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World J Psychiatry. Mar 19, 2025; 15(3): 102643
Published online Mar 19, 2025. doi: 10.5498/wjp.v15.i3.102643
Update on the roles and applications of extracellular vesicles in depression
Jing Wu, Ming-Zhi Pan, Xiao-Chu Gu, Lu Dai, Yun Wang, Bin Shen, Laboratory Medicine, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
Jian Lu, Laboratory Medicine, The Second Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
Xiao-Bin Zhang, Department of Psychiatry, Suzhou Psychiatric Hospital, Institute of Mental Health, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
ORCID number: Jing Wu (0000-0002-1023-5706); Xiao-Bin Zhang (0000-0002-0577-5951).
Co-corresponding authors: Jing Wu and Xiao-Bin Zhang.
Author contributions: Wu J, Lu J and Zhang XB proposed and designed the review; Pan MZ, Gu XC and Dai L collected the depression-related literature; Wang Y and Shen B collected the EVs-related literature. Wu J and Zhang XB prepared the first draft of the manuscript. All the authors have read and approved the final manuscript. Both Wu J and Zhang XB have played important and indispensable roles in the review design and manuscript preparation as the co-corresponding authors. Wu J, Lu J and Zhang XB applied for and obtained the funds for this research project. Wu J searched the literature, revised and submitted the early version of the manuscript; Zhang XB was responsible for figure plotting, comprehensive literature search, preparation and submission of the current version of the manuscript. This collaboration between Wu J and Zhang XB is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by Gusu Talent program, No. (2023)105; Suzhou Science and Technology Development Plan Program, No. SKY2023228; Project of Medical Research Fund of Jiangsu Provincial Health Commission, No. Z2023043; Suzhou Clinical Medical Center for Mood Disorders, No. Szlcyxzx202109; and Suzhou Clinical Key Disciplines for Geriatric Psychiatry, No. SZXK202116.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jing Wu, PhD, Laboratory Medicine, The Affiliated Guangji Hospital of Soochow University, No. 11 Guangqian Road, Xiangcheng District, Suzhou 215137, Jiangsu Province, China. 1156746344@qq.com
Received: October 25, 2024
Revised: December 23, 2024
Accepted: January 22, 2025
Published online: March 19, 2025
Processing time: 124 Days and 22.8 Hours

Abstract

Depression is a prevalent mental disorder that affects numerous individuals, manifesting as persistent anhedonia, sadness, and hopelessness. Despite extensive research, the exact causes and optimal treatment approaches for depression remain unclear. Extracellular vesicles (EVs), which carry biological molecules such as proteins, lipids, nucleic acids, and metabolites, have emerged as crucial players in both pathological and physiological processes. EVs derived from various sources exert distinct effects on depression. Specifically, EVs released by neurons, astrocytes, microglia, oligodendrocytes, immune cells, stem cells, and even bacteria contribute to the pathogenesis of depression. Moreover, there is growing interest in potential of EVs as diagnostic and therapeutic tools for depression. This review provides a comprehensive overview of recent research on EVs from different sources, their roles in depression, and their potential clinical applications.

Key Words: Depression; Extracellular vesicles; Exosomes; Biomarkers; Different sources

Core Tip: Depression is a prevalent mental disorder that affects numerous individuals, manifesting as persistent anhedonia, sadness, and hopelessness. Extracellular vesicles (EVs) are phospholipid membrane-enclosed structures that exhibit diversity in size, origin, activity, composition, and function. They encapsulate a myriad of biomolecules, including proteins, lipids, nucleic acids, and metabolites, contributing significantly to intercellular communication across various physiological and pathological progress. We herein summarize an overview of the latest research on EVs from different sources and their roles and potential applications in depression.



INTRODUCTION

Depression is a psychiatric disorder characterized by persistent sadness and a significant loss of interest in daily activities. Symptoms of mild depression include sadness, anhedonia, and feelings of worthlessness. In its severe form, major depression is a leading cause of disability, morbidity, and mortality worldwide and is often associated with recurrent thoughts of suicide[1]. Depression is a global health priority. According to statistics from the World Health Organization, approximately 5% of adults worldwide suffer from depression, and over 700000 people die by suicide each year. Suicide is the fourth leading cause of death in 15-29-year-olds (https://www.who.int). Given its high rates of disability, morbidity, and mortality, depression represents a significant public health concern that impacts productivity and quality of life.

Depression is a complex and multifaceted condition influenced by biological, physiological, and environmental factors[2]. Its risk factors are diverse and include a family history of depression (with genetics accounting for approximately 35% of the risk), chronic diseases, social stress, unhealthy lifestyles, pregnancy and postpartum changes, substance use, sleep disorders, dysfunctional family, dynamics, and physical and psychological changes during adolescence[1,3-5] (Figure 1). Prolonged exposure to these risk factors can lead to the onset of depressive symptoms.

Figure 1
Figure 1 Risk factors for depression. Risk factors for depression include a family history of depression (approximately 35% of the risk is genetic), chronic diseases, social stress, unhealthy lifestyles, pregnancy and postpartum changes, substance use, sleep disorders, dysfunctional family functioning, and physical and psychological changes during adolescence. Created by Biorender.

While research has identified several critical physiological pathways associated with depression, such as the hypothalamic-pituitary-adrenal (HPA) axis, inflammatory responses, neurotrophic factors, metabolism, glycosylation, neurotransmitters regulation, synaptic plasticity, oxidative stress, and intestinal microbiota[6,7], the precise mechanisms underlying depression remain elusive. Current diagnostic and therapeutic approaches for depression remain limited. Guidelines such as the 11th Revision of the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders provide as essential framework for identifying depression[8]. However, the absence of specific biomarkers complicates accurate diagnosis and treatment evaluation, as symptoms often overlap with those of other neuropsychiatric disorders.

Ongoing efforts aim to elucidate the pathogenesis of depression and identify reliable biomarkers to enable early detection and intervention. These efforts are critical to improving treatment outcomes and addressing this widespread and debilitating mental health condition.

