Journal of Extracellular Vesicles最新文献

{"title":"Nanobody Engineered and Photosensitiser Loaded Bacterial Outer Membrane Vesicles Potentiate Antitumour Immunity and Immunotherapy","authors":"Peng Xia,&nbsp;Chengming Qu,&nbsp;Xiaolong Xu,&nbsp;Ming Tian,&nbsp;Zhifen Li,&nbsp;Jingbo Ma,&nbsp;Rui Hou,&nbsp;Han Li,&nbsp;Felix Rückert,&nbsp;Tianyu Zhong,&nbsp;Liang Zhao,&nbsp;Yufeng Yuan,&nbsp;Jigang Wang,&nbsp;Zhijie Li","doi":"10.1002/jev2.70069","DOIUrl":"https://doi.org/10.1002/jev2.70069","url":null,"abstract":"<p>Bacterial outer membrane vesicles (OMVs) are promising as antitumour agents, but their clinical application is limited by toxicity concerns and unclear mechanisms. We engineered OMVs with cadherin 17 (CDH17) tumour-targeting nanobodies, enhancing tumour selectivity and efficacy while reducing adverse effects. These engineered OMVs function as natural stimulator of interferon genes (STING) agonists, activating the cyclic GMP-AMP synthase (cGAS)-STING pathway in cancer cells and tumour-associated macrophages (TAMs). Loading engineered OMVs with photoimmunotherapy photosensitisers further enhanced tumour inhibition and STING activation in TAMs. Combining nanobody-engineered OMV-mediated photoimmunotherapy with CD47 blockade effectively suppressed primary and metastatic tumours, establishing sustained antitumour immune memory. This study demonstrates the potential of nanobody-engineered OMVs as STING agonists and provides insights into novel OMV-based immunotherapeutic strategies harnessing the innate immune system against cancer. Our findings open new avenues for OMV applications in tumour immunotherapy, offering a promising approach to overcome current limitations in cancer treatment.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840795","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":"Fusobacterium nucleatum-Derived Outer Membrane Vesicles Promote Immunotherapy Resistance via Changes in Tryptophan Metabolism in Tumour-Associated Macrophages","authors":"Weiping Li,&nbsp;Zhen Zhang,&nbsp;Ruoyi Wu,&nbsp;Mengying Mao,&nbsp;Yikang Ji,&nbsp;Xiaoning Wang,&nbsp;Shengjin Dou,&nbsp;Ming Yan,&nbsp;Wantao Chen","doi":"10.1002/jev2.70070","DOIUrl":"https://doi.org/10.1002/jev2.70070","url":null,"abstract":"<p>Only a minority of patients with head and neck squamous cell carcinoma (HNSCC) respond favourably to immunotherapy. The oral oncogenic bacterium <i>Fusobacterium nucleatum</i> (<i>F.nucleatum</i>) was recently observed to suppress the anti-tumour immune response, although the mechanisms remain unclear. In this study, we found that outer membrane vesicles (OMVs) derived from <i>F.nucleatum</i> (<i>F.n</i>-OMVs) promoted HNSCC progression by inducing immunosuppressive phenotypes of tumour-associated macrophages (TAMs), resulting in decreased cytotoxic T lymphocyte infiltration in vivo. Mechanistically, TAMs internalized tryptophanase presented in <i>F.n</i>-OMVs, which activated the tryptophan-2,3-dioxygenase 2/aryl hydrocarbon receptor (TDO2/AHR) pathway and upregulated the transcription of immunosuppressive cytokines and immune checkpoints. TDO2 inhibitor enhanced the therapeutic effect of anti-programmed death-1 in a tumour-bearing mouse model. Both TDO2 and <i>F.nucleatum</i> demonstrated excellent performance in predicting the immunotherapy outcomes in patients with HNSCC. These results indicate that <i>F.n</i>-OMVs induce immunotherapy resistance in HNSCC, providing novel insights into the microbiota–tumour immunity crosstalk.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840794","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":"Use of the Malaria Protein VAR2CSA for the Detection of Small Extracellular Vesicles to Diagnose Adenocarcinoma","authors":"Yaru Zhao,&nbsp;Chenlei Wen,&nbsp;Qi Wang,&nbsp;Yue Qing,&nbsp;Serena Tondi,&nbsp;Chiara Reina,&nbsp;Berina Šabanović,&nbsp;Cherry Yin-Yi Chang,&nbsp;Chu-Hu Lai,&nbsp;Huimin Wang,&nbsp;Mette Ø. Agerbaek,&nbsp;Thomas M. Clausen,&nbsp;Tobias Gustavsson,&nbsp;Thor G. Theander,&nbsp;Ali Salanti,&nbsp;Clara Csilla Meny,&nbsp;Baiyong Shen,&nbsp;Alexandra Aicher,&nbsp;Jiajia Tang,&nbsp;Christopher Heeschen","doi":"10.1002/jev2.70067","DOIUrl":"https://doi.org/10.1002/jev2.70067","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge for early diagnosis due to the lack of sensitive and specific biomarkers. This encouraged us to explore the