{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:47:24Z","timestamp":1789044444125,"version":"build-2803163510"},"reference-count":71,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Extracellular Vesicle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Malignant and non\u2010malignant cells within the tumor microenvironment (TME) actively secrete extracellular vesicles (EVs) that may mediate intercellular communication or enter the blood stream. Circulating EVs in Diffuse Large B\u2010Cell Lymphoma (DLBCL) patients are a promising source of liquid biopsy biomarkers; however, whether different cellular components of the TME preferentially secrete small (S\u2010) and\/or large (L\u2010) EVs is still unknown.<\/jats:p>\n                  <jats:p>With an established density\u2010gradient separation protocol and tunable resistive pulse sensing analysis, we demonstrate that DLBCL cells in culture produce 100\u20101000\u2010fold higher numbers of S\u2010EVs (50\u2013200\u00a0nm) compared with L\u2010EVs (200\u20131000\u00a0nm) and very large EVs (&gt;1000\u00a0nm). In contrast, the plasma from DLBCL patients contains comparable concentrations of S\u2010 and L\u2010EVs, consistent with various cellular origins. Small RNA sequencing showed minor differences in miRNA content between plasma S\u2010 and L\u2010EVs; however, messenger RNA sequencing revealed stark differences in cargo between EV\u2010size subtypes and between healthy donors and patients. Deconvolution analysis with single\u2010cell sequencing data from 17 DLBCL tumor tissues as reference using the Statescope algorithm indicated that circulating S\u2010EVs from malignant cells outnumber the L\u2010EVs. In contrast, TME macrophage\u2010, T cell\u2010, and natural killer\u2010derived L\u2010EVs outnumber S\u2010EVs. Together, these findings suggest that circulating S\u2010 and L\u2010EVs can originate from distinct cellular compartments within the DLBCL TME, representing complementary biological information. These observations have important implications for the development of EV\u2010based liquid biopsy strategies.<\/jats:p>","DOI":"10.1002\/jev2.70259","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:38:13Z","timestamp":1774528693000},"source":"Crossref","is-referenced-by-count":1,"title":["Small and Large Extracellular Vesicles in Circulation of Diffuse Large B\u2010Cell Lymphoma Patients Originate From Different Cell Types of the Tumor Microenvironment"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3666-7755","authenticated-orcid":false,"given":"Filippo","family":"Maltoni","sequence":"first","affiliation":[{"name":"Department of Surgical and Medical Sciences Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna  Bologna Italy"},{"name":"IRCCS Azienda Ospedaliero\u2010Universitaria di Bologna, Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-9415","authenticated-orcid":false,"given":"Steven","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mischa. F. B.","family":"Steketee","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina A.","family":"G\u00f3mez\u2010Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3551-0038","authenticated-orcid":false,"given":"Esther E. E.","family":"Drees","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Morelli","sequence":"additional","affiliation":[{"name":"Department of Surgical and Medical Sciences Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leontien","family":"Bosch","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"van Eijndhoven","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert Jan","family":"Timmers","sequence":"additional","affiliation":[{"name":"Amstelland Ziekenhuis  Amstelveen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Houtenbos","sequence":"additional","affiliation":[{"name":"Spaarne Gasthuis  Haarlem the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9e M.","family":"Zijlstra","sequence":"additional","affiliation":[{"name":"Department of Hematology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Pan\u2010Hammarstr\u00f6m","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Medical Biochemistry and Biophysics Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine E. D.","family":"Chamuleau","sequence":"additional","affiliation":[{"name":"Department of Hematology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Luigi","family":"Zinzani","sequence":"additional","affiliation":[{"name":"Department of Surgical and Medical Sciences Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna  Bologna Italy"},{"name":"IRCCS Azienda Ospedaliero\u2010Universitaria di Bologna, Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Catani","sequence":"additional","affiliation":[{"name":"Department of Surgical and Medical Sciences Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna  Bologna Italy"},{"name":"IRCCS Azienda Ospedaliero\u2010Universitaria di Bologna, Institute of Hematology \u201cL. e A. Ser\u00e0gnoli\u201d  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7357-4406","authenticated-orcid":false,"given":"Dirk Michiel","family":"Pegtel","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adi9156"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40164\u2010024\u201000518\u20102"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2021.05.006"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac363"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa452"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010021\u201002025\u20108"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70037"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2025.117287"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12302"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3233\/CBM\u2010210110"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2956"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.06.003"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1094"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2020.1722433"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12315"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jex2.164"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2020.06.003"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12121"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.2217\/epi\u20102018\u20100123"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.4149\/214_150224N108"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70039"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.935"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.10.021"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201013\u20101024"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.07.009"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomethods\/bpae032"},{"key":"e_1_2_11_28_1","doi-asserted-by":"crossref","unstructured":"Kim Y. J.Janssen T.Radonic et\u00a0al.2024.Hidden RNA Profiles of Cells in the Tumor Microenvironment Accurately Revealed by Malignant Cell Fraction\u2010Informed Deconvolution.https:\/\/doi.org\/10.21203\/rs.3.rs\u20104252952\/v1.","DOI":"10.21203\/rs.3.rs-4252952\/v1"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.2c00806"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010021\u201001829\u2010y"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.29"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2011.04610.x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010021\u201001470\u20105"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.2147\/PGPM.S386085"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2016.11.003"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232113327"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.110742"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.08.002"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.10783"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20010041"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14611"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.29328"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biochem\u2010013118\u2010111902"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16435"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.23641"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102017\u201012\u2010821843"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010023\u201002743\u20109"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad429"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13105\u2010022\u201000904\u20106"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb3461"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102161"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277\u2010014\u20102111\u20103"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaf013"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2018.1505403"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4185"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2023.102645"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.89631"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.125"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201703206"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326\u20106066.CIR\u201015\u20100161"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvad107"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12404"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.11.005"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.3702"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010020\u201001752\u20102"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110713"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giaa151"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2018.1563692"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70034"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010018\u20100040\u20104"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2023.07.007"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty895"}],"container-title":["Journal of Extracellular Vesicles"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/isevjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jev2.70259","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/isevjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jev2.70259","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/isevjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jev2.70259","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T19:03:00Z","timestamp":1777575780000},"score":1,"resource":{"primary":{"URL":"https:\/\/isevjournals.onlinelibrary.wiley.com\/doi\/10.1002\/jev2.70259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":71,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/jev2.70259"],"URL":"https:\/\/doi.org\/10.1002\/jev2.70259","archive":["Portico"],"relation":{},"ISSN":["2001-3078","2001-3078"],"issn-type":[{"value":"2001-3078","type":"print"},{"value":"2001-3078","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,26]]},"article-number":"e70259"}}