Exosomal microRNAs in common mental disorders: Mechanisms, biomarker potential and therapeutic implications

Abstract

To illustrate the mechanisms of exosomal microRNAs (miRNAs) in common mental disorders, and explore their potential as diagnostic biomarkers and therapeutic targets, a systematic literature review of relevant studies on exosomal miRNAs in mental disorders was conducted. Data from cell experiments, animal models, and clinical studies were analyzed and combined to study the mechanisms and roles of exosomal miRNAs in various mental disorders. Research has shown that exosomal miRNAs, such as miR-146a, miR-223, miR-125b, and miR-451a, affect Alzheimer’s disease (AD) formation by regulating key pathways such as toll-like receptor 4 (TLR4) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), respectively. MiR-146a-5p regulates the occurrence of schizophrenia through the Notch pathway. TLR4 regulates miR-146a and miR-155 in major depressive disorder (MDD), and miR-144-5p regulates the disease through PI3K/Akt. Exosomal miR-484, miR-652-3p, miR-142-3p, miR-21a-3p, and miR-21-5p regulate key pathways in bipolar disorder, autism spectrum disorder, and Rett syndrome (e.g., TLR4, PI3K/Akt, and Epha4/TEK) and have an influence on mental disorders. Exosomal miRNAs are involved in the occurrence of mental disorders through TLR4, PI3K/Akt, and Epha4/TEK pathways, which provides a clearer understanding of disease cognition. Of these pathways, the TLR4 and PI3K/Akt pathways play a role in AD, MDD, and neurodevelopmental disorders, which can be used as an effective breakthrough in the study of mental disorders. Exosomal miRNAs could also serve as diagnostic biomarkers and therapeutic targets, providing new insights into precise interventions for mental disorders.

Key Words: Exosomal microRNAs; Common mental disorders; Mechanism; Signal pathway; Diagnostic biomarker; Therapeutic target

Core Tip: This synthesis highlights exosomal microRNAs as dual-functional tools bridging mechanistic insights into mental disorders and paving the way for personalized diagnostics/therapeutics. Focus on shared pathways (e.g., toll-like receptor 4, phosphatidylinositol 3-kinase/protein kinase B) may unify treatment strategies across diverse psychiatric conditions.

INTRODUCTION

Exosomes are nanoscale lipid structures ranging in diameter from 40 nm to 100 nm, which contain microRNAs (miRNAs), circular RNAs long non-coding RNAs, messenger RNAs (mRNAs), and other substances within their encapsulation[1-3]. These secreted membrane-bound particles originate from the inward budding of endosomal membranes. These compartments ultimately undergo fusion with the plasma membrane, facilitating the release of their intraluminal cargo into the extracellular space. Current research indicates that diverse cell populations exhibit the capacity to synthesize and secrete these biologically active vesicles under both physiological and pathological conditions[4]. The secreted exosomes enter blood, saliva, urine, breast milk, etc., and then reach other cells and tissues through the circulatory system, resulting in remote regulation[5].

Recently, the mechanism of exosomes has attracted more and more interest from researchers. The mechanism of endosome sorting complex required for transport (ESCRT) is the most representative classical mechanism. The ESCRT machinery plays a pivotal role in orchestrating the biogenesis of exosomes through sequential activation of its core components ESCRT-I, ESCRT-II, and ESCRT-III. Mechanistically, ESCRT-III subunits assemble into membrane-associated polymeric structures that drive vesicle scission. This ESCRT-mediated process necessitates the calcium-binding apoptosis-linked gene-2-interacting protein X to facilitate the recruitment of ESCRT complexes to ubiquitinated cargo domains within late endosomal compartments (Figure 1). The coordinated action of these molecular components enables the precise intraluminal vesicle formation and subsequent exosomal secretion via membrane abscission mediated by the AAA+ + ATPase Vps4 complex. The mechanism of exosomes plays a vital role in diagnosing and treating mental disorders[6,7].

Figure 1 Exosome content and endosome sorting complex required for transport are involved in the biogenesis of exosomal microRNAs. Exosomes originate from the endosomal system, beginning with early endosome formation via plasma membrane endocytosis. As endosomes mature into late endosomes, they develop into multivesicular bodies through inward budding of the limiting membrane, a process regulated by the endosome sorting complex required for transport machinery. Key regulators and cargo classes are annotated to illustrate exosomes’ dual roles as intercellular messengers and diagnostic/therapeutic targets in diseases. MVB: Multivesicular body; MHC: Major histocompatibility complex; ESCRT: Endosome sorting complex required for transport; CD: Cluster of differentiation; HSP: Heat shock protein; miRNA: MicroRNA; circRNA: Circular RNA; lncRNA: Long non-coding RNA; mRNA: Message RNA.

Mature miRNAs are naturally occurring small non-coding RNA molecules, with a canonical length of 22 ± 1 nucleotides[8]. These miRNAs exhibit partial complementarity with one or several mRNA molecules. The primary role of this process is to inhibit gene expression through various mechanisms, such as suppressing translation, cleaving mRNA, and removing poly (A) tails[9,10].

Several miRNAs can regulate a gene or a molecular pathway, thus forming a complex and powerful regulatory network[11]. This mechanism solves most pathological mechanism problems and broadens the understanding of miRNAs in mental disorders. In addition, miRNAs can be targeted to molecular regulation, bringing new hope for the precise treatment of mental disorders[10,11].

Recently, miRNAs have become a central focus in precision and molecular medicine research. Exosomes are regarded as highly suitable markers for detecting mental disorders, principally due to their unimpeded ability to traverse the blood-brain barrier (BBB). The overarching aim is to identify risk factors for diseases during the incipient stages of their onset, thereby enabling the implementation of preventive measures to curtail further disease progression. Notably, miRNAs have not been observed to cross the BBB freely. Significantly, exosomes conjugated with miRNAs possess the potential not only to predict the development of mental disorders but also to provide targeted therapeutic sites. This characteristic of exosomal miRNA associations could open up novel avenues for both the early diagnosis and targeted treatment of mental disorders, integrating the detection advantages of exosomes and the regulatory functions of miRNAs.

In this review, we summarize the pivotal roles and biomedical potential of exosomal miRNAs as follows: Firstly, exosomal miRNAs actively regulate diverse biological processes, including cell proliferation, differentiation, migration, and disease pathogenesis, leveraging the transport capacity of exosomes[12]. Secondly, these miRNAs exhibit broad detectability across multiple biofluids, such as saliva[13], urine[14], breast milk[15], peripheral blood[14], and cerebrospinal fluid (CSF)[16], mirroring the distribution characteristics of their carrier exosomes. Notably, blood-derived exosomal miRNAs have been extensively studied for cancer diagnostics due to their systemic accessibility and disease-specific signatures[17], while urinary exosomal miRNAs show high specificity for renal disease monitoring[18]. Salivary miRNAs, conversely, provide a non-invasive approach to evaluate systemic disorders such as neurodegenerative diseases, and CSF-enriched exosomal miRNAs are critical for investigating neurological and psychiatric disorders, reflecting direct pathological alterations within the central nervous system (CNS)[19]. Thirdly, their accessibility and disease-associated expression dynamics position exosomal miRNAs as promising non-invasive biomarkers for clinical diagnosis and therapeutic monitoring.

