Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage. The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury. Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury, suggesting that this axis is a novel target and regulatory control point for treatment. This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis, along with the regenerative and repair mechanisms linking the axis to spinal cord injury. Additionally, we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis. This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs, along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs. Nevertheless, there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis. This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

Current treatments for inflammatory bowel disease often fail due to systemic side effects, but bovine milk-derived extracellular vesicles (EVs) show promise for targeted delivery to inflamed gut tissue via the leaky gut effect. This study assessed the stability of EVs as drug carriers in simulated gastrointestinal (GI) fluids and their efficacy in a colitis mouse model. EVs were characterised after incubation in PBS at various pH levels, and their lipid bilayer stability in biorelevant GI fluids was evaluated using the polar probe laurdan. Two small molecules, acridine orange (lipophilic) and riboflavin (hydrophilic), were loaded into EVs to test their release under GI conditions, while unloaded EVs were investigated for therapeutic effect via oral gavage or rectal enema in a colitis mouse model. Although no significant changes in EVs' physical properties were observed at different pH levels, lipid bilayer damage was evident in acidic (p ≤ 0.05) and enzyme-rich environments (p ≤ 0.01). Acridine orange release was significant (p ≤ 0.05), butriboflavin remained encapsulated, and no therapeutic effect was observed with unloaded EVs in vivo. These results suggest that physical characterisation alone does not reflect EV stability, that bovine milk EVs have limited potential for oral drug delivery and are better suited for hydrophilic drugs.

Neuropilin-1 (NRP1) is a transmembrane glycoprotein that functions as a co-receptor with various cellular functions. Our previous studies identified the NRP1 exon 4-skipping (NRP1-ΔE4) splice variant as an aggressive metastasis driver by activating endosomal signals. Here, we demonstrate the critical role of glycosaminoglycan (GAG) modification in regulating NRP1-ΔE4's cellular trafficking and oncogenic activity. NRP1-ΔE4 undergoes constitutive internalization into endosomes and subsequent exosomal release from colorectal cancer (CRC) cells. Exosomal NRP1-ΔE4 enhances the migration and invasion of both donor and recipient CRC cells. Genetic or pharmacological inhibition of exosome secretion, or immunodepletion of exosomal NRP1-ΔE4, markedly reduces its metastatic potential. Notably, GAG modification at the O-glycosylation site Ser612 is essential for NRP1-ΔE4's endosomal trafficking and exosomal release. This modification also promotes the formation of a trimeric complex with Met and β1-integrin, leading to their co-internalization and accumulation in endosomes, which activates FAK signaling and drives CRC metastasis. These findings reveal GAG modification as a key regulatory process that governs the endosomal-exosomal trafficking of NRP1-ΔE4 to facilitate CRC cell dissemination.

Asthma is a chronic respiratory disorder characterized by persistent inflammation, airway hyper‑responsiveness and remodeling, leading to notable morbidity and decreased quality of life for patients. Mesenchymal stem cells (MSCs) have potential in regenerative medicine due to their potent immunomodulatory properties and anti‑inflammatory effects. The therapeutic benefits of MSCs are largely mediated by secreted exosomes that facilitate intercellular communication by transferring bioactive molecules, including proteins, lipids and microRNAs. The present review explores the therapeutic potential of MSC‑derived exosomes in asthma, highlighting their ability to modulate key pathological mechanisms underlying the disease.

The roles of exosomes in osteoblast differentiation has been widely investigated. Low exosome production from donor cells constitutes the greatest challenges in exosome-based therapies. Spexin (SPX) is a neuropeptide that is involved in various biological activities including osteogenic differentiation and bone regeneration. Therefore, the purpose of this study was to investigate the effects of SPX on exosome production in osteogenic medium (OM)-treated MC3T3-E1 cells and SPX induced MC3T3-E1 cell-derived exosomes (OM + SPX-Exos) on osteoblast differentiation.

To evaluate exosome yield, MC3T3-E1 cells were treated with SPX. Exosome marker expression and particle number were validated via reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and nanoparticle tracking analysis (NTA), respectively. MC3T3-E1 cells were then treated with various concentrations of OM + SPX-Exos and osteogenic medium treated MC3T3-E1 derived exosomes (OM-Exos). Cell proliferation, osteogenic differentiation marker expression, alkaline phosphatase (ALP) activity, and mineralization were evaluated using the CCK-8 assay, RT-qPCR, ALP staining, and alizarin red S staining, respectively.

SPX significantly increased exosome production and the expression of the exosome markers; Cd63, Rab27a and Alix in MC3T3E1 cells. Furthermore, OM + SPX-Exos significantly increased in the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase, biomineralized associated (Alpl), collagen type I alpha 1 (Col1a1), secreted phosphoprotein 1 (Spp1) and Integrin-binding sialoprotein (Ibsp) at a concentration of 5 µg/ml. ALP staining and alizarin red S staining also revealed that OM + SPX-Exos (5 µg/ml) resulted in more ALP-positive cells and markedly promoted mineralization, respectively.

In general, these results indicate that SPX stimulates exosome production. OM + SPX-Exos enhances MC3T3-E1 cells proliferation, osteogenic differentiation and mineralization.

Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.

Cellular communication is a cornerstone of metazoan development, orchestrating cell behavior, differentiation, and tissue formation. Morphogens, key signaling molecules for patterning tissue architecture, are traditionally thought to act through diffusion or endocytosis but struggle to explain precise long-range gradient formation in complex tissues. The discovery of cytonemes, specialized actin-based membrane extensions, has introduced a novel mechanism for direct intercellular signaling. Their dynamic structure allows for long-range signaling, ensuring specificity and accuracy in morphogen delivery, which is essential for proper tissue patterning and cell differentiation. In this review, we summarize the latest advances of cytoneme research across different model organisms by focusing on the regulatory mechanisms and functional roles in stem cells and developmental disorders. We establish cytonemes as fundamental mediators of intercellular communication and emphasize their pivotal roles in developmental biology and potential implications in regenerative medicine and cancer therapy.

