Journal of Extracellular Vesicles最新文献

{"title":"Extracellular Vesicles Secreted by Cancer-Associated Fibroblasts Drive Non-Invasive Cancer Cell Progression to Metastasis via TGF-β Signalling Hyperactivation","authors":"Adilson Fonseca Teixeira,&nbsp;Yanhong Wang,&nbsp;Josephine Iaria,&nbsp;Peter ten Dijke,&nbsp;Hong-Jian Zhu","doi":"10.1002/jev2.70055","DOIUrl":"https://doi.org/10.1002/jev2.70055","url":null,"abstract":"<p>Metastasis is the leading cause of cancer-related deaths. Cancer-associated fibroblasts (CAFs) are abundant components within the tumour microenvironment, playing critical roles in metastasis. Although increasing evidence supports a role for small extracellular vesicles (sEVs) in this process, their precise contribution and molecular mechanisms remain unclear, compromising the development of antimetastatic therapies. Here, we establish that CAF-sEVs drive metastasis by mediating CAF-cancer cell interaction and hyperactivating TGF-β signalling in tumour cells. Metastasis is abolished by genetically targeting CAF-sEV secretion and consequent reduction of TGF-β signalling in cancer cells. Pharmacological treatment with dimethyl amiloride (DMA) decreases CAFs’ sEV secretion, reduces TGF-β signalling levels in tumour cells and abrogates metastasis and tumour self-seeding. This work defines a new mechanism required by CAFs to drive cancer progression, supporting the therapeutic targeting of EV trafficking to disable the driving forces of metastasis.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 3","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the Significance of Extracellular Vesicle-Associated DNA in Cancer Biology and Its Potential Clinical Applications","authors":"Jamal Ghanam,&nbsp;Kristína Lichá,&nbsp;Venkatesh Kumar Chetty,&nbsp;Ommolbanin Asad Pour,&nbsp;Dirk Reinhardt,&nbsp;Barbora Tamášová,&nbsp;Peter Hoyer,&nbsp;Jan Lötvall,&nbsp;Basant Kumar Thakur","doi":"10.1002/jev2.70047","DOIUrl":"https://doi.org/10.1002/jev2.70047","url":null,"abstract":"<p>Extracellular vesicles (EVs) play a key role in cell-to-cell communication and have drawn significant attention due to their potential clinical applications. However, much remains to be understood about the biology of EV-associated DNA (EV-DNA). EV-DNA is actively released by both normal and malignant cells and consists of diverse fragments with varying structures. Because EV-DNA spans the entire genome of cells from which it originates, it continues to be attractive as a biomarker for cancer diagnosis and monitoring. Further, EV-DNA delivery can alter the function of recipient cells by interfering with cytoplasmic DNA sensor pathways. This review explores the biology and significance of EV-DNA, including its topology and fragmentomics features, modality of association with EVs, packaging mechanisms, and potential functions. It also emphasizes the specificity of vesicular DNA in identifying genetic and epigenetic changes in cancer. Additionally, it delves into the impact of EV-DNA on cellular behaviour and its potential use as a therapeutic target in cancer. The review discusses new insights into EV-DNA biology and provides perspectives and alternatives to address the challenges and concerns for future EV-DNA studies.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 3","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Lipid Analysis of Extracellular Vesicle Preparations: A Perspective","authors":"Tore Skotland,&nbsp;Kim Ekroos,&nbsp;Alicia Llorente,&nbsp;Kirsten Sandvig","doi":"10.1002/jev2.70049","DOIUrl":"https://doi.org/10.1002/jev2.70049","url":null,"abstract":"<p>Quantitative lipidomic analysis performed by mass spectrometry is required for determination of the lipid content of extracellular vesicles (EVs). Such methods can provide information about the total amount of lipids, the lipid species composition, the purity of EV samples as well as the cellular origin of the EVs. There are, however, many pitfalls when performing lipid analyses. Thus, any non-specialist should collaborate with experts in lipidomics. In addition to many good review articles giving advice about lipid analyses, we recommend the information and guidelines published by the Lipidomic Standard Initiative, an interest group affiliated with the International Lipidomics Society.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 3","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Transmembrane Serine Protease 2 (TMPRSS2) on Human Seminal Fluid Extracellular Vesicles Is Proteolytically Active","authors":"Emile Verhulst,&nbsp;Michelle De Bruyn,&nbsp;Pascale Berckmans,&nbsp;Yani Sim,&nbsp;Koen Augustyns,&nbsp;Isabel Pintelon,&nbsp;Maya Berg,&nbsp;Pieter Van Wielendaele,&nbsp;Anne-Marie Lambeir,&nbsp;Yann G.