The application of exosomal miRNAs as promising biomarkers for disease diagnosis and therapeutic monitoring has driven extensive research into their isolation and detection methodologies. Despite significant advancements, the field currently lacks a standardized protocol for exosomal miRNAs isolation. Established isolation techniques primarily include ultra-speed centrifugation (differential ultracentrifugation and density gradient ultracentrifugation)[20], immunoaffinity capture techniques[21], ultrafiltration membranes[22], size-exclusion chromatography[23], polymer-based precipitation approaches[24], and microfluidic technology[25]. Differential ultracentrifugation is currently the most commonly used technique for isolating exosomes[26].

For subsequent detection and quantification of exosomal miRNAs derived from human biofluids, researchers employ multiple analytical strategies such as quantitative real-time polymerase chain reaction (qRT-PCR), which is the gold standard for miRNA profiling due to its high sensitivity[27], while enzyme-linked immunosorbent assay enables protein-coupled miRNA detection[28]. Complementary approaches include flow cytometry[29] and immunoblotting (Western blot)[28]. While qRT-PCR dominates clinical applications due to its practicality, each method exhibits distinct advantages in specificity, throughput, and compatibility with downstream workflows. Consequently, method selection should be guided by experimental objectives and sample-specific considerations.

For subsequent detection and quantification of exosomal miRNAs derived from human biofluids, researchers employ multiple analytical strategies, qRT-PCR remains the gold standard for miRNA profiling due to its high sensitivity[27], while enzyme-linked immunosorbent assay enables protein-coupled miRNA detection[28]. Complementary approaches include flow cytometry[29] and immunoblotting (Western blot)[28]. While qRT-PCR dominates clinical applications due to its practicality, each method exhibits distinct advantages in specificity, throughput, and compatibility with downstream workflows. Consequently, method selection should be guided by experimental objectives and sample-specific considerations.

MECHANISM OF EXOSOMAL MIRNAS IN MENTAL DISORDERS

Intercellular communication

The complex biological specificity of exosome-mediated cell communication stems from two fundamental features: (1) Different internalization mechanisms, including clathrin-dependent endocytosis, macrophage action, and receptor-ligand docking systems; and (2) Intrinsic target cell selectivity is determined by surface tetradin topography and integrin-mediated tissue tropism (Figure 2). These increase the complexity of exosome functions in intercellular communication[30,31].

Figure 2 The mechanism of exosomal microRNAs in mental disorders. Including intercellular communication, neurogenesis, synaptic plasticity, inflammatory response, mitochondrial function in the brain, and stress response. miRNA: MicroRNA; APC: Antigen presenting cell; BDNF: Brain-derived neurotrophic factor.

As there are no multivesicular bodies on neurons, many multivesicular bodies exist in their cell bodies and dendrites[31]. Due to this distribution, exosomes are crucial to signal transmission in the CNS. As a link carrier between the same or different types of cells, especially between neurons and glial cells, exosomal miRNAs play an essential role in the physiological and pathological processes of neuropsychiatric diseases, and have become an effective target for diagnosis and treatment[32]. For instance, in their research on Alzheimer’s disease (AD), Liu et al[33] discovered that miR-135a can traverse the BBB from CSF to peripheral blood serum. This finding presents novel targets for the diagnosis of AD[33]. Mesenchymal stem cell-derived exosomes improved ethanol-induced prefrontal cortex inflammation in adolescent mice, restored ethanol-treatment-induced myelin and synaptic disorders, as well as memory and learning impairments through intercellular communication[3].

Neurogenesis

Exosomes influence neurodegenerative disorders through two main mechanisms: (1) Regulating neural differentiation and development; and (2) Controlling synaptic vesicle activity in neurons. These dual functions emphasize exosomes as key players in neurogenesis and synaptic balance, connecting their activity to the progression of neurodegenerative disorders. Exosomes may promote or limit the aggregation of unfolded and abnormally folded proteins in the brain. In addition, exosomes can also take part in the clearance of misfolded proteins to play detoxification and neuroprotective functions[34-36]. For example, differentially expressed exosomes and their associated miRNAs in the denervated hippocampal niche could promote the differentiation of neural stem cells into neurons[37].

Exosomal miRNAs exhibit intricate functions in neurogenesis. MiR-146a-5p regulates depression-related neurogenesis through the KLF4/CDKL5 pathway in major depressive disorder (MDD) model mice[38]. In another study of MDD model mice, miR-139-5p modulated neurogenesis and depressive behavior in mice[39]. Exosomal miRNAs are implicated in the pathophysiological processes of neurogenesis in both psychiatric and neurodevelopmental disorders. The injection of human urine-derived exosomal miR-21-5p into Rett syndrome (RTT) mouse models enhanced early neurogenesis via the EPha4/TEK signaling axis[40].

Synaptic plasticity

Synaptic plasticity plays a vital role in the mechanisms underlying cognition. This complex process allows for the up-regulation or down-regulation of synapses based on activity levels, which is essential for forming and consolidating memories. When this plasticity is disrupted due to genetic, environmental, or physiological factors, it can result in significant cognitive impairments[41]. Oligodendrocyte-derived exosomes extracted from mouse serum were administered via tail vein injection into a depressive mouse model. Zhang et al[42] demonstrated that oligodendrocyte-derived exosomes effectively alleviated depression-like behaviors by facilitating the transcellular delivery of silent information regulator 2, thereby influencing protein kinase B (Akt) deacetylation and regulating the Akt/GSK3β signaling pathway. Additionally, oligodendrocyte-derived exosomes promoted neurogenesis and contributed to the restoration of synaptic plasticity[42]. Although this finding demonstrates that exosomes contribute to antidepressant therapy and synaptic restoration in the hippocampus, the specific influence of silent information regulator 2 on this process remains inadequately explored.

Exosomes and exosomal miRNAs play a significant role in synaptic plasticity. Notably, miR-132-3p is crucial for this process. Exosomes derived from mesenchymal stem cells, rich in miR-132-3p, enhanced neuronal and synaptic function by activating the Ras/Akt/GSK3β pathway, thereby facilitating the recovery of cognitive function[43]. Due to its high abundance in brain tissue, miR-132-3p has attracted extensive research attention[44]. The Ras/Akt/GSK3β pathway is not only implicated in the pathogenesis of depression, but also plays a crucial role in other diseases, such as cerebrovascular disorders[43]. The interplay between miR-132-3p and the Ras/Akt/GSK3β pathway offers innovative perspectives on the applications of exosomes and exosomal miRNAs.

Inflammatory response

Exosome receptor-mediated pinocytosis crosses the BBB, establishing two-way communication channels and promoting molecular crosstalk between the CNS and the peripheral system. This inherent BBB penetration makes these vesicles key transporters of neuroactive biomolecules, making intercellular signaling essential for neurohomeostasis and pathological transmission. They can transport a wide range of biochemical molecules, including pro-inflammatory factors from the periphery to the CNS, where they target glial and neuronal cells. Conversely, during CNS inflammation, exosomes can deliver anti-inflammatory molecules to CNS cells, offering potential for targeted therapy[45]. The toll-like receptor 4 (TLR4) pathway is a well-established immune response axis that has been extensively researched in the context of immune regulation and mental disorders. Yang et al[46] reported that lipopolysaccharide-induced exosomal miR-146a modulates the expression of AD risk genes by suppressing the TLR4 signaling pathway[46].