Oxidative stress can affect many aspects of the reproduction process. The embryo implantation process is also one of the critical steps in establishing a successful pregnancy, and several factors, including oxidative stress, can impact the process. Oxidative stress is a state of imbalance between pro-oxidant molecules such as reactive oxygen species (ROS) and antioxidant defenses. Excessive levels of ROS cause damage to the cellular macromolecules such as nucleic acids, proteins, and lipids, resulting in cell dysfunction and pathological conditions. Recently, studies have displayed the therapeutic and antioxidant properties of exosomes derived from stem cells. Exosomes are one type of extracellular vesicles (EVs) secreted by almost all cells and contain different biomolecules. The unique properties of exosomes, like regulation of biological processes, transportation of biomolecules, stability, and biodegradability, can make exosomes a promising therapeutic option in reproductive disorders and diseases. Exosomes also can significantly improve the curative effect of oxidative stress-related pathogenesis. Accordingly, this review aims to provide a novel overview of how exosomes derived from stem cells can regulate oxidative stress and support the process of embryo implantation, hoping to pave the way to clinical applications and future research in this field.

Gastric cancer ranks fifth among the most prevalent cancers globally, with a dismal prognosis. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has emerged as a glimmer of hope for advanced gastric cancer patients. However, not all patients can benefit from this treatment modality, as the tumor microenvironment significantly influences treatment efficacy. Exosomes, pivotal mediators of intercellular communication, exert intricate and diverse effects in shaping and regulating the tumor microenvironment. This review provides a comprehensive overview of the functional mechanisms of exosomes within the gastric cancer tumor microenvironment. It delves into their biogenesis, functions, and impact on innate and adaptive immune cells (such as dendritic cells, myeloid-derived suppressor cells, and T cells) and cancer-associated fibroblasts. Additionally, the potential applications of exosomes in gastric cancer immunotherapy are explored, including their use as biomarkers to predict responses to immune checkpoint inhibitors, and drug delivery vectors, and in the development of exosome-based vaccines and gene therapy. Notably, this review emphasizes the dual nature of exosomes: they can facilitate tumor immune escape, yet they also serve as promising targets for innovative therapeutic strategies. It also compares potential exosome-based strategies with existing immunotherapies like ICIs and emerging CAR-T cell therapies. Finally, insights into the future of exosomes in precision immunotherapy for gastric cancer are offered, presenting a forward-looking perspective on this emerging field.

A stable ocular surface is crucial for maintaining ocular health by protecting against various infections. This is achieved by coordinated function of ocular structures (cornea, limbus, conjunctiva), innervation, and the tear film which forms a protective barrier over the ocular surface ensuring proper hydration, lubrication, and overall ocular comfort. This complex three-layered tear film secreted by different sources ensures its stability by adhesion to the corneal epithelium. Ocular surface fluid kinetics and tear secretion involve complex processes influenced by neural regulation, environmental factors, and molecular composition. Recent advances in cell biology and secretome has unravelled the mysteries of cellular cargo of almost every cell and system i.e. the extracellular vesicles (EVs) which facilitate intercellular communication. EVs are of different sizes, amongst which small EVs (sEVs) potentially are more informative than other EVs.

An extensive review of literature on sEVs in tears and ocular surface was conducted.

Emerging literature on sEVs derived from ocular surface structures such as cornea and limbal stem cells contribute to corneal wound healing, regeneration and reduced fibrosis by the activation of specific proteins. A recent study documents that homeostasis between cornea and conjunctiva is maintained by the expression of specific genes triggering trans differentiation in diseased conditions. There is also mounting evidence on role of tear-derived sEVs in normal and diseased states. The approach in which tear layers secreted from three different sources form into a single tri-layered stable biofilm covering the entire ocular surface remains elusive. Hence not surprisingly, the tear sEVs therefore have been referred to as one entity and not attributed to any of the 3 different sources that they originate from.

This review attempts to present the recent concepts of sEVs, ocular surface, tears and highlight the gaps in our understanding of tear-derived exosomes and its potential role in homeostasis and disease conditions.

Introduction: Coronavirus (CoV) is an extremely contagious, enveloped positive-single-stranded RNA virus, which has become a global pandemic that causes several illnesses in humans and animals. Hence, it is necessary to investigate viral-induced reactions across diverse hosts. Herein, we propose utilizing naturally secreted extracellular vesicles (EVs), mainly focusing on exosomes to examine virus-host responses following CoV infection. Exosomes are small membrane-bound vesicles originating from the endosomal pathway, which play a pivotal role in intracellular communication and physiological and pathological processes. We suggested that CoV could impact EV formation, content, and diverse immune responses in vitro. Methods: In this study, we infected A-72, which is a canine fibroblast cell line, with a feline coronavirus (FCoV) and canine coronavirus (CCoV) independently in an exosome-free media at 0.001 multiplicity of infection (MOI), with incubation periods of 48 and 72 h. The cell viability was significantly downregulated with increased incubation time following FCoV and CCoV infection, which was identified by performing the 3-(4,5-dimethylthiazo-1-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. After the infection, EVs were isolated through ultracentrifugation, and the subsequent analysis involved quantifying and characterizing the purified EVs using various techniques. Results: NanoSight particle tracking analysis (NTA) verified that EV dimensions fell between 100 and 200 nm at both incubation periods. At both periods, total protein and RNA levels were significantly upregulated in A-72-derived EVs following FCoV and CCoV infections. However, total DNA levels were gradually upregulated with increased incubation time. Dot blot analysis indicated that the expression levels of ACE2, IL-1β, Flotillin-1, CD63, caspase-8, and Hsp90 were modified in A-72-derived EVs following both CoV infections. Conclusions: Our results indicated that FCoV and CCoV infections could modulate the EV production and content, which could play a role in the development of viral diseases. Investigating diverse animal CoV will provide in-depth insight into host exosome biology during CoV infection. Hence, our findings contribute to the comprehension and characterization of EVs in virus-host interactions during CoV infection.