Extracellular vesicles (EVs) are phospholipid membrane-enclosed structures that exhibit diversity in size, origin, activity, composition, and function[4]. Traditionally, EVs are classified into three major categories based on their biogenesis mechanisms: Exosomes, microvesicles (MVs), and apoptotic bodies (ABs)[9] (Figure 2A). Recently, a new class known as autophagic EVs-has also been identified. Exosomes, with diameters ranging from 30 to 150 nm, originate from the inward budding of endosomal membranes and are released when multivesicular bodies (MVBs) fuse with the plasma membrane. MVs, which are larger (100-1000 nm), are formed through outward budding of the plasma membrane. ABs, ranging from 500 nm and 5 μm, are released during the final stages of apoptosis when cells fragment. Autophagy is a self-degradative process that maintains cellular homeostasis under stress stimuli through fusion with lysosomes or the plasma membrane. Recent studies indicate that the autophagy-mediated protein secretion mechanism is known as secretory autophagy[10]. However, this mechanism is not well-understood. During this process, autophagosomes fuse with late endosomes/MVBs to form amphisomes, which are subsequently released as autophagic EVs. The relationship between EVs biogenesis-particularly exosomes and autophagy is complex. Autophagy-related proteins contribute to exosomes production, while inhibiting lysosomal activity or autophagy can restore exosomes secretion. Conversely, an increase in autophagic EVs leads to a reduction in exosomes release[11,12].

Figure 2
Figure 2 Overview of different extracellular vesicles and exosomal contents. A: Biogenesis of different extracellular vesicles (EVs). (1) Exosomes (30-150 nm) are secreted via exocytosis of intraluminal vesicles, which are formed by the inward budding of the endosomal membrane. The fusion of multivesicular bodies (MVBs) with the plasma membrane facilitates their release into the extracellular space (blue arrows); (2) Microvesicles (100-1000 nm) originate from the outward budding and shedding of the plasma membrane; (3) Apoptotic bodies (500 nm to 5 μm) are released as cell fragments during the final stages of apoptotic cell death; and (4) The fusion of autophagosome with MVBs generates amphisomes. These amphisomes fuse with the plasma membrane to release autophagic EVs (green arrows); B: Exosomes contents. Exosomes contain a variety of comprise surface markers such as membrane transport/fusion proteins, tetraspanins, immune regulators, adhesion molecules, and lipid rafts. The package contents of exosomes encapsulate diverse biomolecules, such as proteins, nucleic acids, lipids, metabolites, and other cellular components. EVs: Extracellular vesicles; MVBs: Multivesicular bodies; ICAM-1: Intercellular adhesion molecule 1. Created by Biorender.

A major challenge in EVs research lies in their heterogeneity and the methods used to isolate and purify distinct subpopulations. Various isolation techniques exploit the unique properties of EVs, such as size, density, composition, morphology, surface proteins, and charge. International guidelines for EV separation and characterization are now available and are regularly updated[13]. The current EVs separation methods include differential ultracentrifugation (dUC), density gradient/cushion, size exclusion chromatography (SEC), fluid flow-based separation, charge and molecular recognition-based separations. dUC enriches EVs subtypes based on sedimentation coefficient, proportional to their diameter and density. Density gradient/cushion separates certain contents, such as proteins, based on their characteristic densities. SEC facilitates size-based separation of particles and is an accessible technique. Fluid flow-based separation isolates EVs based on particle properties without relying on a stationary phase or matrix. Charge and molecular recognition-based separation captures EVs based on their surface charge or molecular composition. However, no existing isolation method separates EVs based on their specific origin. Therefore, the choice of isolation method should be guided by the heterogeneity of EVs, the scientific question being addressed, and downstream applications[14,15].

The International Society for EVs recommends that researchers explicitly describe the methods used for EVs collection and use precise terminology when referring to small vesicles. For consistency, this review will use the term “EVs” to broadly include all small EVs secreted with diameters less than 200 nm, while references that refer to exosomes will be encompassed within this category[16].

EVs encapsulate a wide range of biomolecules, including proteins, lipids, nucleic acids, and metabolites, and play critical roles in intercellular communication across physiological and pathological processes[17] (Figure 2B). They influence target cells by transporting and releasing their cargo, facilitating signal transduction, and modulating the behavior and function of recipient cells[18]. The growing interest in EVs is driven by their potential as non-invasive biomarkers for diagnosing and prognosticating various illnesses, including neurological and psychiatric disorders, due to their presence in bodily fluids. EVs cargo reflect the physiological and pathological conditions of the parent cells, providing insights into cellular dynamics under specific conditions[19]. Of particular importance is the emerging recognition of EVs as biological indicators of depression. EVs are implicated in critical pathways associated with depression, including neuroinflammation, neurogenesis, neuronal plasticity, and epigenetic modulation. These findings highlight the promise of EVs for improving diagnostic and therapeutic strategies in depression[20]. This review consolidates the current understanding of EVs derived from various sources and their roles in depression. It underscores the potential of EVs as diagnostic and therapeutic tools, providing a foundation for further investigation into EVs-associated mechanisms underlying depression.

THE ROLES OF EVS DERIVED FROM DEFFERENT SOURCES IN DEPRESSION

EVs derived from tissues, cells, blood, and even bacteria have been implicated in the development of depression. This section focuses on the roles of EVs from different sources in depression. Table 1 provides a comprehensive summary of these roles, while Figure 3 illustrates validated findings on the contributions of EVs derived from various sources in depression.