Exosomes, characterized by their bidirectional transport capabilities, can transport substances that contribute to the amelioration of mental disorder symptoms. Wei et al[47] showed that anti-inflammatory microglia could modulate the AD cell model by transferring exosomal miR-223. Zhai et al[48] experimented by injecting exosomes and miR-22-loaded exosomes derived from adipose-derived mesenchymal stem cells into AD model mice. By comparing the two groups, it was found that the expression level of inflammatory factors in the group receiving regular exosomes was higher than that in the group administered miR-22-loaded exosomes. This finding suggests that the intervention with miR-22-loaded exosomes significantly downregulates inflammatory factors in the CSF, effectively preventing further nerve cell damage[48]. In particular, this study subjected exosomes and exosomal miRNAs to independent investigation. The findings suggest that exosomal miRNAs may mediate biological effects distinct from their parent exosomes in certain pathological contexts. This functional dichotomy may enable the development of precision therapeutic strategies for diseases such as AD. Furthermore, these results underscore the critical need to delineate the differential contributions of exosomal miRNAs vs whole exosomes in disease pathogenesis, which is essential for advancing their translation into clinical applications.

Mitochondrial function in the brain

Mitochondria are the primary energy producers within cells and participate in many vital cellular processes, encompassing redox signaling and calcium transport. Their multifaceted functionality highlights their indispensable role in maintaining the normal physiological state and in the pathological alterations of the CNS, particularly concerning brain activities. As a result, recent investigations have primarily focused on elucidating the impact of mitochondrial dysfunction on the pathogenesis of mental disorders[49]. Recently, studies have demonstrated that exosomal miRNAs play an important role in the pathological processes of mitochondrial dysfunction by regulating mitochondrial dynamics, oxidative stress, and energy metabolism. Specifically, exosomal miRNAs can modulate the balance of mitochondrial fusion and fission, mitochondrial autophagy, and the functionality of the electron transport chain by targeting mitochondria-related genes. These results stress the central involvement of exosomal miRNAs in mitochondrial homeostasis and suggest their potential as therapeutic targets for diseases associated with mitochondrial dysfunction.

The dual effects of the increase in exosomal miR-137 and the deletion of COX6A2 lead to the stacking of damaged mitochondria, intensifying mitochondrial oxidative stress and damage to cortical parvalbumin interneurons (PVI), resulting in schizophrenia symptoms. It is worth noting that the mitochondrial antioxidant mitoquinone mesylate can reverse the overexpression of miR-137 induced by oxidative stress, the decrease in COX6A2, mitochondrial autophagy, and PVI damage. This reverse verifies that the upregulation of miR-137 and the subsequent defect in mitochondrial autophagy are one of the molecular mechanisms of oxidative stress-induced PVI damage[49].

Electroacupuncture in combination with neural stem cell-derived exosomes has been demonstrated to ameliorate depression-like behavior in rat models of MDD through the reversal of structural and functional impairments observed in synapses and mitochondria within the hippocampus[50]. However, a limitation of this study is the lack of separate investigations into electroacupuncture and exosomes, thereby leaving the specific role of exosomes somewhat ambiguous. Despite this ambiguity, it is widely acknowledged within the scientific community that exosomes possibly play a significant role in this process. Future studies should aim to disentangle the individual contributions of electroacupuncture and exosomes through more sophisticated experimental designs, perhaps by conducting separate experiments to precisely delineate the mechanisms by which exosomes contribute to the observed effects. Such investigations would enhance our understanding of the therapeutic potential of exosomes and their interaction with electroacupuncture, ultimately leading to more effective and targeted therapeutic strategies for depression. Li et al[51] found that exosomes originating from neural stem cells can enhance mitochondrial biogenesis. This is achieved by activating the SIRT1/PGC1α pathway, which subsequently increases the synthesis of nuclear respiratory factor-1 and cytochrome c oxidase-IV, thereby ameliorating the distribution of abnormal proteins associated with AD[51].

Stress response

Stress responses in the context of mental disorders encompass both biological factors and life events, which interact synergistically throughout the progression of mental disorders, with stressors such as oxidative stress, exposure to light, and various life events being included.

The injection of miR-139-5p antagonists treated depressive behavior in mildly stressed mice, suggesting that elevated levels of exosome miR-139-5p are likely to mediate depressive behavior induced by oxidative stress in mice[39]. Microglia-derived exosomes treated with 1070 nm light reduce endoplasmic reticulum stress that is induced by targeting the activating transcription factor-6 in AD model mice, thereby reducing AD symptoms[52]. In a study concentrating on post-traumatic stress disorder (PTSD) among veterans engaged in military operations within the United States, a correlation was observed between the severity of PTSD symptoms and the levels of exosomal proteins and exosomal miRNAs in the peripheral blood[53]. This finding suggests a possible association between the severity of PTSD symptoms and the presence of these molecular entities in the bloodstream. Essentially, exosomal proteins and exosomal miRNAs could serve as potential markers for assessing the severity of PTSD.

EXOSOMAL MIRNA CHANGES IN MENTAL DISORDERS

AD

AD is a common neurodegenerative disease. Its pathological changes often manifest as senile plaques, neuronal tangles, hippocampal cellular granules, vacuolar degeneration, neuron loss, and so on (Figure 3). These pathological changes are related to genetic factors, abnormal β-amyloid metabolism, and neurotransmitter disorders[54]. Neurotransmitter disorders include exosomes and other transmitters, which are involved in intercellular communication, neurogenesis, and immune response, as well as impacting the occurrence and development of AD (Tables 1 and 2).

Figure 3 The exosomal microRNAs signaling pathways of mental disorders. Including toll-like receptor 4, phosphatidylinositol 3-kinase/protein kinase B, Ras/GSK-3β signaling pathways. miRNA: MicroRNA; TLR4: Toll-like receptor 4; TRIF: Toll/interleukin-1 receptor domain-containing adaptor inducing interferon-β; TRAM: Toll/interleukin-1 receptor domain-containing adaptor molecule; TIRAP: Toll-interleukin 1 receptor domain-containing adapter protein; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; MEK: Mitogen-activated extracellular signal-regulated kinase; ERK: Extracellular regulated protein kinases; mTOR: Mammalian target of rapamycin; MAP: Microtubule-associated protein; NF-kB: Nuclear factor kappa-B.