Autoimmune diseases (AIDs) are marked by systemic inflammation and immune dysregulation, yet current therapies often fail to target their underlying causes. Emerging evidence positions exosomal non-coding RNAs (ncRNAs)-including miRNAs, lncRNAs, and circRNAs-as key regulators of inflammatory pathways, providing critical insights into AID pathogenesis. This review synthesizes recent advances in how these ncRNAs orchestrate immune cell communication, modulate inflammatory mediators, and drive microglial activation in neuroinflammatory AIDs. It evaluates their dual role as disease amplifiers (e.g., miR-155 in lupus, miR-326 in rheumatoid arthritis) and therapeutic targets, emphasizing their potential to reprogram immune responses or deliver anti-inflammatory agents. In this review, we first provide a glimpse into the pathogenesis of autoimmune diseases and delve into the structure and function of exosomes, emphasizing their role in cell-cell communication. We then discuss the regulatory roles of exosomal ncRNAs in immune modulation, detailing their types, functions, and mechanisms of action. Finally, we examine the implications of exosomes and exosomal ncRNAs in the context of autoimmune diseases, with a particular focus on microglial activation and its contribution to neuroinflammation.

Various cell types release extracellular vesicles (EVs) containing proteins, DNA, and RNA essential for intercellular communication. The bioactive molecules from EVs can reflect disease status and monitor progression, while their communication abilities suggest therapeutic potential. We will review various EV isolation methods, EV-enriched fluids, and studies analyzing differential mi-RNA and protein levels extracted from EVs. Specifically, tear-derived EVs, which protect their molecular content and allow for real-time monitoring of ocular conditions such as Dry Eye Disease (DED), Sjögren's disease (SJD), Ocular graft-versus-host disease (oGVHD), and Diabetic Retinopathy (DR), which all currently remain undiagnosed in patients. EVs also provide potential as carriers for gene transfer, and mesenchymal stem cell (MSCs)-derived EVs are shown to be immunomodulatory, demonstrating promise for autoimmune ocular diseases. Through the multi-omic analysis of tear-fluid content, EVs are promising biomarkers and therapeutic agents in ocular diseases.

Circular noncoding RNAs (circRNAs) are implicated in many human diseases, but their role in atrial fibrillation (AF) is poorly understood. In this study, we performed bioinformatics analysis of circRNA sequencing data to identify AF-related circRNAs.

Left atrial appendage (LAA) samples were obtained from patients with valvular heart disease and were categorised into the sinus rhythm (SR; n = 4) and AF (n = 4) groups. CircRNA sequencing analysis was performed to identify differentially expressed (DE) circRNAs in AF patients. Functional enrichment analysis of DE circRNAs was performed to identify enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.

We identified 3338 DE circRNAs, including 2147 upregulated and 1191 downregulated circRNAs, in AF patients. A ceRNA network of 16 DE circRNAs, 11 DE miRNAs, and 15 DE mRNAs was constructed. Functional enrichment analyses revealed that the AF-related DE circRNAs were enriched in response to vitamin D, the potassium channel complex, delayed rectifier potassium channel activity, osteoclast differentiation, primary immunodeficiency, endocrine and other factor-regulated calcium reabsorption and other processes. ROC curve analysis identified circRNA_00324, circRNA_17225, circRNA_16305, circRNA_10233, circRNA_05499, circRNA_03183, circRNA_14211, and circRNA_18422 as potential predictive biomarkers for distinguishing AF patients from SR patients, with AUC values of 0.9138, 0.7370, 0.8526, 0.6803, 0.8163, 0.8662, 0.7664, and 0.9320, respectively.

In this study, we constructed an AF-related ceRNA network and identified eight circRNAs as potential predictive biomarkers of AF.

Exosomes are extracellular vesicles, which are released into the extracellular space by all types of cells, especially stem cells. Compared with stem cells, exosomes are safer and can be considered one of the most promising therapeutic strategies for neurodegenerative disease. We examined the effect of exosomes derived from bone marrow mesenchymal stem cells (BM-MSC) on a rat model of Alzheimer's disease (AD). For this purpose, male Wistar rats weighing 220-250 g were used. For the induction of AD, rats received a daily dosage of 100 mg/kg Aluminum chloride (Alcl3) by oral gavage for 60 days. Also, Primary BM-MSC was extracted from the femora of Wistar rats (male, 100-150 g). Extracted exosomes were Characterized and Qualified using TEM Microscope and Zetasizer Nano. Specific markers of exosomes were evaluated by Flow cytometry. MSC-extracted exosomes (150 µg/µl) were injected 2 or 5 times into the animals via tail vein on specific days. Our data revealed that receiving exosomes significantly prevented AlCl3-induced enhancement of hippocampal APP gene expression, beta-amyloid plaque formation, impairment of passive avoidance learning and spatial memory. However, exosome injections in healthy subjects caused some negative effects such as spatial memory impairment. It seems, MSC-derived exosomes can be considered as a candidate to prevent AD progression.

Liver fibrosis is caused by the activation of hepatic stellate cells due to various reasons. Our previous research has shown that aldose reductase (AR) played an important role in liver ischemia-reperfusion injury and liver regeneration.

Here, we aimed to investigate the role and mechanism of AR in the progression of liver fibrosis induced by various factors.

AR expression was detected in liver tissue of fibrosis patients and mouse models. The role and mechanism of AR in fibrosis progression were investigated in AR knockout mice and cell lines.

AR expression was increased in liver from patients with fibrosis and mouse models. The knockout of AR protected against CCL4 or HFD induced liver injury and development of fibrosis. Furthermore, AR promoted ubiquitization degradation of HUR through competitive binding with OTUB1, thereby exacerbating the accumulation of ROS, and ultimately activating PI3K/AKT pathway. The impaired autophagolysosome resulted in the massive release of exosomes, which activated stellate cells by regulating PTP4a1/SMAD3 pathway. The hepatocyte specific recovery of AR in AR knockout mice aggravated ROS damage and fibrosis, while recovery of HUR in wild-type mice reduced ROS damage and fibrosis.

