remains deficient. Previous research has mostly concentrated on how miRNAs transported by EVs control both physiological and pathological activities in different organs. However, EVs are highly heterogeneous and served as multifunctional messengers that carry various biomolecules [17]. It is worth investigating whether EVs release a wider range of substances, not just limited to miRNAs, that work in concert with target organs to drive and facilitate disease progression. Furthermore, it is worth noting that a number of existing researches heavily rely on in vitro cell culture models or animal models. While these models serve as valuable tools for gaining preliminary understanding of underlying mechanisms, they fail to fully encompass the intricacies and complexities seen in human physiological environments. The limitation not only restricts the breadth and depth of research but also hinders the translation of findings into clinical applications. Addressing these limitations and pursuing deeper insights are essential tasks for future research in the field.

Current and future perspectives on EVs

EVs exhibit substantial potential for applications in the medical field. As drug delivery vehicles, EVs possess numerous advantages and can be loaded with therapeutic agents through various methods to treat diseases. Additionally, EVs serve as valuable biomarkers for disease diagnosis, as their contents reflect cellular states, aiding in early disease detection. Furthermore, EVs play a crucial role in targeted therapies by enabling surface modifications that enhance their targeting specificity, thereby effectively treating a wide range of diseases [164].

Preclinical studies are indispensable for advancing the clinical application of EVs. Researchers investigate the pharmacokinetics of EVs through cell and animal studies to further evaluate the efficacy and safety of EV-based products [165]. Clinical trials involving EVs are currently underway. In diagnostics, EVs are predominantly utilized for cancer-related applications; in therapeutics, most trials employ EVs derived from MSCs, with a few utilizing engineered EVs. Additionally, there are ongoing clinical trials exploring the efficacy of incorporating other therapeutic agents into EVs [166].

As a minimally invasive tool, liquid biopsy represents an emerging field currently utilized in the diagnosis and treatment of diseases. EVs present in human body fluids carry a diverse array of bioactive molecules and contain a wealth of information, making them ideal targets for liquid biopsy [167]. The application of liquid biopsy for detecting EVs holds significant value in disease diagnosis, treatment, and prognosis [165, 167].

As research on EVs advances, novel applications and capabilities are continually being demonstrated. However, the field is also encountering several challenges during its development. Addressing these challenges will be crucial for the continued advancement of the EV field.

Currently, EVs are mainly categorized into cell culture-derived EVs, fluid-derived EVs, and tissue-derived EVs (Ti-EVs). The first two categories constitute the main focus of current EV research [168]. However, Ti-EVs offer a more accurate depiction of the pathophysiological characteristics and cellular behavior, with minimal contamination, thereby providing a distinct advantage for elucidating disease progression [168]. Additionally, the development of appropriate models for real-time tracking of endogenous EVs in vivo could provide valuable insights into the long-distance communication networks mediated by EVs across organs. This would be of significant scientific value in elucidating the complex dynamics between liver and extrahepatic diseases [169].

Second, unique combinations of size, origin, and surface markers impart distinctive characteristics to EV subpopulations, contributing to their high heterogeneity [170]. The insufficient knowledge of specific EV markers hinders the ability to distinguish them from EVs already present in the body, whether derived from parental or normal cells. This limitation makes it challenging to achieve therapeutic goals by blocking the biogenesis and uptake of pathological EVs [152]. A better understanding of EV heterogeneity is becoming increasingly important for recognizing the critical role in health and disease [171]. As a high-throughput method, the proximity barcoding assay can identify the protein composition on individual EV surfaces, offering a novel technique for resolving EV heterogeneity [172]. This method facilitates comparisons of EV heterogeneity across different sources [173] and contributes to the development of disease biomarkers [174, 175]. Therefore, employing advanced technologies to identify heterogeneous EV subgroups originating from various organs and cell lineages will significantly enhance our comprehension of EV functions in disease progression.

Third, due to their distinct biological characteristics, EVs hold immense promise as novel therapeutic tools, in addition to serving as essential mediators of intercellular communication and carriers of vital signals [176]. However, the heterogeneity of EVs poses significant challenges, including the lack of standardized techniques for isolating EV subpopulations. Existing methods are often limited in terms of efficiency and purity, necessitating an ideal solution that combines simplicity, cost-effectiveness, and high efficiency to bridge this technological gap [177]. Moreover, while various modalities such as electroporation and sonication have been developed, the efficiency of drug loading into EVs remains suboptimal [178]. Furthermore, the absence of clinical-grade production capabilities constitutes a significant barrier to the translation of EV research from laboratory settings to clinical applications [179]. Consequently, researchers have explored several strategies to enhance EV secretion, including donor cell optimization and the use of bioreactors, which offer innovative approaches to scaling up EV production [180]. Addressing these issues is imperative for advancing the therapeutic application of EVs.

Summary

EV-mediated bidirectional communication between the liver and other organs is crucial for maintaining systemic homeostasis. In this review, we highlight the biological characteristics of EVs, summarize the involvement in physiological and pathological processes that mediate interactions between the liver and various organs (as detailed in Table 2), and discuss the therapeutic potential, as well as the challenges facing this field. Current research on the mechanisms of EV-mediated interactions between the liver and multiorgan systems is progressing rapidly. However, the exploration in this field is still far from exhaustive, and a deeper understanding may lie in the intricate details of EV biology.

With advancements in research, we anticipate revealing how EVs cross physiological barriers to establish sophisticated interorgan communication networks and how they serve as crucial mediators in the propagation of pathological phenotypes among different organs under disease conditions. The studies will provide significant insights into the multifaceted processes of understanding complex diseases, while also opening the door to a new era of precision therapeutic treatments and customized medicine.

Table 2 EV-mediated communication between the liver and other organs