Table 1 Summary of changes of exosomal microRNAs in Alzheimer's disease-related animal experiments.

	miRNAs	Alteration	Model	Type tissue	Significance	Ref.
Intercellular communication	miR-135a	Increase	AD mouse models, human patients	CSF, serum, plasma	ATP-binding cassette transporter-A1 reduces the false negatives of exosomal miRNAs. Possible biomarker for AD	Liu et al[33]
	miR-193b	Increase	Cell models, AD mouse models, human patients	CSF, serum, cell	Possible biomarker for AD	Liu et al[55]
	miR-770-3p		AD mouse models	Brain tissue	As the downstream target of circ-Epc1, overexpression of circ-Epc1 affects M1 microglia and forms AD	Liu et al[56]
	miR-29	Decrease	AD rice models	Hippocampus	Exosomal miR-29 has protective effects on amyloid pathogenesis	Jahangard et al[57]
	miR-185-5p	Decrease	AD mouse models, AD cell models, human patients	Brain tissue, cell, serum and CSF	The expression of exosomal miR-185-5p was decreased by binding of APP 3’UTRs to miR-185-5p	Ding et al[58]
	miR-532-5p		AD mouse models	Brain tissue	The exosomal miR-532-5p targets EPHA4, and reduces EPHA4 its expression. Possible biomarker of AD	Liang et al[59]
	miR1385p		AD mouse models, cell models	Brain tissue, hippocampus, cell	By targeting Tau as a protective factor for AD. Possible therapeutic targets	Meng et al[60]
	miR-451a, miR-19a-3p		AD mouse models	Hippocampus	Possible biomarker for AD	Yan et al[61]
	miR-29b-2		Cell models	Cell	Reduces PSEN1 levels and inhibits secretory enzymes. Possible therapeutic targets	Lin et al[62]
	miR-196b-5p, miR-339-3p, miR-34a-5p, miR-376b-3p, miR-677-5p, miR-721		AD mouse models	Urine	Urinary exosomal miRNAs are promising to supplement or replace invasive cerebrospinal fluid. Possible biomarker for AD	Song et al[63]
Inflammatory response	miR-146a	Increase	AD mouse models	Hippocampus	Macrophage tolerance to TLR4 was induced	Yang et al[46]
	miR-124-3p		AD mouse models	Brain tissue	Neurodegeneration is mitigated by targeting Rela/ApoE signaling pathways to transfer into hippocampal neurons	Ge et al[64]
	miR-124	Increase	AD cell models	Cell	Regulation by the secretome miR-124-3p released through the AD cell models. A promising therapy in AD	Garcia et al[65]
	miR-21	Increase	AD mouse models	Brain tissue, hippocampus	Take part in immune processes. Possible biomarker for AD	Garcia et al[66]
	miR-146a-5p		AD mouse models, AD cell models	Cell, brain tissue, hippocampus, plasma	Targeted regulation of the HIF1α/mtROS pathway and improvement of NLRP3 inflammasome and inflammatory factors can alleviate cognitive impairment in IH mice	Zhang et al[67]
	miR-223		Cell models	Cell	Yb-1-mediated microglial exosomal sorting of miR-223 improves nerve cell damage repair and is a promising therapeutic target for AD	Wei et al[68]
	miR-223	Decrease	AD cell models	Cell	It acts as a protective factor for AD through the PI3K/Akt signaling pathway	Wei et al[47]
	miR-146a	Increase	AD mouse models	Hippocampus, CSF	Exosomal transfer of miR-146a is involved in the correction of cognitive dysfunction in AD	Nakano et al[69]
	miR-22		AD mouse models	CSF and peripheral blood	MiR-22-loaded ADMSC-derived exosomes can reduce the release of inflammatory cytokines by inhibiting pyroptosis	Zhai et al[48]
	miR-7670-3p		AD mouse models	Brain tissue	MiR-7700-3p reduces ATF6 expression, protects the integrity of dendritic spines in cortical and hippocampal neurons, and ultimately improves cognitive function	Chen et al[52]
Others	miR-124	Increase	AD cell models	Cell	A novel diagnostic biomarker in circulating exosomes is a potential therapeutic target for AD whenever its deregulation is determined	Garcia et al[70]
	miR-1306-5p	Decrease	Cell models, human patients	Cell, serum	CircAXL promotes the inhibition of PDE4A by targeting miR-1306-5p. Possible biomarker for AD	Meng et al[71]
	miR-211-5p		AD cell models	Cell	Inhibition of miR-211-5p may improve the efficacy of HUCMSC-derived exosomes in the treatment of AD by increasing the expression of NEP	Chen et al[72]

miRNA: MicroRNA; AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; ATP: Adenosine triphosphate; APP: Amyloid precursor protein; 3’UTR: 3’untranslated region; NLRP3: NOD-like receptor thermal protein domain associated protein 3; TLR4: Toll-like receptor 4; HIF1α: Hypoxia inducible factor-1α; mtROS: Mitochondrial reactive oxygen species; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; ADMSC: Adipose derived mesenchymal stem cells; HUCMSC: Human umbilical cord mesenchymal stem cells; NEP: Neprilysin.

Table 2 Summary of changes of exosomal microRNAs in Alzheimer’s disease patients.

miRNA	Alteration	Model	Type tissue	Significance	Ref.
miR-320a, miR-328-3p, miR-204-5p	Decrease	Human patients	CSF	Potential targets for miR-328-3p involve AMPK signaling pathways associated with amyloid and tau metabolism in AD. Reliable biomarkers of AD	Tan et al[73]
miR-455-3p	Increase	Human patients	CSF	A potential biomarker for AD	Kumar and Reddy[74]
miR-9, miR-21, miR29-b, miR-122, miR-132	Decrease	Human patients	Plasma	MiR-122 is related to alpha-tocopherol and may be a new targeted therapy	Boccardi et al[75]
miR-125b, miR-451a	Increase	Human patients	Peripheral blood	It plays a role through the PI3K/Akt signaling pathway. Possible biomarker for AD	Duan et al[76]
miR-342-5p	Increase	Human patients	Peripheral blood	Degradation of BACE1 mRNA in cells by targeting the 3’UTR sequence of BACE1 ameliorates β-Amyloid formation	Dong et al[77]
miR-16-5p, miR-25-3p, miR-92a-3p, miR-451a	Decrease	Human patients	Plasma	May have been involved in the early development of AD	Visconte et al[78]
miR-373, miR-204	Decrease	Human patients	Peripheral blood	Potential biomarkers for AD	Taşdelen et al[79]
miR-30b-5p, miR-22-3p, miR-378a-3p	Decrease	Human patients	Peripheral blood	Potential biomarkers for the diagnosis of AD	Dong et al[80]
miR-483-5p, miR-502-5p	Decrease	Human patients	Plasma	Possible biomarker for AD	Liu et al[81]
miR-29c-3p	Increase	Human patients	Plasma	Possible biomarker for AD	Li et al[82]
miR-23a	Increase	Human patients	Plasma	Possible biomarker for AD	Barbagallo et al[83]
miR-126-3p, miR-142-3p, miR-146a-5p, miR-223-3p	Decrease	Human patients	CSF and peripheral blood	As a biomarker reflecting AD severity	Aharon et al[84]
miR-384	Increase	Human patients	CSF and plasma	MiR-384 downregulates the expression and activity of ACE-1 to alleviate AD symptoms	Li et al[85]
miR-485-3p	Increase	Human patients	Saliva	Possible biomarker and treatment for AD	Ryu et al[86]
miR-486-3P	Increase	Human patients	Brain tissue and peripheral blood	Possible biomarker for AD	Cheng et al[87]
miR-185-5p		Human patients	Blood sample	Education decreased AD expression, depression increased AD expression, and participated in the production and accumulation of Aβ in patients, and enhanced depression, which participated in the production and accumulation of Aβ	Wang et al[88]

miRNA: MicroRNA; AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; AMPK: Adenosine 5’-monophosphate-activated protein kinase; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; 3’UTR: 3’untranslated region.