In conclusion, these findings suggest that AR might be a promising therapeutic target for treating liver fibrosis.

Neurological disorders such as Alzheimer's disease, Parkinson's disease, and stroke pose significant challenges for conventional therapy due to the complexities of the blood-brain barrier (BBB) and the restricted delivery of drugs to the central nervous system. Exosomes, a type of small extracellular vesicle secreted by nearly all cell types, hold substantial promise as delivery vehicles for therapeutic agents in treating these conditions. Notably, stem cell-secreted exosomes have emerged as particularly effective due to their regenerative potential and natural ability to cross the BBB. Similarly, hydrogels have gained recognition as versatile biomaterials capable of supporting sustained release and targeted delivery of therapeutics. The combination of the regenerative properties of stem cell-derived exosomes (SC-Exos) with the structural and functional benefits of hydrogels offers a promising approach for enhancing neurogenesis, modulating neuroinflammation, and facilitating tissue repair. This review explores the origin, structure, and modifications of exosomes as well as the synthesis and incorporation methods of hydrogels in the therapeutic context for debilitating neurological disorders. It highlights recent advancements in using SC-Exos and hydrogels for therapeutic delivery, addressing both current challenges and future applications. Improving our understanding of hydrogels loaded with SC-Exos for cargo transportation and neural tissue regeneration may pave the way for novel therapeutic strategies.

The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods.

This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions.

By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.

Cancer metastasis is a complicated biological process that critically affects cancer progression, patient outcomes, and treatment plans. A significant step in metastasis is the formation of a pre-metastatic niche (PMN). A small subset of cells within tumors, known as cancer stem cells (CSCs), possess unique characteristics including, differentiation into different cell types within the tumor, self-renewal, and resistance to conventional therapies, that enable them to initiate tumors and drive metastasis. PMN plays an important role in preparing secondary organs for the arrival and proliferation of CSCs, thereby facilitating metastasis. CSC-derived exosomes are crucial components in the complex interplay between CSCs and the tumor microenvironment. These exosomes function as transporters of various substances that can promote cancer progression, metastasis, and modulation of pre-metastatic environments by delivering microRNA (miRNA, miR) cargo. This review aims to illustrate how exosomal miRNAs (exo-miRs) secreted by CSCs can predispose PMN and promote angiogenesis and metastasis.

Leishmaniasis continues to be a critical international health issue due to the scarcity of efficient treatment and the development of drug tolerance. New developments in the research of extracellular vesicles (EVs), especially exosomes, have revealed novel disease management approaches. Exosomes are small vesicles that transport lipids, nucleic acids, and proteins in cell signalling. Its biogenesis depends on several cellular processes, and their functions in immune response, encompassing innate and adaptive immunity, underline their function in the pathogen-host interface. Exosomes play a significant role in the pathogenesis of some parasitic infections, especially Leishmaniasis, by helping parasites escape host immunity and promote disease progression. This article explains that in the framework of parasitic diseases, exosomes can act as master regulators that define the pathogenesis of the disease, as illustrated by the engagement of exosomes in the Leishmaniasis parasite and immune escape processes. Based on many published articles on Leishmaniasis, this review aims to summarize the biogenesis of exosomes, the properties of the cargo in exosomes, and the modulation of immune responses. We delve deeper into the prospect of using exosomes for the therapy of Leishmaniasis based on the possibility of using these extracellular vesicles for drug delivery and as diagnostic and prognostic biomarkers. Lastly, we focus on the recent research perspectives and future developments, underlining the necessity to continue the investigation of exosome-mediated approaches in Leishmaniasis treatment. Thus, this review intends to draw attention to exosomes as a bright new perspective in the battle against this disabling affliction.

Extracellular vesicles (EVs) have emerged as key cell-to-cell communication mediators and play significant roles in both physiological and pathological processes. In EVs, exosomes represent a distinct subpopulation of EVs that have been found to be involved in cancer initiation and therapeutic resistance. Exosomes transfer a diverse spectrum of molecular cargos that have significant effects on the tumor microenvironment (TME), thereby enabling cancer initiation, metastasis, and therapeutic resistance. Exosomes have recently been of interest in cancer therapy due to their role as important mediators of treatment resistance. The exosomal molecular content-proteins, miRNAs, and lncRNAs-allows exosomes to perform functions including drug efflux and detoxification, cell death pathway modulation, induction of epithelial-to-mesenchymal transition (EMT), and suppression of the immune system. In addition to facilitating immune and stromal cell interactions, exosomes cause extracellular matrix remodeling and induce tumor heterogeneity, making it more difficult to respond to therapy. This review covers intricate roles of exosomes in cancer therapy resistance with regard to their biogenesis, molecular content, and functional impact in the TME. Along with this, we also discuss new therapeutic strategies to overcome exosome-mediated resistance including utilizing exosome inhibitors, designed exosome therapy, and combination with conventional therapies. While exosomes hold promise in prediction and diagnosis through their biomarker function, their heterogeneous origins and cryptic functions make it difficult to target interventions. This review emphasizes that research on exosome-mediated pathways is urgently required to develop new therapeutic strategies that can improve cancer treatment outcomes.