Figure 3
Figure 3 A summary of validated roles of extracellular vesicles derived from different sources in depression. (1) Astrocyte-derived extracellular vesicles (EVs) containing Apo-D act on neurons in the brain and play a neuroprotection role under oxidative stress; (2) Neuron-derived EVs containing miRNAs act on microglia; (3) Neuron-derived EVs containing miR-135a-3p, miR-6790-3p, and miR-11399 act on astrocytes to promote neuronal regeneration; (4) Neuron-derived EVs containing miR-9-5p promote M1 microglial polarization and neuronal damage; (5) Neurons stimulated by BDNF-derived EVs containing miR-132-5p, miR-218-5p, and miR-690 act on neurons and increase excitatory synapse clustering; (6) Microglia-derived EVs containing miR-146a-5p act on neurons and inhibit neurogenesis; (7) Oligodendrocyte-derived EVs containing sirtuin 2 act on neurons, promoting neurogenesis and synaptic plasticity; (8) Bone marrow mesenchymal stem cell-derived EVs containing miR-26a act on neurons and promote neuronal proliferation; (9) NK EVs containing miR-207 act on astrocytes and reduce neuroinflammation; (10) Neural stem cell-derived EVs containing miR-16-5p inhibit neuron apoptosis; (11) Aggregatibacter actinomycetemcomitans-derived EVs containing exRNA act on microglia and promote neuroinflammation; (12) Serum-derived EVs act on neurons, promoting neuronal proliferation and neurogenesis; (13) Astrocyte-derived EVs in plasma act on neurons and promote neuroinflammation; (14) EVs derived from blood act on neuronal stem cells and promote neuronal differentiation; and (15) Brain-derived EVs transfer to the periphery through the blood-brain barrier, with abnormal expression of certain proteins and miRNAs observed in blood. BDNF: Brain-derived neurotrophic factor; IL: Interleukin; TNF-α: Tumor necrosis factor α; BMSCs: Bone marrow mesenchymal stem cells; NSCs: Neural stem cells; SIRT2: Sirtuin 2; Aa: Aggregatibacter actinomycetemcomitans. Created by Biorender.
Table 1 The Extracellular vesicles from different sources and their functions/applications in depression.
Sources
EVs types
Cargos
Alternations
Roles/functions
Potential applications
Ref.
Cells-derived EVs
AstrocytesExosomesApoDMediate neuronal survival upon oxidative stressTherapeutic target[25]
EVsVEGFMaintaining the BBB permeabilityBiomarkers[27]
EVsInflammatory markers (Interferon-γ, IL-12p70, IL-1β, IL-2, IL-4, IL-6, TNF-α, IL-17A)Promote neuroinflammationBiomarkers[29]
NeuronsEVsmiR-135a-3p, miR-6790-3p, miR-11399Suppress neuronal functions-[30]
ExosomesmiR-9-5pPromote microglia polarization through the SOCS2-STAT3 axis and neuronal injuryTherapeutic target[31]
EVsmiR-17-5p-Diagnosis biomarkers[32]
EVsmiR-93Lead to interoceptive processing dysfunctions through altered epigenetic modulation of insular functionTherapeutic target[33]
EVsmiR-132-5p, miR-218-5p, miR-690Increase synaptic transmission and synchronous neuronal activity-[35]
EVsMitochondrial proteins↑/↓Regulate neuronal metabolism and survivalBiomarkers and drug targets[40]
ExosomesIRS-1Regulate central insulin signalingTherapeutic target[38]
EVsmiR-21-5p, miR-30d-5p, miR-486-5p-Biomarker for ADT response[36]
ExosomesIL-34/CD81, synaptophysin/CD81Regulate neuroinflammation and synaptic functionsBiomarkers[37]
MicrogliaEVsmiR-146a-5pInhibit neurogenesisBiomarkers and therapeutic target[41]
ExosomesVDBP-Biomarker[44]
OligodendrocytesExosomesPLP, CNP, MBP, MOGPromote myelin synthesis and turnover-[46]
ExosomesSIRT2Restore hippocampal neurogenesis and synaptic plasticity via the AKT/GSK-3β pathwayTherapeutic target[47]
Anterior cingulate cortexEVsmiR-92a-3p, miR-129-5pInvolve neurotransmission and synaptic plasticity-[48]
Brain tissuesExosomesmiR-210-5p, miR-143-5p, miR-574-5p, miR-551b-3p, let-7a-2-3p, etc.↑/↓Involve neuroplasticity, insulin resistance, and hypoxic responseBiomarkers[49]
MSCsExosomesmiR-132Reduce neuroinflammation and protect the integrity of BBBDiagnosis and therapeutic target[52]
BMSCsExosomesmiR-26aInhibit oxidative stress and inflammation, boost neuron proliferation and restrain apoptosisTherapeutic target[53]
ASCsEVs--Inhibition of ER stress-mediated apoptoticTherapeutic target[54]
NSCsEVsmiR-16-5pNeuroprotection-[55]
Macro-phagesExosomesLFA-1, ICAM-1, BDNFMediate its lateral migration and crossing the BBB, relieve neuroinflammationTherapeutic target[58]
DCsExosomes--Improve myelination and reduce oxidative stressTherapeutic target[59]
NKsExosomesmiR-207Inhibit neuroinflammationTherapeutic target[60]
Bacteria-derived EVs
A. actinomycetemcomitansOMVexRNAInduce neuroinflammation-[68]
L. plantarumEVs--Rescue the stress-induced decrease of BDNF, Sirt1 and MeCP2Treatment[69]
B. subtilisRescue stress-induced reduction of BDNF, Nt3, Nt4/5, and Sirt1
A. muciniphila
Blood-derived EVs
SerumsEVsAldolase C-Biomarkers[22]
ExosomesmiRNAs↑/↓Regulate neuronal functions involving MAPK, Wnt, and mTOR pathwayBiomarkers for the early diagnosis of depression[75]
EVsmiR-93-5p, miR-712-5p, miR-467b-3p, etc.-Modulate pro- or anti-inflammatory responsesBiomarkers[76]
ExosomesmiR-144-3pInvolve synthesis, metabolism, and breakdown of fatty acidsDiagnostic biomarkers[78]
ExosomesmiR-144-5pInduce abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammationTherapeutic target for MDD[79]
EVsmiR-450a-2-3p-Diagnostic biomarkers[80]
EVsmiR-4433b-5p, miR-584-5p, miR-625-3p, miR-432-5p, miR-409-3p-Diagnostic biomarkers[81]
EVsmiR-2277-3p miR-6813-3Involve glucocorticoid and gamma-aminobutyric acid receptor signalingDiagnostic biomarkers for severity[84]
Involve dopaminergic neural pathway
Exosomes15 metabolites-Diagnostic biomarkers for BD and MDD[95]
PlasmaExosomesmiR-16-5p, miR-129-5p, miR-363-3p, miR-92a-3p-Diagnosis and treatment[82]
ExosomesmiR-335-5pInvolve the synaptic synthesis and transport of many neurotransmittersBiomarkers of diagnosis and treatment for ADT[83]
miR-1292-3p
ExosomesmiR-30a-5pInhibit osteogenic differentiationBiomarker and therapeutic target for osteoporosis caused by depression[86]
ExosomesCXCL8Facilitate astrocyte-neuron communicationTherapeutic target for PTSD[91]
EVsC3-Diagnosis biomarkers for MDD[92]
Exosomessigma-1RAmeliorate inflammation responseTreatment[94]
Blood/brainExosomesmiR-139-5pA negative regulator for neural stem cell proliferation and neuronal differentiationDiagnosis and treatment[85]
BloodEVs13 mRNAs-Involve synaptic function and myelinationDiagnosis biomarkers for PPD[88]
BloodExosomesSERPINF1A target of miR-186-5pBiomarker for predicting MDD development[89]
Central nervous system cell-derived EVs