In animal experiments related to AD, further understanding of the disease can be obtained by studying the pathological mechanisms, including intercellular communication, inflammatory response, stress response, synaptic plasticity, etc.

Intercellular communication

Liu et al[55] conducted a systematic investigation and demonstrated that the utilization of ABCA1 significantly enhances the detection efficiency of exosomes. Their findings revealed a consistent up-regulation of exosomal miR-135a and miR-193b across multiple experimental paradigms. The study employed a comprehensive approach, incorporating AD mouse models, in vitro cell cultures, and clinical samples, including CSF and serum obtained from AD patients. These results underscore the pivotal role of ABCA1 in exosome detection and suggest that miR-135a and miR-193b may serve as promising biomarkers for AD. It is necessary to conduct further research to elucidate the functional implications of these exosomal miRNAs in the pathogenesis of AD[33,55].

Studies on the brain tissue of AD model mice demonstrated that hypoxia-pretreated adipose-derived stem cell-derived exosomes can significantly enhance cognitive function. This improvement is mediated through the delivery of circEpc1, which regulates the M1/M2 polarization of microglia. Notably, circEpc1 functions as an upstream regulator of miR-770-3p. Intriguingly, miR-770-3p and circEpc1 do not exhibit synergistic changes during this process, suggesting a complex regulatory mechanism underlying their roles in microglial polarization and cognitive enhancement. These findings highlight the therapeutic potential of hypoxia-preconditioned adipose-derived stem cell exosomes in AD and provide insights into the molecular interactions between circEpc1 and miR-770-3p[56].

In a study focused on the hippocampus of a rat AD model, Jahangard et al[57] conclusively demonstrated the down-regulation of miR-29 expression. Subsequent experiments revealed that the administration of miR-29-enriched exosomes into the mouse hippocampus markedly reduced the extent of Aβ aggregation. These compelling findings suggest that miR-29 might serve as a significantly hopeful therapeutic miRNA target for the treatment of AD. This study revealed the prospects of exosome-based delivery systems for modulating miRNA expression and illustrated miR-29 as a critical player in mitigating Aβ pathology in AD. Ding et al[58] revealed that dysregulation of the amyloid precursor protein led to the binding and anchoring of miR-185-5p to the 3’untranslated region (3’UTR) of amyloid precursor protein. This interaction resulted in a significant reduction in exosome levels in both brain tissue and serum samples from AD patients and AD mouse models. In particular, this study was the first to identify a direct regulatory relationship between miR-185-5p and the 3’UTR region of amyloid precursor protein, providing new insights into the molecular mechanisms underlying exosome dysregulation in AD. These results point out the potential role of miR-185-5p in modulating amyloid precursor protein expression and its implications for exosome biogenesis in AD pathogenesis[58].

Liang et al[59] reported that in AD model mice, exercise led to an improvement in AD symptoms. This was achieved by exosomal miR-532-5p, which could cross the BBB, and targeted erythropoietin-producing hepatocellular carcinoma A4. In addition, Meng et al[60] discovered that miR-138-5p within neural stem cell-derived exosomes functioned as a protective factor against AD by targeting the Tau protein. Also, by a thorough study of the mechanism of action of fasudil on AD, Yan et al[61] identified that miR-451a and miR-19a-3p could serve as effective targets for diagnosing and treating AD. In cell culture investigations on AD, it was demonstrated that miR-29 b-2 decreased presenilin 1 and inhibited gamma-secretase activity. This indicates that miR-29 b-2 could be a promising target for developing AD therapies[62].

Notably, miR-196 b-5p, miR-339-3p, miR-34a-5p, miR-376 b-3p, miR-677-5p, and miR-721 were identified in the urine of AD model mice. This significant discovery not only highlights the potential of urinary exosomes as a non-invasive source of biomarkers for AD but also broadens the scope of exosome applications in disease diagnosis and monitoring. These findings demonstrate the utility of exosomes as valuable tools for identifying miRNA signatures in biofluids, offering new avenues for early detection and therapeutic intervention in AD[63].

Inflammatory response

Yang et al[46] injected lipopolysaccharide into the lateral ventricles of AD model mice. Their findings revealed that the expression of miR-146a in hippocampal exosomes was upregulated, and this upregulation was mediated through inhibition of the TLR4 signaling pathway. Research on brain tissues of cognitively impaired mice demonstrated that miR-124-3p transfers to hippocampal neurons and alleviates neurodegeneration by targeting the Rela/ApoE signaling pathway[64]. However, in another study, miR-124-3p was used as a target of miR-124 in AD cell models to regulate microglia inflammation and alleviate neurodegenerative changes[65]. These results suggest distinct yet potentially complementary roles of miR-124-3p and miR-146a in modulating neuroinflammation and neurodegeneration in AD, showing the complexity of miRNA-mediated regulatory mechanisms in the disease.

By studying the brain tissue and hippocampus of AD model mice, it was reported that miR-21 plays a role in reprogramming dysregulated activation of microglia or astrocytes, thereby regulating the formation of AD[66]. In cellular and mouse studies of AD models, the findings showed that miR-146a-5p regulates mitochondrial reactive oxygen species by targeting hypoxia-inducible factor-1α, thereby affecting the secretion of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 inflammasomes and inflammatory factors and influencing AD formation[67]. These results indicate the important roles of miR-21 and miR-146a-5p in regulating neuroinflammation and mitochondrial dysfunction, illustrating their possibility as therapeutic targets for AD.

In an experiment employing AD cell models, exosomal miR-223 derived from microglia was demonstrated to alleviate neuronal damage and neuroinflammation[68]. Research on exosomes sourced from mesenchymal stem cells revealed that exosomal miR-223 can activate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, suppress inflammation, and inhibit neuronal apoptosis in vitro by targeting phosphatase and tensin homolog deleted on chromosome ten. These observations present a novel potential avenue for treating AD[47]. These findings suggest a promising therapeutic strategy for AD, stressing the promise of exosomal miR-223 as a novel intervention to modulate neuroinflammation and neuronal survival.

Nakano et al[69] injected exosomes from bone marrow mesenchymal stem cells into the lateral ventricles of an AD mouse model and up-regulated miR-146a levels in the hippocampus. Also, alleviation of AD-related cognitive dysfunction was achieved through the attenuation of astrocyte-mediated inflammatory responses. Exosomes derived from bone marrow mesenchymal stem cells were transfected with miRNA-22 mimics and subsequently injected into mouse models of AD. Analysis indicated that miRNA-22 was capable of ameliorating neuroinflammation and enhancing neurocognitive function. These findings suggest that miRNA-22 holds promise as a possible therapeutic agent for AD[48].