diagnostic value of cancer-derived small extracellular vesicles (sEVs) as early detection biomarkers. We previously showed that the recombinant malaria protein VAR2CSA (rVAR2) selectively binds to oncofetal chondroitin sulfate (ofCS) on the surfaces of cancer cells, which might be useful for identifying cancer-derived sEVs. Indeed, flow cytometry revealed strong ofCS expression in PDAC cell-derived sEVs, as evidenced by the presence of mutant <i>KRAS</i>, a common genetic alteration in PDAC. Plasma from PDAC patients showed significantly higher ofCS⁺ sEV levels compared to healthy donors and patients with benign gastrointestinal diseases. ROC analysis for ofCS⁺ sEVs revealed an AUC of 0.9049 for the detection of all-stage and 0.9222 for early-stage PDAC. Notably, mutant <i>KRAS</i> was also detected in these patient-derived sEVs. Most intriguingly, combining ofCS⁺ sEVs and CA19-9 resulted in an AUC of 0.9707 for the detection of early PDAC. Our study demonstrates that rVAR2 is suitable for detecting ofCS⁺ cancer-derived sEVs in plasma, thereby providing high efficiency for identifying PDAC patients among a diverse population. These findings suggest that rVAR2-based sEV detection could serve as a powerful diagnostic tool to improve patient survival through early detection.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840797","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":"Yersinia pestis Actively Inhibits the Production of Extracellular Vesicles by Human Neutrophils","authors":"Katelyn R. Sheneman,&nbsp;Timothy D. Cummins,&nbsp;Michael L. Merchant,&nbsp;Joshua L. Hood,&nbsp;Silvia M. Uriarte,&nbsp;Matthew B. Lawrenz","doi":"10.1002/jev2.70074","DOIUrl":"https://doi.org/10.1002/jev2.70074","url":null,"abstract":"<p><i>Yersinia pestis</i> is the etiologic agent of the plague. A hallmark of plague is subversion of the host immune response by disrupting host signalling pathways required for inflammation. This non-inflammatory environment permits bacterial colonization and has been shown to be essential for disease manifestation. Previous work has shown that <i>Y. pestis</i> inhibits phagocytosis and degranulation by neutrophils. Manipulation of these key vesicular trafficking pathways suggests that <i>Y. pestis</i> influences extracellular vesicle (EV) secretion, cargo selection, trafficking and/or maturation. Our goals were to define the EV population produced by neutrophils in response to <i>Y. pestis</i> and determine how these vesicles might influence inflammation. Towards these goals, EVs were isolated from human neutrophils infected with <i>Y. pestis</i> or a mutant lacking bacterial effector proteins known to manipulate host cell signalling. Mass spectrometry data revealed that cargoes packaged in EVs isolated from mutant infected cells were enriched with antimicrobial and cytotoxic proteins, contents which differed from uninfected and <i>Y. pestis</i> infected cells. Further, EVs produced in response to <i>Y. pestis</i> lacked inflammatory properties observed in those isolated from neutrophils responding to the mutant. Together, these data demonstrate that <i>Y. pestis</i> actively inhibits the production of antimicrobial EVs produced by neutrophils, likely contributing to immune evasion.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840792","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 Vesicles Alter Trophoblast Function in Pregnancies Complicated by COVID-19","authors":"Thea N. Golden,&nbsp;Sneha Mani,&nbsp;Rebecca L. Linn,&nbsp;Rita Leite,&nbsp;Natalie A. Trigg,&nbsp;Annette Wilson,&nbsp;Lauren Anton,&nbsp;Monica Mainigi,&nbsp;Colin C. Conine,&nbsp;Brett A. Kaufman,&nbsp;Jerome F. Strauss III,&nbsp;Samuel Parry,&nbsp;Rebecca A. Simmons","doi":"10.1002/jev2.70051","DOIUrl":"https://doi.org/10.1002/jev2.70051","url":null,"abstract":"<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease (COVID-19) cause placental dysfunction, which increases the risk of adverse pregnancy outcomes. While abnormal placental pathology resulting from COVID-19 is common, direct infection of the placenta is rare. This suggests that pathophysiology associated with maternal COVID-19, rather than direct placental infection, is responsible for placental dysfunction. We hypothesized that maternal circulating extracellular vesicles (EVs), altered by COVID-19 during pregnancy, contribute to placental