In the central nervous system (CNS), cells, EVs derived from astrocytes, neurons, microglia, and oligodendrocytes serve as information carriers facilitating communication between adjacent and distant cells. These EVs mediate various physiological and pathological responses associated in depression.

Astrocytes: Astrocytes play a crucial role in EV-mediated responses linked to depression. Previous research has identified the glycolytic enzyme aldolase C presented in astrocytes was detected in the cerebrospinal fluid (CSF) of depressed mice[21]. Additionally, aldolase C tagged with green fluorescent protein has been recovered in serum small EVs, indicating that astrocyte-derived proteins can be detected in blood EVs[22]. Repeated or uncontrolled stress leads to region-specific changes in astrocyte density and morphology, which impacts EV formation, release, and molecular composition. When stimulated, astrocytes release EVs enriched with neuroprotective molecules such as heat shock proteins, synapsin 1, microRNAs (miRNAs), and glutamate transporters. In contrast, resting astrocytes release EVs containing factors like fibroblast growth factor-2, apolipoprotein-D (ApoD), and vascular endothelial growth factor (VEGF)[23]. Oxidative stress is a critical factor in the pathogenesis of depression[24]. Astrocyte-derived exosomes transport ApoD to neurons, providing neuroprotection under oxidative stress condition[25]. VEGF, a component of astrocyte-derived EVs (ADEVs), is known to increase the permeability of the blood-brain barrier (BBB) and modulate synaptic transmission, influencing hippocampal neurogenesis and depression development[26]. Elevated plasma levels of VEGF, along with ADEVs expressing AQP4 and GFAP, have been observed in individuals with stress-induced exhaustion disorder (SED), a subtype of depression[27]. Furthermore, increased leakage of ADEVs across the BBB has been reported in patients with SED and potentially in those with major depressive disorder (MDD)[28]. While the exact mechanisms are not fully understood, VEGF likely plays a central role in facilitating the transport of ADEVs across the BBB. Depressed individuals frequently exhibit elevated levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α). These cytokines are partly derived from astrocytes and the EVs they release. Astrocytes with hyper-inflammatory responses generate EVs enriched with pro-inflammatory markers, contributing to the inflammatory processes observed in depression[29].

Neurons: Lund human mesencephalic cells (LUHMEs), human embryonic neuronal precursor cells capable of proliferation, have been widely studied for their role in EV production. Research by Nishi et al[30] demonstrated that EVs by LUHMEs upon IL-6 stimulation, carry miRNAs such as miR-135a-3p, miR-6790-3p, and miR-11399, which regulate neuroregeneration-related gene expression in astrocytes and microglia. In a cultured cell model, miR-9-5p in neuron-derived exosomes can mediate M1 microglial polarization via the SOCS2-STAT3 axis. M1-polarized microglia release pro-inflammatory factors that exacerbate neuronal damage and contribute to depression. Elevated levels of miR-9-5p have also been detected in serum EVs of MDD patients[31]. Strikingly, alterations in the levels of specific miRNAs, such as miR-17-5p and miR-93 in neuron-derived EVs (NDEVs), have been correlated with the severity of depressive symptoms, highlighting their potential as biomarkers for disease progression. Subthreshold depression (StD) is a depressive state that does not meet the criteria for MDD but carries a risk of progressing to MDD. miR-17-5p in NDEVs correlates positively with Patient Health Questionnaire-9 scores in patients with StD, a state that may progress to MDD[32]. In contrast, miR-93 expression is reduced in neuronal EVs of individuals with elevated serum levels of pro-inflammatory cytokines such as IL-1 receptor antagonist, IL-6, and TNF[33]. Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal dendrite morphogenesis[34] mediates synapse formation through the transfer of neuronal EVs and their miRNA cargo. BDNF-stimulated EVs, enriched with miR-132-5p, miR-218-5p, and miR-690, promote synaptic vesicle clustering at presynaptic terminals, enhance synaptic activity, and improve neuronal circuit connectivity[35]. Neuronal EVs expressing markers such as L1CAM and SNAP-25A (neuronal markers) can be isolated from plasma. Specific miRNA signatures in these exosomes, including miR-21-5p, miR-30d-5p, and miR-486-5p, may predict treatment response in depression[36]. In an exploratory pilot case-control study, SNAP-25A+ neuronal EVs were analyzed for neuroinflammatory and synaptic function markers. This study identified IL-34 and synaptophysin in CD81+ exosomes, suggesting their peripheral blood transport during depression[37]. Nasca et al[38] reported increased secretion of L1CAM+exosomes in MDD patients compared to age- and sex-matched controls. These exosomes exhibited elevated levels of insulin receptor substrate-1 (IRS-1), which was associated with suicidality and anhedonia. IRS-1 regulates insulin signaling pathways, which are critical for neuroplasticity. Mitochondrial dysfunction is a fundamental pathogenic mechanisms in depression[39]. Abnormal levels of functional mitochondrial proteins have been observed in plasma neuronal EVs of MDD patients. Interestingly, these protein levels were normalized in patients who responded to 8 weeks of treatment with selective serotonin reuptake inhibitors but remained unchanged in non-responders[40]. These findings highlight the intricate roles of neuronal EVs in neuroinflammation, neuroplasticity, and energy metabolism, revealing their potential as biomarkers and therapeutic targets in depression. Further exploration of these mechanisms may offer novel insights into the pathogenesis and treatment of depression.