-J. Sterckx,&nbsp;Inge Nelissen,&nbsp;Ingrid De Meester","doi":"10.1002/jev2.70061","DOIUrl":"https://doi.org/10.1002/jev2.70061","url":null,"abstract":"<p>Human transmembrane serine protease 2 (TMPRSS2) has garnered substantial interest due to its clinical significance in various pathologies, notably its pivotal role in viral entry into host cells. The development of effective strategies to target TMPRSS2 is a current area of intense research and necessitates a consistent source of active TMPRSS2 with sufficient stability. Here, we comprehensively characterised human seminal-fluid extracellular vesicles (SF-EVs, also referred to as prostasomes), bearing a native source of surface-exposed, enzymatically active TMPRSS2 as demonstrated by high-sensitivity flow cytometry and a fluorometric activity assay. Additionally, we recombinantly produced human TMPRSS2 ectodomain in mammalian cells adopting a directed activation strategy. We observed comparable catalytic parameters and inhibition characteristics for both native SF-EV-associated and recombinant TMPRSS2 when exposed to serine protease inhibitor Nafamostat mesylate. Leveraging these findings, we developed a robust in vitro biochemical assay based on these SF-EVs for the screening of TMPRSS2-targeting compounds. Our results will accelerate the discovery and advancement of efficacious therapeutic approaches targeting TMPRSS2 and propel further exploration into the biological role of SF-EV-associated active TMPRSS2.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 3","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Hydrogels on Mesenchymal Stem/Stromal Cells Paracrine Activity and Extracellular Vesicles Production","authors":"Oscar Fabian Garcia-Aponte,&nbsp;Simon Kahlenberg,&nbsp;Dimitrios Kouroupis,&nbsp;Dominik Egger,&nbsp;Cornelia Kasper","doi":"10.1002/jev2.70057","DOIUrl":"https://doi.org/10.1002/jev2.70057","url":null,"abstract":"<p>Mesenchymal stem/stromal cells (MSCs) are a valuable source of paracrine factors, as they have a remarkable secretory capacity, and there is a sizeable knowledge base to develop industrial and clinical production protocols. Promising cell-free approaches for tissue regeneration and immunomodulation are driving research towards secretome applications, among which extracellular vesicles (EVs) are steadily gaining attention. However, the manufacturing and application of EVs is limited by insufficient yields, knowledge gaps, and low standardization. Facing these limitations, hydrogels represent a versatile three-dimensional (3D) culture platform that can incorporate extracellular matrix (ECM) components to mimic the natural stem cell environment in vitro; via these niche-mimicking properties, hydrogels can regulate MSCs’ morphology, adhesion, proliferation, differentiation and secretion capacities. However, the impact of the hydrogel's architectural, biochemical and biomechanical properties on the production of EVs remains poorly understood, as the field is still in its infancy and the interdependency of culture parameters compromises the comparability of the studies. Therefore, this review summarizes and discusses the reported effects of hydrogel encapsulation and culture on the secretion of MSC-EVs. Considering the effects of cell-material interactions on the overall paracrine activity of MSCs, we identify persistent challenges from low standardization and process control, and outline future paths of research, such as the synergic use of hydrogels and bioreactors to enhance MSC-EV generation.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 3","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of Centrosomal Protein 55 (CEP55) Loading Into Exosomes","authors":"Christian Dahlstroem,&nbsp;Johanna Barezani,&nbsp;Jing Li,&nbsp;Kostiantyn Sopelniak,&nbsp;Stefanie Muhs,&nbsp;Carola Schneider,&nbsp;Roland Thünauer,&nbsp;Rudolph Reimer,&nbsp;Sabine Windhorst","doi":"10.1002/jev2.70046","DOIUrl":"https://doi.org/10.1002/jev2.70046","url":null,"abstract":"<p>Up-regulation of Centrosomal Protein 55 (CEP55) in cancer cells increases malignancy, and the protein can be transferred via exosomes. However, the mechanism of how CEP55 is delivered to exosomes is unknown. In this study, we addressed this issue and analysed trafficking of EGFP-CEP55 from early to late endosomes by using high-resolution microscopy. Our data show that endogenous as well as EGFP-CEP55 appeared as dot-like structures in cancer cells. However, we did not find an internalization of CEP55 into early Rab5- and late Rab7-positive endosomes but only into secretory late CD63-positive endosomes. In addition, an association of the CEP55 dots with the endoplasmic reticulum and with ALG-2-interacting protein X (Alix) dots was detected. Moreover, mutation of the CEP55-Alix interaction site strongly reduced the formation of CEP55 dots as well as CEP55 localization in extracellular vesicles. In summary, our data indicate that delivery of CEP55 into exosomes does not occur by the canonical early-to-late endosome pathway but by Alix-mediated recruitment to secretory late secretory CD63 endosomes.