The tumor microenvironment (TME) plays a crucial role in the development and progression of gastric cancer (GC). The TME comprises a network of cancer cells, immune cells, fibroblasts, endothelial cells, and extracellular matrix components, which provide a supportive niche for cancer cells. This study investigates the role of TME-derived exosomal competitive endogenous RNAs (ceRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as major regulating agents in GC development. Exosomal ceRNAs control gene expression across several TME components, amplifying cancer hallmarks like cell proliferation, invasion, metastases, and chemoresistance. They promote dynamic interplay between cancer cells and adjacent stromal cells, enabling tumor development through immune suppression, angiogenesis, and epithelial-mesenchymal transition (EMT). Exosomal ceRNAs can modify the TME, creating a pro-tumorigenic milieu and preparing cancer cells to avoid immunological responses, defy death, and adapt to therapeutic pressures. This review highlights the understudied interactions between the TME and exosomal ceRNAs in gastric cancer and emphasizes their potential utility as diagnostic and therapeutic tools.

Extracellular vesicles (EVs), defined as membrane-bound vesicles released from all cells, are being explored for their diagnostic and therapeutic role in dry eye disease (DED). We systematically shortlisted 32 articles on the role of EVs in diagnosing and treating DED. We cover the progress in the last 2 decades on the classification and isolation of EVs and their role in DED. The diagnostic predictability of exosomes was evaluated in Sjögren syndrome (SS) patients' tears, plasma, and saliva, where upregulation of inflammatory proteins was reported uniformly across studies. Also, we evaluate the therapeutic effects of MSC-derived EVs in in vitro and in vivo studies of SS and DED mouse models. A significant response occurs at a functional level with improved tear production and saliva flow rate and at a cellular level with reduced lymphocyte infiltration, improved corneal structural integrity, decreased epithelial cell apoptosis, and dampening of the inflammatory cytokine response. The proposed mechanisms of EV action include PD-L1, PRDM, NLRP-3, and Nf-kb pathways, and an increase in M2 macrophage phenotype. Current use of exosomes in DED is limited due to their cumbersome isolation techniqus. Further research on human subjects is needed, in addition to optimizing exosome isolation and delivery methods.

Extracellular vesicles (EVs) are released by all kind of cells into the extracellular space, where they shuttle parental cell-derived molecular cargoes (DNA, RNA, proteins) to both adjacent and distant cells, influencing the physiology of target cells. Their specific cargo content and abundance in liquid biopsies make them excellent candidates for biomarker studies. Indeed, EVs isolated from various body fluids, including blood, pleural fluid, urine, cerebrospinal fluid, saliva, milk, ascites, and tears, have been recognized for their potential as biomarkers in diagnosis, monitoring treatment, and predicting outcomes for various diseases. Increasing studies suggest that tears have great promise as a noninvasive liquid biopsy source for EVs. Our aim here is to provide a comprehensive review of the exploration of tears as a noninvasive reservoir of EVs and their contents, evaluating their accessibility and potential utility as a liquid biopsy method. Additionally, the potential of tear EVs in various cancers, including ocular cancer, is discussed. Finally, the advantages and challenges of employing tear-based liquid biopsy for EVs for the disease's biomarker studies are evaluated.

The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy. Within the tumor microenvironment, exosomes have emerged as pivotal mediators of intercellular communication, with their cargo of non-coding RNAs (ncRNAs) serving as key regulatory elements. This review examines the multifaceted roles of immune cell-derived exosomal ncRNAs in tumor biology. The involvement of various immune cells, including T cells, B cells, natural killer cells, macrophages, neutrophils, and myeloid-derived suppressor cells, in utilizing exosomal ncRNAs to regulate tumor initiation and progression is explored. Additionally, the biogenesis and delivery mechanisms of these immune cell-derived exosomal ncRNAs are discussed, alongside their potential clinical applications in cancer.

The effect of Curcumin-enhanced stem cell exosomes on the learning and memory impairment induced by streptozotocin (STZ) and neuro-inflammation in rats was evaluated. An animal model of Alzheimer's disease (AD) was established by intracerebroventricular (ICV) injection of STZ (3 mg/kg) in male Wistar rats (250 ± 50 g). ICV STZ injections chronically reduce cerebral glucose uptake and produce other effects similar to pathological, molecular and behavioral features of AD. Numerous studies confirmed the anti-inflammatory and antioxidant properties of curcumin (a natural polyphenol) against free radicals, as well as its ability to inhibit the aggregation of proteins such as beta-amyloid and alpha-synuclein in disorders such as AD and Parkinson's disease. The use of extracellular vesicles has garnered a lot of interest in research studies because of the important roles that mesenchymal stem cell-derived exosomes play in permeability, retention, and drug delivery as well as their ability to reduce inflammatory cytokines (TNF-α, IL-1β, and IL-6). Furthermore, researches highlighted the positive effect of curcumin on neuronal differentiation of stem cells in vivo and in vitro. Since studies emphasized the ameliorating effect of curcumin-treated macrophage-exosomes on symptoms of Alzheimer's disease by inhibiting tau protein phosphorylation, we proposed that Curcumin-primed MSC exosomes may offer greater efficacy to alleviate AD compared to naïve MSC exosomes. In this study, we investigated the effect of curcumin in stimulating the anti-inflammatory potential of exosome-derived stem cells. We evaluated the effect of MSC-EXO and pre-treated MSC-EXO with curcumin (CUR-MSC-EXO) on inhibiting inflammation and memory and learning impairments. Following four intraperitoneal injections of MSC-EXO and CUR-MSC-EXO at a dosage of 30μg/body over 30 days, we found that MSC-EXO and CUR-MSC-EXO elevated anti-inflammatory cytokines (IL10, TGF-β) and reduced pro-inflammatory cytokines (IL1, TNF-α) in peripheral blood compared to the AD group. The elevated level of M2 anti-inflammatory microglia markers (Arg1, CD206) and decreased level expression of M1 pro-inflammatory markers (iNOS, CD86) indicated that the CUR-MSC-EXO effect was more significant in the polarization of microglia into the M2 phenotype in the rat hippocampus. Both treatment groups demonstrated improvements in memory and learning skills. The results of the passive avoidance learning in the rats with STZ-induced memory impairment, however, were better in the CUR-MSC-EXO. Additionally, after therapy, a decrease in degenerative neurons was seen. Therefore, using curcumin may stimulate the anti-inflammatory and neuroprotective potential of exosome-derived stem cells which could provide hope for Alzheimer's disease treatment in the future.

Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In addition, due to the brain's unique immune status and the suppressor tumor microenvironment (TME), glioblastoma treatment has faced more challenges. Exosomes play a critical role in cancer metastasis by regulating cell-cell interactions that promote tumor growth, angiogenesis, metastasis, treatment resistance, and immunological regulation in the tumor microenvironment. This review explores the pivotal role of exosomes in the development of glioblastoma, with a focus on their potential as non-invasive biomarkers for prognosis, early detection and real-time monitoring of disease progression. Notably, exosome-based drug delivery methods hold promise for overcoming the blood-brain barrier (BBB) and developing targeted therapies for glioblastoma. Despite challenges in clinical translation, the potential for personalized exosome = -054321`therapies and the capacity to enhance therapeutic responses in glioblastoma, present intriguing opportunities for improving patient outcomes. It seems that getting a good and current grasp of the role of exosomes in the fight against glioblastoma would properly serve the scientific community to further their understanding of the related potentials of these biological moieties.

Bacterial extracellular vesicles (BEVs) produced by members of the intestinal microbiota can not only contribute to digestion but also mediate microbe-host cell communication via the transfer of functional biomolecules to mammalian host cells. An unresolved question is which host factors and conditions influence BEV cargo and how they impact host cell function. To address this question, we analysed and compared the proteomes of BEVs released by the major human gastrointestinal tract (GIT) symbiont Bacteroides thetaiotaomicron (Bt) in vivo in fed versus fasted animals using nano-liquid chromatography with tandem mass spectrometry (LC-MSMS). Among the proteins whose abundance was negatively affected by fasting, nine of ten proteins of the serine protease family, including the regulatory protein dipeptidyl peptidase-4 (DPP-4), were significantly decreased in BEVs produced in the GITs of fasted animals. Strikingly, in extracellular vesicles produced by the intestinal epithelia of the same fasted mice, the proteins with the most increased abundance were serine protease inhibitors (serpins). Together, these findings suggest a dynamic interaction between GI bacteria and the host. Additionally, they indicate a regulatory role for the host in determining the balance between bacterial serine proteases and host serpins exported in bacterial and host extracellular vesicles.

Extracellular vesicles (EVs) are important mediators of intercellular communication and play key roles in the regulation of pathophysiological processes. In diabetic kidney disease (DKD), it has been reported that macrophages recruited in the mesangial region may play pathogenic roles through inducing local inflammation in glomeruli. We focused on EV-mediated crosstalk between mesangial cells (MC) and macrophages as a novel therapeutic target for DKD. EVs released from MC induced inflammation in macrophages and the effect was enhanced under high-glucose conditions. For discovering novel therapeutic agents which can inhibit such EV-mediated mechanisms, drug repositioning is considered as an effective tool. We established a unique screening strategy and screened agents to aim at maximizing their specificity and potency to inhibit EV mechanisms, along with minimizing their toxicity. We succeeded in identifying alvespimycin, an HSP90 inhibitor. Treatment of diabetic rats with alvespimycin significantly suppressed mesangial expansion, inflammatory gene activation including macrophage markers, and proteinuria. The inhibitory effect on EV uptake was specific to alvespimycin compared with other known HSP90 inhibitors. MC-derived EVs are crucial for inflammation by intercellular crosstalk between MC and macrophages in DKD, and alvespimycin effectively ameliorated the progression of DKD by suppressing EV-mediated actions, suggesting that EV-targeted agents can be a novel therapeutic strategy.

Exosomes (30-150 nm) are small extracellular vesicles that are secreted by cells into the extracellular environment and are known to mediate cell-to-cell communication. Exosomes contain proteins, lipids, and RNA molecules in relative abundance, capable of modifying the activity of target cells. Melanoma-derived exosomes (MEXs) promote the transfer of oncogenic signals and immunosuppressive factors into immune cells, resulting in a bias of the immune response towards tumor-promoting processes. MEXs could suppress the activation and proliferation of T cells and dendritic cells and induce differentiation of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). They can induce apoptosis of antigen-specific CD8 + T cells and promote the transfer of tumor antigens, resulting in immune evasion. Specifically, MEXs can shuttle cytokines like interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) to immune cells or express programmed death-ligand 1 (PD-L1 or CD274), creating an immune-suppressive microenvironment that promotes tumorigenesis. Since exosomes preferentially accumulate in melanoma tissues, this targeted delivery could enhance the bioavailability of treatments while limiting side effects. Here, we review the molecular composition of melanoma-derived exosomes, their mechanisms of action, and their potential as therapeutic targets or biomarkers in melanoma. The summarizations of these mechanisms to appropriately influence exosome-mediated interactions could yield new tactics to elicit anti-melanoma immunity or augment the therapeutic effects of current therapies.

There remains a critical need for biomarkers of acute cellular rejection (ACR) in heart transplantation. We hypothesized that immunopathophysiology of ACR is reflected via dynamic changes in the protein and RNA cargoes of small extracellular vesicles (sEVs) released by cardiac allograft and T cells into circulation, thus enabling noninvasive window into ACR.

T-cell sEVs were enriched using anti-CD3 antibody beads, and antidonor HLA I antibody beads for donor sEVs. Cargoes of donor sEVs (cardiac troponin T [cTnT] protein and mRNA) and T-cell sEVs (CD4, CD8, T-cell receptor proteins, miRNAs [miRs] let 7i, 101b, 21a) were compared with time-matched endomyocardial biopsy samples (n = 70) in 12 patients to postoperative day 120.