Microglia: Microglial cells play a pivotal role in the progression of depression, particularly in cases driven by neuroinflammation. A notable study by Fan et al[41] identified an upregulation of miR-146a-5p in serum-derived exosomes from rats subjected to chronic unpredictable mild stress (CUMS). They demonstrated that miR-146a-5p is transferred from microglia to neurons via microglia-secreted exosomes. Downregulating of miR-146a-5p mitigated deficits in adult neurogenesis within the dentate gyrus regions and alleviated depression-like behaviors in rats by post-transcriptional regulating Krüppel-like factor 4. These findings align with earlier research by Jovičić et al[42], which identified microglia as the primary source of miR-146a-5p and suggested that serum EVs containing this miRNA originate from microglia. Recent investigations have also linked cerebral cortex thickening and overexpression of miR-146a-5p in EVs from medication-naïve major depression patients, highlighting the intricate relationship between EVs-associated miR-146a-5p and depression[43]. Currently, microglia-derived EVs (MDEVs) can be isolated using specific markers like TMEM119 through immunoprecipitation techniques. Zhang et al[44] reported a selective reduction in vitamin D-binding protein (VDBP) levels in MDEVs from the plasma of MDD patients compared to healthy controls (HCs), with VDBP levels inversely correlating with the Hamilton Depression Rating Scale scores. Their findings suggest that MDEV-associated VDBP may serve as a potential biomarker for MDD diagnosis.

Oligodendrocytes: Oligodendrocytes, the primary cells responsible for synthesizing and maintaining the myelin sheath in the CNS, play a critical role in providing electrical insulation and trophic support to axons. Genes related to myelination and synaptic plasticity have been implicated in the pathogenesis of depression[45]. Post-mortem studies of suicide victims with major depression revealed reduced oligodendrocyte density and notable demyelination in the white matter regions. Furthermore, oligodendroglial exosomes, stimulated by elevated intracellular Ca2+ levels, carry specific myelin components, including proteolipid protein, 2’3’-cyclic-nucleotide-phosphodiesterase, myelin basic protein, and myelin oligodendrocyte glycoprotein, suggesting the potential involvement of oligodendrocyte-derived EVs (ODEVs) in depression pathogenesis[46]. For example, oligodendrocyte-derived exosomes carrying sirtuin 2 were shown to alleviate depressive-like behaviors by restoring hippocampal neurogenesis and enhancing synaptic plasticity in depressed mice via the AKT/GSK-3β pathway[47]. This finding highlights a promising therapeutic avenue for depression treatment.

In addition to the role of CNS cell-derived EVs in depression discussed in the previous review, there have been reports highlighting the involvement of EVs derived from brain tissue. An analysis of small RNA profiles revealed that EVs from postmortem human anterior cingulate cortex tissue contain various RNA biotypes, with a notable down-regulation of miR-92a-3p and miR-129-5p. These miRNAs are thought to play significant roles in neurotransmission and synaptic plasticity, as indicated by in silico functional analysis[48]. Other studies have also highlighted the differential expression of miRNAs in brain tissue-derived EVs, suggesting their involvement in biological processes such as insulin resistance, neuroplasticity, and hypoxic response. These processes may influence brain functions and potentially contribute to depression-like behaviors[49]. In essence, a diverse array of EVs derived from CNS cells is implicated in signaling pathways crucial for neuroprotection, neuroinflammation, neurogenesis, synaptogenesis, and metabolism, collectively influencing the onset and progression of depression.

Stem cell-derived EVs

Stem cells are well known for their unique ability to self-renew and differentiate, and both stem cells and their derived EVs have garnered significant attention for their potential impact on depression[50]. Mesenchymal stromal cells (MSCs) improved depression-like behavior through their immunomodulatory and paracrine properties[51], with their derived EVs and miR-132 showing promise in improving the prognosis of epileptic patients and reducing the incidence of depression by reducing CNS inflammation[52]. Bone marrow MSCs (BMSCs)-derived EVs improve hippocampal neurons injury in rats with depression by upregulating miRNA-26a expression[53]. Corticosterone (CORT) induction increases neuronal apoptosis in brain tissue and induces depression-like behaviors. Adipose stem cells (ASCs)-derived EVs can ameliorate CORT-induced apoptosis in the cortical neurons by inhibiting endoplasmic reticulum stress[54], suggesting that treatment with ASCs-derived EVs might play an antidepressant role. Similarly, Min et al[55] discovered that neural stem cell-derived EVs reduce neuronal injury in CORT-induced depression rats via the miR-16-5p/MYB axis.

Immune cell-derived EVs

In depression research, the involvement of inflammatory processes in its pathophysiology has been well-established[56]. Dysregulation of both the innate and adaptive immune systems is frequently observed in individuals suffering from depression[57]. A variety of immune cells, including macrophages, dendritic cells (DCs), and natural killer cells (NKs), have been implicated in the pathological mechanisms of depression. Yuan et al[58] explored the role of macrophage-derived exosomes, highlighting the presence of lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1 on macrophage-derived exosomes. These molecules facilitate the uptake of macrophage-derived exosomes by BBB cells. Moreover, macrophage-derived exosomes loaded with exogenous BDNF can be transported to the brain, where they accumulate in the inflammation sites. This suggests that macrophage-derived exosomes may serve as natural nanocarriers for delivering BDNF to inflamed regions in the brain, offering a promising therapeutic strategy for depression. In the context of migraine with aura, spreading depression is recognized as a primary cause of headache pain. The administration of interferon gamma-stimulated DCs EVs has been shown to reduce the susceptibility to spreading depression. This effect occurs by enhancing myelination and reducing oxidative stress both in vivo and in vitro, suggesting that DC-derived exosomes could be a potential therapeutic approach for migraines triggered by spreading depression[59]. Furthermore, NK-derived EVs, particularly those carrying miR-207, have been shown to inhibit NF-κB signaling pathway by directly targeting the toll-like receptor 4 interactor with leucine-rich repeats (Tril) in astrocytes. This action results in a reduction of pro-inflammatory cytokines and alleviates depression-like symptoms in animal models, underscoring the therapeutic potential of NK cell-derived EVs in modulating neuroinflammation and mitigating depressive behaviors[60].