dysfunction. To examine this hypothesis, we characterized circulating EVs from pregnancies complicated by COVID-19 and tested their effects on trophoblast cell physiology in vitro. Trophoblast exposure to EVs isolated from patients with an active infection (AI), but not controls, altered key trophoblast functions including hormone production and invasion. Thus, circulating EVs from participants with an AI, both symptomatic and asymptomatic cases, can disrupt vital trophoblast functions. EV cargo differed between participants with COVID-19, depending on the gestational timing of infection, and Controls, which may contribute to the disruption of the placental transcriptome and morphology. Our findings show that COVID-19 can have effects throughout pregnancy on circulating EVs, and circulating EVs are likely to participate in placental dysfunction induced by COVID-19.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809564","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 Vesicles Released From Skeletal Muscle Post-Chronic Contractile Activity Increase Mitochondrial Biogenesis in Recipient Myoblasts","authors":"Patience O. Obi,&nbsp;Tamiris F. G. Souza,&nbsp;Berkay Özerkliğ,&nbsp;Samira Seif,&nbsp;Benjamin Bydak,&nbsp;Nicholas Klassen,&nbsp;Todd A. Duhamel,&nbsp;Adrian R. West,&nbsp;Joseph W. Gordon,&nbsp;Ayesha Saleem","doi":"10.1002/jev2.70045","DOIUrl":"https://doi.org/10.1002/jev2.70045","url":null,"abstract":"<p>The effect of chronic contractile activity (CCA) on the biophysical properties and functional activity of skeletal muscle extracellular vesicles (Skm-EVs) is poorly understood due to challenges in distinguishing Skm-EVs originating from exercising muscle in vivo. To address this, myoblasts were differentiated into myotubes, and electrically paced (3 h/day, 4 days @ 14 V). CCA evoked an increase in mitochondrial biogenesis in stimulated versus non-stimulated (CON) myotubes as expected. EVs were isolated from conditioned media (CM) from control and stimulated myotubes using differential ultracentrifugation (dUC) and characterised biophysically using tunable resistive pulse sensing (TRPS, Exoid), TEM and western blotting. TEM images confirmed isolated round-shaped vesicles of about 30–150 nm with an intact lipid bilayer. EVs ranged from 98 to 138 nm in diameter, and the mean size was not altered by CCA. Zeta potential and total EV protein yield remained unchanged between groups, and total EV secretion increased after 4 days of CCA. Concomitant analysis of EVs after each day of CCA also demonstrated a progressive increase in CCA-EV concentration, whilst size and zeta potential remained unaltered, and EV protein yield increased in both CON-EVs and CCA groups. CCA-EVs were enriched with small-EVs versus CON-EVs, concomitant with higher expression of small-EV markers CD81, Tsg101 and HSP70. In whole cell lysates, CD63 and ApoA1 were reduced with CCA in myotubes, whereas CD81, Tsg101, Flotillin-1 and HSP70 levels remained unchanged. To evaluate the functional effect of EVs secreted post-CCA, we treated C2C12 myoblasts with all EVs isolated from CON or CCA myotubes after each day of stimulation, and measured cell count, cell viability, protein yield and mitochondrial biogenesis in recipient cells. There was no effect on cell count, viability and protein yield. Myoblasts treated with CCA-EVs exhibited increased mitochondrial biogenesis as indicated by enhanced MitoTracker Red staining, cytochrome <i>c</i> oxidase (COX) activity and protein expression of electron transport chain subunit, CIV-MTCO1. Further, CCA-EV treatment enhanced maximal oxygen consumption rates (OCR) in a dose-dependent manner, and ATP production in treated myoblasts. This increase in maximal OCR was abrogated when CCA-EVs pre-treated with proteinase K were co-cultured with myoblasts, indicating the pro-metabolic effect was likely mediated by transmembrane or peripheral membrane proteins in CCA-EVs. Our data highlight the novel effect of Skm-EVs isolated post-CCA in mediating pro-metabolic effects in recipient cells and thereby transmitting the effects associated with traditional exercise. Further investigation to interrogate the underlying mechanisms involved in downstream cellular metabolic adaptations is warranted.