In an AD model, mice treated with 1070-nm light modulation demonstrated significant alleviation of microglial inflammation. Specifically, exosomal miR-7670-3p was found to downregulate the expression of the target gene, activating transcription factor 6, thereby reducing endoplasmic reticulum estrogen receptor stress and subsequently attenuating the inflammatory response. These findings provide a novel therapeutic strategy for the treatment of AD, highlighting the potential of light-modulated exosomal miRNAs in regulating estrogen receptor stress and neuroinflammation[52]. This discovery paves the way for developing targeted interventions to address the underlying pathological mechanisms of AD.

Others (synaptic plasticity, stress response, etc.)

MiR-124 showed different effects in two different AD model cell types. In SH-SWE neurons, the exosome miR-124 caused neurite growth, mitochondrial activation, and a decrease in the level of small Aβ oligomers. In contrast, in iNEU-PSEN cells, it reduced Tau phosphorylation. In addition, the use of miR-124 inhibitors resulted in a decrease in dendrite spine density. These findings suggest that the effects of miR-124 may be highly dependent on specific types of neuronal cells[70]. This cell type-specific function highlights the complexity of the regulatory mechanisms of miR-124 in AD and underscores the need for further study of its environmentally dependent effects.

When the circular AXL receptor tyrosine kinase was silenced in AD model cells, it was observed that this action inhibited phosphodiesterase 4A by liberating miR-1306-5p. Consequently, the pathological neurotoxicity of AD triggered by Aβ1-42 was eased[71]. Studies have demonstrated that purified exosomes derived from human umbilical cord mesenchymal stem cells exhibit overexpression of miR-211-5p inhibitors. This was significantly more effective than control exosomes in alleviating damage caused by Aβ1-40 treatment. These researchers reported that exosomal miR-211-5p inhibition enhanced the protective effects of human umbilical cord mesenchymal stem cells-derived exosomes against Aβ-induced neurotoxicity, highlighting their potential as a therapeutic intervention for AD[72]. This investigation underscores the importance of exosome engineering in optimizing therapeutic outcomes for neurodegenerative disorders.

In the study of clinical exosomes and AD, although there are still some gaps in the in-depth mechanism exploration compared with animal experiments, there have been many interesting discoveries with clinical application potential.

Clinical evidence reveals significant down-regulation of specific exosomal miRNAs particularly miR-320a, miR-328-3p, and miR-204-5p in CSF samples from AD patients. Notably, miR-328-3p has been mechanistically linked to the adenosine 5’-monophosphate-activated protein kinase signaling pathway, where it modulates critical pathways governing amyloid precursor protein processing and tau phosphorylation dynamics, suggesting its potential role in AD-related proteostasis dysregulation[73]. However, the exosomal miR-455-3p was up-regulated in CSF[74]. Although these exosomal miRNAs exhibit different trends in CSF, they can all be used as probable diagnostic markers for AD.

Boccardi et al[75] demonstrated that the plasma levels of exosomal miR-9, miR-21, miR-29b, miR-122, and miR-132 in patients were decreased. Specifically, miR-122 is associated with vitamin E’s participation in oxidative stress and might play a role in the onset of AD. Of particular interest, miR-122 has been functionally linked to vitamin E-mediated antioxidant pathways, suggesting its potential involvement in oxidative stress regulation and subsequent neurodegenerative processes characteristic of AD pathogenesis[75]. In clinical randomized controlled studies conducted by Duan et al[76], it was revealed that the levels of exosomal miR-125b and miR-451a in the peripheral blood of AD patients were increased. These exosomal miRNAs exert regulatory effects on AD through the PI3K-Akt signaling pathway. Interestingly, Dong et al[77] found that miR-342-5p levels in patients' peripheral blood were also elevated. miR-342-5p can target the 3’UTR sequence of the BACE1 gene mRNA, leading to degradation of BACE1 mRNA in cells. This mechanism has the potential to mitigate beta-amyloid formation. This finding further emphasizes the significance of BACE1 in AD treatment[77].

Comprehensive profiling of peripheral blood-derived exosomes revealed significant down-regulation of multiple miRNA species in AD patients, including miR-16-5p, miR-25-3p, miR-92a-3p, miR-451a, miR-373, miR-204, miR-126-3p, miR-30 b-5p, miR-22-3p, miR-378a-3p, miR-483-5p, and miR-502-5p[78-81]. In peripheral blood, miR-29c-3p and miR-23a were up-regulated[82,83]. These studies provide compelling evidence that peripheral blood exosome miRNAs hold important promise as effective biomarkers for early AD diagnosis and prognostic assessment.

Some exosomal miRNAs are detectable in CSF and peripheral blood. For example, miR-126-3p, miR-142-3p, miR-146a-5p, and miR-223-3p exhibit down-regulation[84]. In addition, miR-384 shows an up-regulated expression pattern. Up-regulation of miR-384 exerts a regulatory effect on angiotensin-converting enzyme 1. Specifically, it can suppress the expression and activity of angiotensin-converting enzyme 1. By doing so, miR-384 can potentially mitigate the symptoms associated with AD[85].

Interestingly, patient saliva also contains exosome components, and the content of exosomes and exosomal miRNA can also predict AD, and the expression of miR-485-3p is up-regulated[86]. Studies on patients’ tissue and plasma exosomes showed that Has-miR-486-3P was up-regulated[87]. Moreover, Wang et al[88] discovered that miR-185-5p is associated with both education level and depression status. A higher level of education is linked to a reduced likelihood of AD manifestations, while depression exacerbates AD-related symptoms. Mechanistically, Has-miR-185-5p is involved in the production and accumulation of amyloid-β-β peptides.

Schizophrenia

Exosomes and exosomal miRNAs represent an emerging field of research in schizophrenia, offering exciting possibilities for improving diagnosis, treatment, and patient outcomes. As research progresses, they are poised to become integral to the precision medicine approach for schizophrenia, ultimately transforming how we understand and manage this complex disorder (Tables 3 and 4).

Table 3 Summary of changes of exosomal microRNAs in schizophrenia related animal experiments.

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-137	Increase	Gclm-KO mice, human patients	Plasma, prefrontal cortex	The changes in the level of miR-137/COX6A2 in plasma exosomes may be a marker of schizophrenia caused by PVI injury resulting from mitochondrial oxidative stress	Khadimallah et al[49]
miR-146a-5p	Increase	Schizophrenia mouse models, cell models	Plasma, cell	It may target NOTCH1, inhibit synaptic activity mediated by the Notch signaling pathway, and ultimately promote the occurrence and progression of schizophrenia in mice	Wang et al[89]
miR-223-3p	Increase	Mouse models, human postmortem brain, cell models	Cortical neuron, postmortem brain, astrocyte	miR-223 is a miRNA secreted by exosomes targeting glutamate receptors	Amoah et al[90]

miRNA: MicroRNA; PVI: Parvalbumin interneurons.

Table 4 Summary of changes of exosomal microRNAs in schizophrenia patients.