Bacteria-derived EVs

Microbiota dysbiosis is a pathological feature of depression, contributing to subclinical inflammation, HPA axis imbalance, and alterations in neural, metabolic, and endocrine pathways[61,62]. Bacteria-derived EVs carrying nucleic acids, polysaccharides, and proteins are involved in the onset and progression of depression[63]. Outer membrane vesicles (OMVs) produced by the microbiota carry various signals that are crucial for spreading OMVs to distant organs through the bloodstream[64,65]. EVs produced by Gram-negative bacteria through the shedding of the outer membrane are a key factor in neuroinflammation-induced depression[66]. Lipopolysaccharides (LPS) from Gram-negative bacteria mediate systemic inflammatory responses and can be transported to the brain through EVs to trigger neuroinflammation by activating microglia and promoting the secretion of inflammatory cytokines such as TNF-α, IL-1β, and IL-6[67]. EVs derived from the periodontopathogen Aggregatibacter actinomycetemcomitans can infiltrate mouse brain monocytes and carry bacterial extracellular RNA to microglia, leading to a significant increase in NF-κB expression, stimulating IL-6 secretion, and ultimately triggering neuroinflammation[68]. On the other hand, EVs derived from probiotics have antidepressant effects. Gram-positive probiotics Bacillus subtilis and Lactobacillus plantarum, as well as the Gram-negative probiotic Bacteroides fragilis EVs, show antidepressant-like effects by varying degrees of restoring stress-induced alterations in BDNF, Sirtuin1, and MeCP2[69,70]. Dysregulation of serotonin is closely associated with the development of depression[71]. Research by Yaghoubfar et al[72] confirmed that Akkermansia muciniphila-derived EVs could affect the serotonergic system in the colon and hippocampus of mice. Serotonin, an intermediate product of tryptophan metabolism, is primarily found in enterochromaffin cells of the intestine, serotonergic neurons in the brain, and platelets in the blood. Approximately 90 percentage of the serotonin in the body is synthesized in the gut, with the remainder produced in the brain. Notably, the brain and gut serotonin systems are separated by the BBB[73]. Therefore, EVs may serve as vehicles for bidirectional communication of serotonin between the gut and the brain.

Blood-derived EVs

In various physiological and pathological states, EVs carrying bioactive molecules can be found in biological fluids like blood, urine, milk, saliva, and amniotic fluid. The presence of these EVs provides valuable insights into disease conditions. By examining EVs in the bloodstream, researchers can gain a deeper understanding of the mechanisms involved in depression and explore novel diagnostic and therapeutic strategies. This section will focus on the significance of the contents within blood-derived EVs (blood-EVs) in relation to depression.

miRNAs: miRNAs are small endogenous RNAs, approximately 21 nucleotides in length, that regulate gene expression post-transcriptionally, serving as vital regulators and promising biomarkers[74]. Blood-EVs miRNAs have emerged as a focal point in depression biomarkers research. Extensive studies have been dedicated to exploring their potential in unraveling complexities of depression. Through miRNA sequencing in CUMS rat models, differentially expressed miRNAs in serum exosomes have been identified, showing intricate associations with key pathways such as MAPK, Wnt, and mTOR[75]. In a chronic social defeat stress (CSDS) mice model, miR-31-5p, miR-712-5p, miR-212-3p, miR-451a, miR-467b-3p, miR-193b-3p, and miR-93-5p found in serum EVs were shown to modulate pro- or anti-inflammatory responses, shedding light on the immune dysregulation observed in depression[76]. MiR-144-3p, differentially expressed in circulating blood from the CSDS model, has been identified as a predictor of MDD severity and ketamine response in humans[77]. Furthermore, miR-144 displays differential expression in serum EVs from depression patients. The expression level of exo-miR-144-3p was negatively correlated with the severity of depressive symptoms in heart failure patients[78]. In contrast, the knockdown of miR-144-5p in normal mice induced depression-like behaviors by promoting microglial M1-polarization. Moreover, upregulation of miR-144-5p ameliorated depression-like behavior and attenuated neuronal abnormalities by directly targeting TLR4 and PTEN/PI3K/Akt/FoxO-1 signaling pathway[79]. In studies of adolescent depression, miR-450a-2-3p, miR-556-3p, and miR-2115-3p in serum EVs were significantly upregulated in untreated adolescents with MDD[80], while miR-4433b-5p, miR-584-5p, miR-625-3p, miR-432-5p, and miR-409-3p in serum EVs were downregulated in adolescents with MDD[81]. Serum EV miR-450a-2-3p showed potential diagnostic and prognostic value in identifying and managing depression in younger populations[80]. The correlation between substance use and depression was further elucidated through the identification of plasma exosomal miRNAs associated with depressive symptoms in substance-dependent individuals. Plasma EV miR-92a-3p, miR-363-3p, miR-16-5p, and miR-129-5p exhibited a significant correlation with total HAM-D scores in methamphetamine-dependent patients[82]. In plasma EVs of treatment-resistant depression patients, miR-335-5p was significantly upregulated, while miR-1292-3p was significantly downregulated compared to HCs. These miRNAs play roles in the MAPK, Ras, and PI3K-AKT signaling pathways, affecting synaptic synthesis and neurotransmitter transport[83]. Downregulation of serum EV miR-2277-3p and miR-6813-3 were correlated with the severity of MDD. miR-2277-3p influences the dopaminergic neural pathway, while miR-6813-3p is linked to glucocorticoid receptor and gamma-aminobutyric acid receptor signaling. Notably, these two miRNAs are highly expressed in astrocytes, suggesting their potential astrocytic origin[84]. Elevated levels of miR-139-5p were identified in blood-EVs of MDD patients[85]. miR-139-5p, known to impair neural stem cell proliferation and neuronal differentiation, has been implicated in inducing depression-like behaviors in mice through the regulation of neurogenesis. Depression-induced osteoporosis, increasing with rising social stress, was investigated in a CUMS model, where plasma EV miR-30a-5p alleviated depressive osteoporosis by inhibiting the expression of osteogenic markers in BMSCs[86].