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 2","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Histones as Exosome Membrane Proteins Regulated by Cell Stress","authors":"Birendra Singh,&nbsp;Marcus Fredriksson Sundbom,&nbsp;Uma Muthukrishnan,&nbsp;Balasubramanian Natarajan,&nbsp;Stephanie Stransky,&nbsp;André Görgens,&nbsp;Joel Z. Nordin,&nbsp;Oscar P. B. Wiklander,&nbsp;Linda Sandblad,&nbsp;Simone Sidoli,&nbsp;Samir El Andaloussi,&nbsp;Michael Haney,&nbsp;Jonathan D. Gilthorpe","doi":"10.1002/jev2.70042","DOIUrl":"https://doi.org/10.1002/jev2.70042","url":null,"abstract":"<p>Histones are conserved nuclear proteins that function as part of the nucleosome in the regulation of chromatin structure and gene expression. Interestingly, extracellular histones populate biofluids from healthy individuals, and when elevated, may contribute to various acute and chronic diseases. It is generally assumed that most extracellular histones exist as nucleosomes, as components of extracellular chromatin. We analysed cell culture models under normal and stressed conditions to identify pathways of histone secretion. We report that core and linker histones localize to extracellular vesicles (EVs) and are secreted via the multivesicular body/exosome pathway. Upregulation of EV histone secretion occurs in response to cellular stress, with enhanced vesicle secretion and a shift towards a population of smaller EVs. Most histones were membrane associated with the outer surface of EVs. Degradation of EV-DNA did not impact significantly on EV-histone association. Individual histones  and histone octamers bound strongly to liposomes and EVs, but nucleosomes did not, showing histones do not require DNA for EV binding. Histones colocalized to tetraspanin positive EVs but using genetic or pharmacological intervention, we found that all known pathways of exosome biogenesis acted positively on histone secretion. Inhibition of autophagy and lysosomal degradation had a strong positive effect on EV histone release. Unexpectedly, EV-associated histones lacked the extensive post-translational modification of their nuclear counterparts, suggesting loss of PTMs may be involved in their trafficking or secretion. Our data does not support a significant role for EV-histones existing as nucleosomes. We show for the first time that histones are secreted from cells as membrane proteins via EVs/exosomes. This fundamental discovery provides support for further investigation of the biological activity of exosome associated histones and their role in disease.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 2","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stoichiometric constraints for detection of EV-borne biomarkers in blood","authors":"Nataša Zarovni,&nbsp;Danilo Mladenović,&nbsp;Dario Brambilla,&nbsp;Federica Panico,&nbsp;Marcella Chiari","doi":"10.1002/jev2.70034","DOIUrl":"https://doi.org/10.1002/jev2.70034","url":null,"abstract":"<p>Stochiometric issues, encompassing both the quantity and heterogeneity of extracellular vesicles (EVs) derived from tumour or other tissues in blood, pose important challenges across various stages of biomarker discovery and detection, affecting the integrity of data, introducing losses and artifacts during blood processing, EV purification and analysis. These challenges shape the diagnostic utility of EVs especially within the framework of established and emerging methodologies. By addressing these challenges, we aim to delineate crucial parameters and requirements for tumour-specific EV detection, or more precisely, for tumour identification via EV based assays. Our endeavour involves a comprehensive examination of the layers that mask or confound the traceability of EV markers such as nucleic acids and proteins, and focus on ‘low prevalence—low concentration’ scenario. Finally, we evaluate the advantages versus limitations of single-particle analysers over more conventional bulk assays, suggesting that the combined use of both to capture and interpret the EV signals, in particular the EV surface displayed proteins, may ultimately provide quantitative information on their absolute abundance and distribution.