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809565","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":"Intranasal Delivery of Brain-Derived Neurotrophic Factor (BDNF)-Loaded Small Extracellular Vesicles for Treating Acute Spinal Cord Injury in Rats and Monkeys","authors":"Zhonghai Huang,&nbsp;Jing Li,&nbsp;Jin Wo,&nbsp;Cheng-Lin Li,&nbsp;Zi-Cong Wu,&nbsp;Xiao-Hui Deng,&nbsp;Yaying Liang,&nbsp;Fuxiang Li,&nbsp;Boli Chen,&nbsp;Bin Jia,&nbsp;Lu Wang,&nbsp;Ying Wang,&nbsp;Guodong Sun,&nbsp;Zhizhong Li,&nbsp;Hui Zhu,&nbsp;James D Guest,&nbsp;Kwok-Fai So,&nbsp;Qing-Ling Fu,&nbsp;Libing Zhou","doi":"10.1002/jev2.70066","DOIUrl":"https://doi.org/10.1002/jev2.70066","url":null,"abstract":"<p>Besides surgical decompression, neuroprotection and neuroinflammation reduction are critical for acute spinal cord injury (SCI). In this study, we prepared small extracellular vesicles (sEVs) from immortalised mesenchymal stem cells overexpressing brain-derived neurotrophic factor (BDNF) and evaluated whether intranasal administration of BDNF-sEVs is a therapeutic option for acute SCI. In cultured neurons, BDNF loading enhanced neurite outgrowth promoted by sEVs. After intranasal administration, mCherry-labelled sEVs were transported to the injured spinal cords of rats and monkeys and mainly taken up by neurons. In acute SCI rats, intranasal administration of sEVs and BDNF-sEVs reduced glial responses and proinflammatory cytokine production, enhanced neuronal survival and angiogenesis in the lesion, promoted injured axon rewiring, delayed lumbar spinal motoneuron atrophy below the lesion, and improved functional performance. The rats receiving BDNF-sEV treatment showed improved neural repair and functional recovery compared to those with sEV treatment. Intranasal administration of BDNF-sEVs, but not of sEVs, increased BDNF levels and phosphorylation of downstream signals in the rat-injured spinal cord samples, indicating activation of the BDNF/TrkB signalling pathway. In acute SCI monkeys, intranasal administration of BDNF-sEVs was further confirmed to inhibit glial reactivities and proinflammatory cytokine release, increasing BDNF levels in the cerebrospinal fluid, enhancing neural network rewiring of injured spinal cords and neuronal activities of the brain, and improving functional performances in behavioural tests and electrophysiological recordings. In conclusion, BDNF-sEVs play a combinatory therapeutic role of sEVs and BDNF, and intranasal administration of BDNF-sEVs is a potential option for the clinical treatment of acute SCI.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793351","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":"Unique Patterns of Circulating Extracellular Vesicles in Preterm Infants During Adaptation to Extra-Uterine Life","authors":"Claire A. Murphy,&nbsp;Daniel O'Reilly,&nbsp;Luisa Weiss,&nbsp;Stephen Madden,&nbsp;Hayley Macleod,&nbsp;Ana Le Chevillier,&nbsp;Elaine Neary,&nbsp;John O'Loughlin,&nbsp;Afif EL-Khuffash,&nbsp;Barry Kevane,&nbsp;Fionnuala NíAinle,&nbsp;Jan Zivny,&nbsp;Naomi McCallion,&nbsp;Patricia B. Maguire","doi":"10.1002/jev2.70064","DOIUrl":"https://doi.org/10.1002/jev2.70064","url":null,"abstract":"<p>There is growing interest in the role of extracellular vesicles (EVs) in neonatal pathology. This study aimed to characterise circulating EVs following preterm birth. This single-centre prospective observational study included cord and postnatal plasma from preterm (<i>n</i> = 101) and full-term infants (<i>n</i> = 66). EVs were analysed using nanoparticle tracking analysis, flow cytometry, proteomics and procoagulant activity assay. We found changes in the concentration, size, cellular origin and proteomic content of circulating EVs in preterm infants during perinatal adaptation. To understand if these changes were related to prematurity or normal adaptation to extrauterine life, they were also investigated in term infants. There was a dramatic increase in the concentration of small and large EVs on Day 3 in the preterm group; specific subsets of platelet (CD42b⁺ and CD62P⁺), endothelial (VEGFR2) and tissue factor EVs were elevated. Differentially expressed proteins relating to haemostasis, pulmonary physiology and immunity were identified between Day 1 and 3 in preterm infants. These changes have never previously been described in a large cohort of preterm infants and differ from healthy term infants. These findings have major implications for future neonatal EV studies, particularly the timing of sample collection. Further work is required to understand the clinical implications of this unique EV profile following preterm birth.