Six patients had 11 moderate ACR (15.7%) episodes, 1 had antibody-mediated rejection, and 5 had ≤ mild ACR. By Wilcoxon rank-sum tests, cTnT protein (P = 6.04 × 10-5) and mRNA (P = 6.87 × 10-7) were decreased with moderate ACR compared with grades 0/1 ACR. T-cell sEV CD4, CD8, and TCR protein cargoes (P ≤ 3.92 × 10-5) and miRs let 7i, 101b, and 21a (P ≤ 9.05 × 10-5) were increased with moderate ACR. Successful treatment of moderate ACR led to dynamic reversal in sEV profiles, especially donor heart sEV cTnT mRNA (Spearman coefficient 0.87) and miR 21a (coefficient 0.85).

Our first investigation in heart transplant patients demonstrated that circulating T cell-sEV and donor heart-sEV profiles enable diagnosis of moderate ACR with high diagnostic accuracy. A large sample cohort external validation study is warranted to better understand diagnostic potential of this platform for ACR monitoring in heart transplantation.

Small extracellular vesicles (sEVs), also known as exosomes, are membranous vesicles filled with various proteins and nucleic acids, serving as a communication vector between cells. Recent research has highlighted their role in viral diseases. This review synthesizes current understanding of viral sEVs and includes recent findings on sEVs infected with flaviviruses. It discusses the implications of viral sEVs research for advancing arbovirus sEVs research and anticipates the potential applications of sEVs in flavivirus infections.

Renal inflammatory diseases are a group of severe conditions marked by significant morbidity and mortality. Extracellular vesicles (EVs), as facilitators of intercellular communication, have been recognized as pivotal regulators of renal inflammatory diseases, significantly contributing to these conditions by modulating immune responses among other mechanisms. This review highlights the intricate mechanisms through which EVs modulate macrophage-kidney cell interactions by regulating macrophages, the principal immune cells within the renal milieu. This regulation subsequently influences the pathophysiology of renal inflammatory diseases such as acute kidney injury and chronic kidney disease. Furthermore, understanding these mechanisms offers novel opportunities to alleviate the severe consequences associated with renal inflammatory diseases. In addition, we summarize the therapeutic landscape based on EV-mediated macrophage regulatory mechanisms, highlighting the potential of EVs as biomarkers and therapeutic targets as well as the challenges and limitations of translating therapies into clinical practice.

Pancreatic cancer is one of the most aggressive malignancies with poor prognostic outcomes, necessitating the exploration of novel biomarkers and therapeutic targets for early detection and effective treatment. Small extracellular vesicles (sEVs) secreted by cells, have gained considerable attention in cancer research due to their role in intercellular communication and their potential as non-invasive biomarkers. This review focuses on the role of sEVs in the progression of pancreatic cancer and their application as biomarkers. We delve into the biogenesis, composition, and functional implications of sEVs in pancreatic tumor biology, emphasizing their involvement in processes such as tumor growth, metastasis, immune modulation, and chemotherapy resistance. In addition, we discuss the challenges in isolating and characterizing sEVs. The review also highlights recent advances in the utilization of sEV-derived biomarkers for the early diagnosis, prognosis, and monitoring of pancreatic cancer. By synthesizing the latest findings, we aim to underscore the significance of sEVs in pancreatic cancer and their potential to revolutionize patient management through improved diagnostics and targeted therapies.

Specialized pro-resolving mediators (SPMs), including lipoxins derived from arachidonic acid and resolvins, protectins, and maresins derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), orchestrate the active resolution of inflammation. These SPMs are biosynthesized through the coordinated interaction of various cells in a process known as transcellular biosynthesis, involving the sequential action of cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), 12-lipoxygenase (12-LOX), and/or 15-lipoxygenase (15-LOX) enzymes. Additionally, Aspirin-triggered Resolvins are produced by acetylated COX-2, along with various lipoxygenases. Although SPMs regulate various cellular processes to actively resolve inflammation, their in vivo levels are typically low. To address this limitation, we engineered a multigene expression vector that co-expresses COX-2, 5-LOX, and 15-LOX, potentiating the synthesis of various SPMs. HEK293T cells transfected with this vector and cultured with fatty acid-free BSA-complexed DHA, EPA, and aspirin, successfully mimicked both transcellular and aspirin-triggered biosynthesis of Resolvins. These Resolvins are packaged into extracellular vesicles, which significantly inhibited neutrophil adhesion to endothelial cells, preserved endothelial monolayer barrier integrity, suppressed NF-κB reporter activity, and enhanced macrophage efferocytosis in vitro . Notably, post-injury administration of Resolvin-loaded EVs mitigated pulmonary inflammation in LPS-treated mice without causing systemic or pulmonary toxicity. In summary, we report a novel cell-based platform for generating Resolvin-loaded EVs that mitigate pulmonary inflammation in mouse models, underscoring their potential for treating other acute inflammatory diseases.

Background: Podocyte injury leading to proteinuria is the primary feature of a vast majority of glomerular diseases, while mesangial cell activation is the hallmark of glomerulosclerosis. Whether and how these two events are connected remains elusive. In this study, we investigated the role of extracellular vesicles (EVs) in linking podocyte injury to mesangial activation in glomerular disease. Methods: EVs were characterized by nanoparticle tracking analysis and electron microscopy. Differentially expressed proteins from podocyte-derived EVs were analyzed by protein microarray. The role and mechanism by which EVs-packaged sonic hedgehog (Shh) mediates mesangial cell activation were investigated in vitro and in vivo. Results: An increased production of EVs in mouse podocytes (MPC5) was observed after injury induced by angiotensin II (Ang II). Shh and N-Shh were identified as major constituents of the proteins encapsulated in EVs isolated from Ang II-treated MPC5 cells (Ang II-EVs). In vitro, Ang II-EVs induced the activation and proliferation of rat mesangial cells (HBZY-1), whereas inhibition of EV secretion with dimethyl amiloride, depletion of EVs from conditioned media or knockdown of Shh expression abolished the ability of Ang II-EVs to induce HBZY-1 activation. In vivo, intravenous injection of Ang II-EVs exacerbated glomerulosclerosis, which was negated by hedgehog inhibitor. Furthermore, blocking EV secretion also ameliorated glomerulosclerosis in mouse model of glomerular disease. Conclusions: These findings suggest that podocyte injury can cause mesangial cell activation and glomerulosclerosis by releasing Shh-enriched EVs. Therefore, strategies targeting EVs may be a novel way to ameliorate proteinuric kidney disease.