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-203a-3p	Increase	Human patients, cells	Blood sample, cell	Targeted regulation of the 3’UTRs of DJ-1. Possible therapeutic target for schizophrenia	Tsoporis et al[91]
miR-675-3p		Human patients, cell models	Peripheral blood, cell	Associated with clozapine therapy. Understanding new pathogenesis	Funahashi et al[92]
miR-486-5p, miR-199a-3p, miR-144-5p, miR-451a, miR-143-3p, miR-142- 3p	Decrease	Human patients	Urine	Urinary exosomal miRNA is a biomarker for predicting schizophrenia	Tomita et al[93]

miRNA: MicroRNA; 3’UTR: 3’untranslated region.

In the prefrontal cortex and blood of mice with disrupted redox homeostasis (Gclm-KO ± GBR), oxidative stress induces the up-regulation of exosomal miR-137. This increase in exosomal miR-137 expression results in the down-regulation of cytochrome c oxidase subunit 6A2, a critical component of mitochondrial complex IV, as well as a reduction in markers of mitochondrial phagocytosis. The consequent accumulation of damaged mitochondria further exacerbates oxidative stress, leading to selective impairment of parvalbumin-expressing interneurons, which are particularly vulnerable to redox imbalance[49]. These results demonstrate the role of exosomal miR-137 as a critical mediator in the interplay between oxidative stress, mitochondrial dysfunction, and neuronal pathology. Following its up-regulation, exosomal miR-146a-5p may suppress the synaptic activity of cortical pyramidal neurons in mice by targeting NOTCH1, a key component of the Notch signaling pathway. This inhibition of NOTCH1-mediated signaling disrupts synaptic function and neuronal communication, thereby contributing to the pathogenesis and progression of schizophrenia-like phenotypes in mice[89].

Preclinical studies (mouse models and cell cultures) demonstrated that elevated miR-223 expression in the orbitofrontal cortex is strongly associated with neuroinflammatory activation. Specifically, the expression of exosomal miR-223 in astrocytes was significantly elevated under inflammatory conditions. Antipsychotic treatment resulted in a significant down-regulation of exosomal miR-223 in astrocytes[90]. Clinical investigations and experimental models (encompassing murine studies and in vitro cell culture systems) have consistently demonstrated a strong association between miR-223 overexpression in the orbitofrontal cortex and neuroinflammatory activation. Detailed mechanistic analyses revealed that astrocyte-derived exosomal miR-223 exhibits marked up-regulation in response to pro-inflammatory stimuli. Notably, pharmacological intervention with antipsychotic agents was shown to effectively suppress this miR-223 elevation in astrocytic exosomes, suggesting a potential therapeutic modulation of neuroinflammatory pathways.

In a study of patients treated with olanzapine, miR-203a-3p was identified as a crucial mediator that targets the 3’UTR of DJ-1, a protein associated with schizophrenia. Antipsychotic monotherapy restores the antioxidant capacity of DJ-1 by modulating the expression of miR-203a-3p, thereby exerting a therapeutic effect[91]. In a study focusing on patients undergoing clozapine treatment, researchers discovered that compared with the control group, miR-675-3p expression was up-regulated following clozapine administration. This alteration in miR-675-3p expression holds potential as a biomarker for evaluating the efficacy of clozapine treatment[92].

The investigation of exosomes and their associated miRNAs extends beyond traditional sources such as nerve tissue and common body fluids like blood. For example, urinary exosomal miRNAs have emerged as promising predictive biomarkers for persistent psychotic experiences. In a comparative analysis involving 15 patients, miR-486-5p was identified as a potential biomarker. Additionally, six exosomal miRNAs, specifically miR-199a-3p, miR-144-5p, miR-451a, miR-143-3p, and miR-142-3p, exhibited significant up-regulation in this cohort[93].

MDD

The etiology of MDD remains a subject of diverse perspectives. A growing body of empirical data indicates that inflammation originating from multiple systems, including peripheral blood and the CNS, contributes to the development of MDD. Inflammation impacts the pathogenesis of MDD by regulating neurogenesis, dopaminergic and serotonergic metabolism, and activation of the hypothalamic-pituitary-adrenal axis. Conversely, MDD can influence cellular immune function via the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, leading to alterations in the levels of central and peripheral inflammatory mediators[94,95] (Table 5).

Table 5 Summary of changes of exosomal microRNAs in major depressive disorder.

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-146a, miR-155	Increase	Human patients	Blood sample	Interference by negative regulation of the TLR4 signaling pathway. It provides a potential diagnostic and therapeutic approach for MDD	Figueroa-Hall et al[96]
miR-21-5p, miR-145, miR-146a, miR-155	Decrease	Human patients	Serum	Exosomal miRNA may play an important role in predicting the response to antidepressant drugs	Hung et al[97]
miR-9-5p	Increase	MDD mouse models, MDD cell models	Serum, cell	It polarizes M1 of microglia, leading to further neuronal damage. Possible be a new therapeutic target for MDD	Hung et al[98]
miR-144-5p	Decrease	MDD mouse models	Hippocampus	Mediated by the PI3K/Akt/FoxO1 signaling pathway. A new potential therapeutic target	Xian et al[99]
miR-139-5p	Increase	MDD mouse models	Serum, hippocampus	It is activated during stress and mediates depression-like behavior in mice. A potential new approach to the diagnosis and treatment of MDD	Wei et al[39]
miR-139-5p	Decrease	Human patients	Serum	A promising biomarker for diagnosing MDD	Wu et al[100]
miR-186-5p	Decrease	MDD mouse models	Hippocampus	The exosome SERPINF1 in peripheral blood uses miR-186-5p as a potential therapeutic target for this disease	Liang et al[101]

miRNA: MicroRNA; MDD: Major depressive disorder; TLR4: Toll-like receptor 4; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B.

The recognition, activation, and induction of pro-inflammatory mediators by TLRs may be a crucial connection between inflammation and MDD[96]. Serum analysis of patients indicated that the down-regulation of exosomal miR-146a and miR-155 Led to MDD through negative modulation of the TLR4 signaling cascade[97]. Further research demonstrated that, in serum exosomes, the expression profiles of miRNAs modulating the TLR4 signaling pathway, including miR-21-5p, miR-145, miR-146a, and miR-155, were down-regulated both before and after antidepressant treatment. After treatment, miR-145 and miR-146a displayed distinct expression patterns between the remission and non-remission groups, suggesting their potential as biomarkers for treatment response. Conversely, miR-21-5p and miR-155 could not distinguish between these two groups[98].

In other investigations exploring the relationship between inflammation and depression, various signaling pathways are implicated in MDD and inflammation. Analysis of serum and cells from MDD mouse models and cell-based models revealed that the up-regulation of miR-9-5p promoted the polarization of microglia towards the M1 phenotype. This polarized state triggered a pathological cascade characterized by the dysregulated secretion of pro-inflammatory mediators, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, thereby amplifying neuronal injury through sustained neuroinflammatory responses. Mechanistically, this process occurs through suppression of the suppressor of cytokine signaling 2 expression, which in turn reactivates the Janus tyrosine kinase/signal transducer and activator of transcription 3 pathway that is usually inhibited by suppression of the suppressor of cytokine signaling 2[99]. In MDD model mice, miR-144-5p expression in the hippocampus is significantly down-regulated. This down-regulation gives rise to depression-like behaviors, including abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation. The neuronal damage mediated by miR-144-5p is regulated by the PI3K/Akt/FoxO1 signaling pathway[100].