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 2","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small Extracellular Vesicles Engineered Using Click Chemistry to Express Chimeric Antigen Receptors Show Enhanced Efficacy in Acute Liver Failure","authors":"Yen-Ting Lu,&nbsp;Tzu-Yu Chen,&nbsp;Hsin-Hung Lin,&nbsp;Ya-Wen Chen,&nbsp;Yu-Xiu Lin,&nbsp;Duy‑Cuong Le,&nbsp;Yen-Hua Huang,&nbsp;Andrew H.-J. Wang,&nbsp;Cheng-Chung Lee,&nbsp;Thai-Yen Ling","doi":"10.1002/jev2.70044","DOIUrl":"https://doi.org/10.1002/jev2.70044","url":null,"abstract":"<p>Acetaminophen (APAP) overdose can cause severe liver injury and life-threatening conditions that may lead to multiple organ failure without proper treatment. N-acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)-based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC-derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC-derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor-modified sEVs (CAR-sEVs) for the treatment. First, we engineered azido-modified sEVs (N₃-sEVs) through metabolic glycoengineering by treating MSCs with the azide-containing monosaccharide N-azidoacetyl-mannosamine (Ac4ManNAz). Next, we conjugated N₃-sEVs with a dibenzocyclooctyne (DBCO)-tagged single-chain variable fragment (DBCO-scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR-sEVs for precise liver targeting. The efficacy of CAR-sEV therapy in ALF models by targeting ASGR1 was validated. MSC-derived CAR-sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP-induced injury. Overall, CAR-sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell-free targeted therapy.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 2","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Profiling of Brain Tissue and Brain-Derived Extracellular Vesicles in Alzheimer's Disease","authors":"Patricia Hernandez,&nbsp;Elisabeth Rackles,&nbsp;Oihane E. Alboniga,&nbsp;Pablo Martínez-Lage,&nbsp;Emma N. Camacho,&nbsp;Arantza Onaindia,&nbsp;Manuel Fernandez,&nbsp;Ana Talamillo,&nbsp;Juan M. Falcon-Perez","doi":"10.1002/jev2.70043","DOIUrl":"https://doi.org/10.1002/jev2.70043","url":null,"abstract":"<p>Alzheimer´s disease (AD) is the most frequent neurodegenerative disorder in the world and is characterised by the loss of memory and other cognitive functions. Metabolic changes associated with AD are important players in the development of the disease. However, the mechanism underlying these changes is still unknown. Extracellular vesicles (EVs) are nano-sized particles that play an important role in regulating pathophysiological processes and are a non-invasive manner to obtain information of the cell that is secreting them. The analysis of brain-derived EVs (bdEVs) will provide new insights in the metabolic processes associated with AD. To characterize bdEVs in AD, we optimised a method to isolate them from tissue of different brain regions, obtaining the highest enrichment in isolations from the temporal cortex. We performed unbiased untargeted metabolomics analysis on post-mortem human temporal cortex tissue and bdEVs from the same region of AD patients and healthy controls. Both, univariate and multivariate statistical analysis were used to determine the metabolites that influence the separation between AD patients and controls. Interestingly, a clear separation between control and AD groups was obtained with bdEVs, which allowed to select 12 relevant features by a validated PLS-DA model. Furthermore, comparison of tissue and bdEVs identified 68 common features. The pathway enrichment analysis of the common metabolites showed that the alanine, aspartate and glutamate pathway and the arginine, phenylalanine, tyrosine pathway were the most significant ones in the separation between the AD patients and controls. The phenylalanine, tyrosine and tryptophan pathway, still had a very high influence in the separation between groups, albeit not significant. Notably, some metabolites were identified for the first time in bdEVs. For example, the N-acetyl aspartic acid (NAA) metabolite present in bdEVs was suitable to differentiate AD patients from healthy controls. Furthermore, the analysis of the hippocampus, midbrain, temporal and entorhinal cortex and their respective bdEVs indicated that the metabolic profiles of different brain areas were distinct and showed some correlation between the metabolome of the tissue and its respective bdEVs. Thus, our study highlights the potential of bdEVs to understand the metabolic fingerprint associated with AD and their potential use as diagnostic and therapeutic targets.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 2","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}