Exosomes, characterized by their bilayer lipid structure, are crucial in mediating intercellular signaling and contributing to various physiological processes. Tumor cells produce distinct exosomes facilitating cancer progression, angiogenesis, and metastasis by conveying signaling molecules. A notable feature of these tumor-derived exosomes is the presence of programmed death-ligand 1 (PD-L1) on their surface. The PD-L1/programmed cell death receptor-1 (PD-1) signaling axis serves as a critical immune checkpoint, enabling tumors to evade immune detection and antitumor activity. The advancement of immunotherapy targeting the PD-1/PD-L1 pathway has significantly impacted the treatment landscape for non-small cell lung cancer (NSCLC). Despite its promise, evidence indicates that many patients experience limited responses or develop resistance to PD-1/PD-L1 inhibitors. Recent studies suggest that exosomal PD-L1 contributes to this resistance by modulating immune responses and tumor adaptability. This study reviews the PD-1/PD-L1 pathway's characteristics, current clinical findings on PD-L1 inhibitors in NSCLC, and exosome-specific attributes, with a particular focus on exosomal PD-L1. Furthermore, it examines the growing body of research investigating the role of exosomal PD-L1 in cancer progression and response to immunotherapy, underscoring its potential as a target for overcoming resistance in NSCLC treatment.

This paper presents a review of the potential role of the endoplasmic reticulum/Golgi complex and intracellular vesicles in mediating events leading to or associated with vertebrate tissue mineralization. The possible importance of these organelles in this process is suggested by observations that calcium ions accumulate in the tubules and lacunae of the endoplasmic reticulum and Golgi. Similar levels of calcium ions (approaching millimolar) are present in vesicles derived from endosomes, lysosomes and autophagosomes. The cellular level of phosphate ions in these organelles is also high (millimolar). While the source of these ions for mineral formation has not been identified, there are sound reasons for considering that they may be liberated from mitochondria during the utilization of ATP for anabolic purposes, perhaps linked to matrix synthesis. Published studies indicate that calcium and phosphate ions or their clusters contained as cargo within the intracellular organelles noted above lead to formation of extracellular mineral. The mineral sequestered in mitochondria has been documented as an amorphous calcium phosphate. The ion-, ion cluster- or mineral-containing vesicles exit the cell in plasma membrane blebs, secretory lysosomes or possibly intraluminal vesicles. Such a cell-regulated process provides a means for the rapid transport of ions or mineral particles to the mineralization front of skeletal and dental tissues. Within the extracellular matrix, the ions or mineral may associate to form larger aggregates and potential mineral nuclei, and they may bind to collagen and other proteins. How cells of hard tissues perform their housekeeping and other biosynthetic functions while transporting the very large volumes of ions required for mineralization of the extracellular matrix is far from clear. Addressing this and related questions raised in this review suggests guidelines for further investigations of the intracellular processes promoting the mineralization of the skeletal and dental tissues.

The treatment of congenital deformities, traumatic injuries, infectious diseases, and tumors in the craniomaxillofacial (CMF) region is complex due to the intricate nature of the tissues involved. Conventional treatments such as bone grafts and cell transplantation face limitations, including the need for multiple surgeries, complications, and safety concerns.

This paper aims to provide a comprehensive analysis of the role of exosomes (EXOs) in CMF and dental tissue regeneration and to explore their potential applications in regenerative dental medicine.

An extensive review of advancements in tissue engineering, materials sciences, and nanotechnology was conducted to evaluate the development of delivery systems for EXOs-based therapies. The analysis included how EXOs, as nanovesicles released by cells, can be modified to target specific cells or loaded with functional molecules for drug or gene delivery.

EXOs have emerged as a promising alternative to cell transplant therapy, offering a safer method for cell communication and epigenetic control. EXOs transport important proteins and genetic materials, facilitating intercellular communication and delivering therapeutics effectively. The potential of EXOs in personalized medicine, particularly in diagnosing, customizing treatment, and predicting patient responses, is highlighted.

EXO-mediated therapy holds significant potential for advancing tissue regeneration, offering targeted, personalized treatment options with reduced side effects. However, challenges in purification, production, and standardized protocols need to be addressed before its clinical application can be fully realized.

Cervical cancer (CC) remains a critical public health issue, highlighting the importance of early detection. However, current methods such as cytological and HPV testing face challenges of invasiveness and low patient compliance. Exosomes, emerging as crucial in cancer diagnosis, offer promise due to their noninvasive, highly specificity, and abundant biomarkers. However, isolating exosomes efficiently remains challenging. In this study, we designed and synthesized a bifunctional affinity nanomaterial Fe3O4 @CD63-CLIKKPF, based on the synergistic interaction between its modified aptamer CD63 and peptide CLIKKPF, and CD63 protein and PS of exosomes which can achieve high specificity and high yield separation of urinary exosomes. Notably, the co-modified aptamer CD63 and peptide CLIKKPF not only enable efficient exosome isolation by leveraging dual-affinity mechanisms through a synergistic "AND" logic analysis, but also could be achieved on the Fe3O4 in one-step reaction at room temperature via Fe-S bonding. Combined with LC-MS/MS, we conducted exosome metabolomics analysis in healthy individuals and CC patients across various stages, and machine learning models demonstrated accurate classification (accuracy >0.822) and prediction capabilities for CC. Furthermore, six key metabolites indicative of CC progression were identified and validated in additional patient samples, highlighting their potential as biomarkers. Overall, this study establishes a novel method for exosome metabolomics in CC, offering insights for non-invasive early diagnosis and progression prediction on a large scale.