In the serum and hippocampus of MDD mice, miR-139-5p is up-regulated. This up-regulation causes neural damage in the adult hippocampus, leading to the development of depression-like behaviors in the mice. miR-139-5p is a negative regulator of neural stem cell proliferation and neuronal differentiation[39]. After validating the association between miR-139-5p and MDD in mice, the research team obtained consistent results by analyzing patient serum. Specifically, compared with healthy controls, miR-139-5p levels were elevated in the serum of patients. Thus, miR-139-5p holds potential as a biomarker for diagnosing and treating MDD[101]. In the hippocampus of MDD mice, miR-186-5p is down-regulated. This down-regulation inhibits serpin family F member 1 in the hippocampus, contributing to the manifestation of depression-like behaviors[102].

Bipolar disorders

In an analysis of blood samples drawn from patients, researchers observed significant alterations in the expression levels of various miRNAs. Specifically, exosomal miR-484, miR-652-3p, and miR-142-3p exhibited marked down-regulation, indicating decreased presence. Conversely, exosomal miR-185-5p demonstrated a significant increase in expression, highlighting an upregulation of this miRNA. These modifications in the levels of exosomal miRNAs are not merely coincidental; they are intricately connected to multiple biological pathways. For instance, they have implications for key signaling pathways, including the PI3K/Akt signaling pathway, which plays a crucial role in cellular growth and survival. Additionally, these miRNAs participate in the pathways of fatty acid synthesis and metabolic processes, as well as the extracellular matrix and adhesion pathways, which are essential for maintaining tissue structure and facilitating cellular communication. Thus, the alterations in these specific miRNAs may have significant biological repercussions that warrant further investigation[103] (Table 6).

Table 6 Summary of changes of exosomal microRNAs in bipolar disorder.

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-484, miR-652-3p, miR-142-3p	Decrease	BD human patients	Plasma	Abnormally regulated miRNAs enrich multiple target pathways, including the PI3K/Akt signaling pathway, fatty acid biosynthesis/metabolism, and extracellular matrix	Ceylan et al[103]
miR-185-5p	Increase	BD human patients	Plasma	Regulate the adhesion pathway	Ceylan et al[103]

miRNA: MicroRNA; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; BD: Bipolar disorder.

Neurodevelopmental disorders

Autism spectrum disorder: Exosomes rich in miR-29 b-3p cross the BBB to reach the medial prefrontal cortex and subsequently induce inhibition of insulin-like growth factor 1 expression in neurons. Excitatory neuron activation in the medial prefrontal cortex improved behavioral abnormalities in autism spectrum disorder (ASD) mice. miR-29 b-3p was up-regulated in the medial prefrontal cortex of mice[104]. Exosomes derived from human adipose-mesenchymal stem cells can improve neurodevelopmental abnormalities and inhibit the inflammatory microenvironment in the brain of ASD mice. This change is mediated through the miR-21a-3p/PI3K/AKT axis[105] (Table 7).

Table 7 Summary of changes of exosomal microRNAs in neurodevelopmental disorder.

Disease	miRNAs	Alteration	Model	Type tissue	Significance	Ref.
ASD	miR-29b-3p	Increase	Mouse	Medial prefrontal cortex	Exosome-derived miR-29 b-3p negatively regulates IGF-1 in the mPFC	Chen et al[104]
	miR-21a-3p		ASD mouse models	Brian tissue	MiR-21a-3p/PI3K/Akt, as a signaling pathway, promotes neurogenesis and thus plays a regulatory role	Fu et al[105]
RTT	miR-21-5p		RTT mouse models	Brian tissue	Modulating the Epha4/TEK axis promotes early neurogenesis possible biomarker for RTT	Pan et al[40]

ASD: Autism spectrum disorder; RTT: Rett syndrome; miRNA: MicroRNA; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; IGF: Insulin like growth factor; mPFC: Medial prefrontal cortex.

RTT: RTT is a rare neurodevelopmental disorder. Pan et al[40] found that exosomal miR-21-5p derived from human uro-derived stem cells can promote early neurogenesis by modulating the EPha4/TEK axis, which may represent a promising therapeutic approach for this debilitating disease.

PTSD: In the PTSD mouse model, exosomal miR-15a-5p, miR-497a-5p, and miR-511-5p were down-regulated in the hippocampus and medial prefrontal cortex, and stress behaviors were expressed through brain-derived neurotrophic factor and FKBP5[106]. Plasma analysis of patients after explosive traumatic brain injury showed that exosomal miR-326 was found. Changes in miR-361 and miR-767-5p may be related to pathological mechanisms of dysregulation of cellular pathways associated with neurodegeneration, inflammation, and central hormone regulation[107]. Exosomal miR-139-5p was down-regulated in blood samples of veterans with mild traumatic brain injury, mainly because the target molecules of the glucocorticoid receptor signaling pathway were involved in this process[53] (Table 8).

Table 8 Summary of changes of exosomal microRNAs in post-traumatic stress disorder.

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-15a-5p, miR-497a-5p, miR-511-5p	Decrease	PTSD mouse models	Hippocampus, medial prefrontal cortex	Brain region-dependent regulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes	Maurel et al[106]
miR-326, miR-361, miR-767-5p		PTSD human patients	Plasma	Possible biomarker of PTSD	Devoto et al[107]
miR-139-5p	Decrease	PTSD human patients	Blood sample	MiR-139-5p was associated with the severity of PTSD symptoms in remote mTBI participants	Guedes et al[53]

mTBI: Mild traumatic brain injury; PTSD: Post-traumatic stress disorder; BDNF: Brain-derived neurotrophic factor; miRNA: MicroRNA.

CONCLUSION

Exosomal miRNAs can mediate post-transcriptional gene silencing by binding to the 3'UTR or the open reading frame region of target miRNA, and play a role in disease neurogenesis, synaptic plasticity, inflammatory responses, mitochondrial function, and stress response. The altered levels of miR-320a, miR-328-3p, and miR-204-5p in CSF, along with the variations in miR-9, miR-21, and miR-122 in plasma, could potentially serve as early indicators of AD. In schizophrenia, the up-regulation of miR-137 and miR-146a-5p in relevant brain areas and their influence on synaptic activity and mitochondrial function could serve as biomarkers of schizophrenia. In MDD, exosomal miR-146a and miR-155 are involved in inflammatory responses and other pathological mechanisms. The probability as a predictor of response to antidepressant treatment creates a new direction for research. Similarly, in PTSD, ASD, RTT, and bipolar disorder, the alterations in exosomal miRNAs have provided insights into the disease mechanisms. Despite persistent challenges, including methodological inconsistencies in exosome isolation, sample heterogeneity, and technical limitations in miRNA profiling, recent advancements in bioengineering technologies and multi-omics integration present transformative potential for elucidating disease mechanisms. Continued research in this field is expected to bring new hope for the diagnosis and treatment of mental disorders. New technologies are required to break through the existing limitations and promote their clinical transformation in the field of psychiatric medicine in the future.