Messenger RNAs: Other RNA components in EVs, such as messenger RNAs (mRNAs), have also been reported to be associated with depression. mRNAs are the intermediate step between the translation of protein-encoding DNA and the production of proteins by ribosomes in the cytoplasm. The release of mRNA packaged in EVs into the cytosol of recipient cells initiates translation and protein expression[87]. Smirnova et al[88] demonstrated that blood-EVs carrying brain-specific mRNAs could serve as potential biomarkers for detecting gene expression changes in the female brain. Gene Ontology analysis revealed that these mRNAs are involved in synaptic function and myelination and are enrich in genes associated with mood disorders. A particularly notable finding was the correlation between the levels of 13 EV mRNAs and postpartum depression.

Proteins: Proteins found in EVs play a crucial role in depression and serve as important biological markers of depression. Research by Jiang et al[89] revealed that serpin family F member 1 is significantly diminished in the peripheral blood-derived exosomes of MDD patients compared to the HCs. EVs, essential in immune communication within the “gut-brain-immune axis”, are implicated in the pathophysiology of depression[90]. Plasma exosomes enhance communication between astrocytes and neurons by transmitting the immune factor C-X-C motif chemokine ligand 8 (CXCL8)[91], which astrocytes release to induce neuroinflammation. The exosomal marker CD63 regulates the packaging and delivery of CXCL8 into exosomes. Inhibiting CXCL8 has been shown to improve depression caused by post-traumatic stress disorder[91]. Complements are crucial immune regulatory factors, and complement C3 in plasma EVs has been found to be differentially expressed between MDD patients and HCs[92]. Sigma-1 receptor (sigma-1R), an upstream regulator of endoplasmic reticulum stress and signaling, has been linked to antidepressant effects[93]. Plasma exosomes from depressed individuals exhibit antidepressant-like effects through a sigma-1R-dependent mechanism in LPS-induced depression[94].

Metabolites: Metabolomics has emerged as a valuable tool in identifying potential biomarkers for diagnosing major neuropsychiatric diseases. Fifteen differentially expressed metabolites in EVs (Chenodeoxycholic Acid, and Lysope 18:0, Lysope 14:0, N-Acetylmethionine, 13-oxoODE, Glycine, 1-Naphthylacetic Acid, 2-Aminoethanesulfonic Acid, D-2-Aminobutyric Acid, Lysopc 18:0, Lysopc 20:1, Biopterin, Phosphoric Acid, Glucosamine, and PAF C-16) related to sugar metabolism in serum EVs have been found to distinguish bipolar disorder patients from those with MDD[95]. A recent study also highlighted differences in the contents of plasma EVs, including metabolites, proteins, and miRNAs, between non-depressed and depressed rats following traumatic spinal cord injury (TSCI), offering potential insights for diagnosing depression following TSCI[96]. These findings underscore the potential of metabolomics in providing valuable insights for the accurate diagnosis and management of depression.

THE POTENTIAL APPLICATIONS OF EVS IN DEPRESSION

The potential applications of EVs in depression are multifaceted and promising[97]. Firstly, EVs act as dynamic indicators of disease progression, offering real-time insights into the evolving state of depression. Secondly, their non-invasive extraction from biological fluids enables early detection, facilitating timely intervention. Moreover, the protective membranous structure of EVs preserves their contents, safeguarding valuable biomarkers over extended periods. Additionally, the traceable origin of EVs through cell surface markers enhances their diagnostic utility. Lastly, the ability of EVs to traverse the BBB opens avenues for accessing crucial information about CNS cells, which would otherwise require invasive procedures. These attributes highlight the significant clinical value of EVs in diagnosing, assessing treatment efficacy, and managing depression.

Diagnosis tools

Currently, the diagnosis of depression primarily relies on clinical symptomatology and depression scales, which lack objective biochemical indicators. Detection based on EVs holds significant promise for the early diagnosis of depression. The positive correlation between the cargos found in EVs from blood and CSF suggests that EVs, as peripheral indicators, can potentially replace CSF for depression diagnosis[44]. While EVs isolated from CSF has been used in biomarker discovery studies for depression, EVs from the peripheral circulation are more easily accessible and non-invasive[98]. Specific surface molecular markers carried by EVs can be utilized to isolate cell-specific EVs-such as ADEVs, NDEVs, MDEVs, and ODEVs-from the bloodstream. Techniques like dUC, density gradients, precipitation, filtration, SEC, and immunoisolation can be employed to achieve this[19]. Analyzing the differential expression of cargos in these EVs provides an effective method for diagnosing depression and distinguishing it from other conditions[92,95].

miRNAs have emerged as the most common molecular tools for predicting and diagnosing depression among all EV cargo types. In the circulating EVs of depressed patients, miRNAs often exhibit significant change in expression and play a key role in the onset and progression of depression. They are closely associated with diagnosis, treatment assessment, and prognosis. In addition to miRNAs, protein and lipid cargos in EVs are hold crucial diagnostic potential. Recently, EVs-derived metabolites have been discovered and are emerging as new molecular tools for diagnosing depression.

Building on these advances, scientists are working to develop platforms for diagnosing depression. Topuzoğlu and Ilgın[99] are developing a rapid diagnostic platform, called the “Mentalexo” approach, which focuses on detection of EVs from CNS cells. They aim to apply this approach to identify suitable EV biomarkers for depression. Similarly, Shin et al[100] demonstrated a novel and precise method for diagnosing MDD using deep learning analysis and surface-enhanced Raman spectroscopy of plasma EVs, confirming that the diagnostic scores were correlated with the severity of depression.