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793352","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":"Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles","authors":"Xiabing Lyu,&nbsp;Tomoyoshi Yamano,&nbsp;Kanto Nagamori,&nbsp;Shota Imai,&nbsp;Toan Van Le,&nbsp;Dilireba Bolidong,&nbsp;Makie Ueda,&nbsp;Shota Warashina,&nbsp;Hidefumi Mukai,&nbsp;Seigo Hayashi,&nbsp;Kazutaka Matoba,&nbsp;Taito Nishino,&nbsp;Rikinari Hanayama","doi":"10.1002/jev2.70035","DOIUrl":"https://doi.org/10.1002/jev2.70035","url":null,"abstract":"<p>Extracellular vesicles (EVs) are important mediators of cell–cell communication, including immune regulation. Despite the recent development of several EV-based cancer immunotherapies, their clinical efficacy remains limited. Here, we created antigen-presenting EVs to express peptide-major histocompatibility complex (pMHC) class I, costimulatory molecule and IL-2. This enabled the selective delivery of multiple immune modulators to antigen-specific CD8⁺ T cells, promoting their expansion in vivo without severe adverse effects. Notably, antigen-presenting EVs accumulated in the tumour microenvironment, increasing IFN-γ⁺ CD8⁺ T cell and decreasing exhausted CD8⁺ T cell numbers, suggesting that antigen-presenting EVs transformed the ‘cold’ tumour microenvironment into a ‘hot’ one. Combination therapy with antigen-presenting EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumours. We successfully engineered humanized antigen-presenting EVs, which selectively stimulated tumour antigen-specific CD8⁺ T cells. In conclusion, engineering EVs to co-express multiple immunomodulators represents a promising method for cancer immunotherapy.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726850","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":"Dynamic Change of PD-L2 on Circulating Plasma Extracellular Vesicles as a Predictor of Treatment Response in Melanoma Patients Receiving Anti-PD-1 Therapy","authors":"Linzi Sun,&nbsp;Xiaoting Wei,&nbsp;Qian Zhao,&nbsp;Lili Mao,&nbsp;Xue Bai,&nbsp;Caili Li,&nbsp;Junjie Gu,&nbsp;Yan Kong,&nbsp;Chuanliang Cui,&nbsp;Zhihong Chi,&nbsp;Xinan Sheng,&nbsp;Bin Lian,&nbsp;Xuan Wang,&nbsp;Siming Li,&nbsp;Xieqiao Yan,&nbsp;Bixia Tang,&nbsp;Li Zhou,&nbsp;Juan Li,&nbsp;Jun Guo,&nbsp;Lu Si,&nbsp;Jie Dai","doi":"10.1002/jev2.70054","DOIUrl":"https://doi.org/10.1002/jev2.70054","url":null,"abstract":"<p>Immune checkpoint inhibitors (ICIs) have provided new hope for melanoma patients, however, not all patients benefit. Furthermore, ICI-related therapies cause significant immune-related adverse events that adversely affect patient outcomes. Therefore, there is a pressing need for reliable biomarkers to identify patients most likely to benefit from these treatments. In this study, we employed an extracellular vesicles (EVs) protein expression array to explore the longitudinal membrane protein profiles of plasma-derived EVs from 32 melanoma patients receiving anti-PD-1 and anti-angiogenesis therapy at baseline and early treatment. We found that the dynamic changes in PD-L2 on the EV membrane were associated with treatment response and patient survival. The dynamic change of EV PD-L2 as an indication of treatment efficacy was validated in an independent cohort of melanoma patients treated with anti-PD-1 monotherapy. Plasma-derived PD-L2+ EVs from patients with mucosal melanoma significantly reduced the frequency of granzyme B+ CD8 T cells within the peripheral blood mononuclear cells (PBMCs) of healthy individuals. The inhibitory effect of PD-L2+ EVs on CD8 T cells was further validated using human melanoma cell lines and the B16-F10 mouse model. Although intratumoural injection of PD-L2+ EVs could promote melanoma growth in vivo, tumours with PD-L2+ EVs showed a higher response to anti-PD-1 than those without PD-L2+ EVs. Collectively, our study demonstrates that PD-L2+ EVs inhibit CD8 T cell activation and promote melanoma growth, and changes in PD-L2 on circulating EVs during early treatment could serve as a biomarker for ICI-based therapy.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 4","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698865","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}