Therapeutic effect evaluation

EV-derived regulatory miRNAs are valuable parameters for assessing the response to ADT, including let-7e, miR-21-5p, miR-145, miR-146a, miR-155, miR-21-5p, miR-30d-5p, and miR-486-5p[36,101]. In patients with MDD, neuronal EV levels of MPs of all functional classes were normalized in those who responded to SSRI therapy, but not in those who failed to respond, as determined by psychiatric evaluation. This highlights the importance of neuronal EV contents in evaluating treatment response[40]. EV-derived BDNF can also serve as a biomarker for the efficacy of antidepressant drugs, as BDNF levels in serum and EVs fluctuate in opposite directions during antidepressant therapy[102]. Additionally, the red blood cell-specific miR-144-3p has shown potential in predicting the response to ketamine treatment in stress-susceptible mice and MDD patients[77].

Therapy tools

As the substrates from the blood to the CNS are controlled by the BBB[103], effective drug transfer to the brain poses a challenge for treating CNS disorders like depression. However, EVs offer promising potential as drug carriers due to their nanoscale size, low immunogenicity, and stable structure, which enable them to cross the BBB and exert therapeutic effects. Lactobacillus-derived EVs can afford antidepressant-like effects in mice with stress-induced depression, with effects lasting for 30 days[69,104]. Further advancements in drug delivery include engineered RVG-circDYM-EVs, which effectively transport circDYM to the brain, inhibiting microglial cell activation, BBB leakage, peripheral immune cell infiltration, and alleviating chronic unpredictable stress-induced depression-like behavior[105]. Hu et al[106] developed a nanogel loaded with PACAP and estrogen (E2), sheathed with EVs and responsive to reactive oxygen species, referred to as HA NGs@EVs, These exhibit notable antioxidant and anti-inflammatory properties, and their intranasal application in a CUMS mouse model led to improved behavioral performance, demonstrating rapid-onset antidepressant effects for perinatal depression. In Traditional Chinese Medicine, herbal medicine and acupuncture focus on prevention and regulation, with Chinese herbal medicine showing antidepressant effects, though its action is slow and non-specific. Interestingly, research has shown that exogenous plant contents carried by EVs can be absorbed by intestinal enterocytes and stably exist in the gastrointestinal tract[107,108]. This discovery opens the possibility of using such EVs as a drug delivery system and for gene therapy via oral administration of herbal medicine to treat depression. Some experts also suggest that acupuncture may influence the distribution of exosomes in vivo, potentially using exosomes as carriers in acupuncture treatment of MDD in the future[109]. The enzyme neutral sphingomyelinase 2 (nSMase2), involved in the biogenesis of ceramide and EVs, is dysregulated in MDD. Zhu et al[110] reported that inhibiting nSMase2 could represent a new therapeutic strategy for HIV-associated MDD, as EcoHIV-infected mice exhibited increased levels of brain-derived EVs and altered miRNA cargo. Additionally, intravenous injection of ceramide-loaded exosomes induced MDD-like behavior in untreated mice, which was reversed by ex vivo pre-incubation of purified exosomes with anti-ceramide antibodies or ceramidase[111].

Although research is still limited, current literature supports the potential of EVs for diagnostic, assessment, and therapeutic purposes in depression, with transformative applications on the horizon.

CONCLUSION

Depression is a type of psychiatric disorder characterized by abnormal neuroinflammation, neurotransmitters, dysregulation of the HPA axis, and altered neural transmission. As key intercellular communication mediators, EVs play a crucial role in understanding the etiology, diagnosis, and treatment of depression. Previous studies have demonstrated that EVs from various sources have distinct roles in depression. This article reviews the contribution of EVs from different cells and biological sources to depression and briefly discusses their potential applications in diagnosing and treating the disorder. While the potential of EVs for diagnosing and treating depression is promising, several challenges remain. CNS cell-derived EVs show great potential as diagnostic biomarkers for depression that can be detected in peripheral blood. However, accurately and selectively isolating, identifying, and quantifying these brain-derived EVs remains challenging due to the incomplete development of EV preparation and purification methods. For example, conflicting reports exist regarding the use of L1CAM as a surface marker for isolating neuronal EVs. L1CAM expression is not only non-specific to neurons or the CNS but also occurs as a cleaved secretory protein. Furthermore, acquiring EVs requires a substantial volume of blood samples, which may hinder large-scale metabolomics and the assessment of multiple biomarkers. Thus, further advancements in EV separation methods are essential, particularly for obtaining higher concentrations of EVs from smaller sample volumes. Given the heterogeneity of depression, more extensive multisite prospective studies should be conducted, using robust data analysis techniques to improve the accuracy and feasibility of clinical findings. Studies on the role of EVs in depression have largely focused on the abundant contents of EVs, particularly miRNAs, which are the most widely studied biological molecules in EVs. However, miRNA alternation in EVs have shown inconsistent results, which may be attributed to methodological differences in extraction techniques, the complex and heterogeneous nature of depression, and unclear mechanisms of EV biosynthesis and release. Therefore, when determining the specific roles and potential applications of EVs, especially in miRNA-based diagnostic and therapeutic strategies for depression, it is critical to account for individual differences, methodological consistency, and other influencing factors. Additionally, many studies have only identified differentially expressed biomolecules, including miRNAs in EVs, without thoroughly investigating their specific functions and regulatory mechanisms. Hence, further exploration of the functions and mechanisms of bioactive substances in EVs is necessary. Besides miRNAs and proteins, other bioactive molecules, such as lipids and metabolites, should also be considered. Although recent studies have begun to address the roles of these molecules, more research is needed to fully understand their contribution. Moreover, the relationship between peripheral EVs and the brain, as well as the bidirectional transport mechanism of EVs across the BBB, needs further investigation. Understanding this mechanism is crucial for unraveling the pathogenesis of depression and could significantly advance the development of precise clinical diagnostic tools. In conclusion, future research should focus on developing more efficient, accurate and stable methods for isolating EVs, conducting in-depth studies of their biological mechanism, and undertaking clinical trials to facilitate the adoption of EV-based treatment strategies for depression.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Psychiatry

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade B

Novelty: Grade B

Creativity or Innovation: Grade B

Scientific Significance: Grade B

P-Reviewer: Eid N S-Editor: Li L L-Editor: A P-Editor: Zhao S

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