{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T19:12:39Z","timestamp":1788549159358,"version":"build-2803163510"},"reference-count":73,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"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":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in cancer. We previously demonstrated that re\u2010expression of the leucine\u2010rich domain (LRD) of neurofibromin (NF1) suppresses glioblastoma (GBM) invasion and limits microglia\/macrophage infiltration into the tumor microenvironment (TME). Given the central role of tumor\u2010associated microglia\/macrophages (TAMs) in GBM progression, we investigated whether NF1\u2010LRD\u2010containing EVs (NF1\u2010LRD\u2010EVs) could modulate TAM function and remodel the TME. Our results showed that NF1\u2010LRD\u2010EVs attenuated microglia and macrophage recruitment in migration assays, consistent with reduced microglia\/macrophage recruitment observed\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In parallel, treatment with NF1\u2010LRD\u2010EVs enhanced phagocytic activity of both microglia and iPSC\u2010derived macrophages, accompanied by induction of pro\u2010inflammatory cytokines TNF\u2010\u03b1, IL\u20106, and IL\u20101\u03b2, and downregulation of immunosuppressive mediators such as Arginase\u20101 and IL\u201010. Mechanistically, NF1\u2010LRD\u2010EVs induced ADAM17\u2010associated inflammatory signaling, accompanied by NF\u2010\u03baB activation. Pharmacological inhibition of ADAM17 reduced TNF\u2010\u03b1 release and attenuated NF\u2010\u03baB activation, supporting a role for ADAM17\u2010dependent signaling in amplifying this inflammatory response. Together, these findings show that NF1\u2010LRD\u2010EVs reprogram TAMs toward a pro\u2010inflammatory phenotype and modulate the GBM immune microenvironment. These results provide a framework for understanding NF1\u2010LRD\u2010EV\u2010mediated immune regulation and support further investigation of EV\u2010mediated immune modulation of the TME.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70355","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T17:55:42Z","timestamp":1787334942000},"source":"Crossref","is-referenced-by-count":0,"title":["NF1 Leucine Rich Domain\u2010Derived Extracellular Vesicles Remodel the Glioblastoma Immune Microenvironment via an ADAM17\u2010Associated Inflammatory Program"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9971-7690","authenticated-orcid":false,"given":"Yuganthini","family":"Vijayanathan","sequence":"first","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline YT","family":"Yeo","sequence":"additional","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5652-5548","authenticated-orcid":false,"given":"Janice HY","family":"Tan","sequence":"additional","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6181-0559","authenticated-orcid":false,"given":"Fikri Bin","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2709-1972","authenticated-orcid":false,"given":"Bernett","family":"Lee","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Informatics Lee Kong Chian School of Medicine  Singapore Singapore"},{"name":"Singapore Immunology Network  Singapore Singapore"},{"name":"Infectious Disease Labs (ID Labs), Agency for Science Technology and Research (A*STAR)  Singapore Singapore"},{"name":"Khoo Teck Puat Hospital  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kozaki","sequence":"additional","affiliation":[{"name":"Singapore Immunology Network  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1115-7439","authenticated-orcid":false,"given":"Nurashikin Abdul","family":"Halim","sequence":"additional","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel LY","family":"Ho","sequence":"additional","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7499-0682","authenticated-orcid":false,"given":"Hai Tao","family":"Tu","sequence":"additional","affiliation":[{"name":"Neural Stem Cells Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Neural Stem Cells Laboratory National Neuroscience Institute  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-4885","authenticated-orcid":false,"given":"Jann N.","family":"Sarkaria","sequence":"additional","affiliation":[{"name":"Department of Radiology Mayo Clinic  Rochester USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3242-2286","authenticated-orcid":false,"given":"Li","family":"Zeng","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Informatics Lee Kong Chian School of Medicine  Singapore Singapore"},{"name":"Neural Stem Cells Laboratory National Neuroscience Institute  Singapore Singapore"},{"name":"Duke\u2010NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-7755","authenticated-orcid":false,"given":"Florent","family":"Ginhoux","sequence":"additional","affiliation":[{"name":"Singapore Immunology Network  Singapore Singapore"},{"name":"Institute Gustave Roussy  Paris France"},{"name":"Translational Immunology Institute SingHealth Duke\u2010NUS Academic Medical Centre  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2948-3726","authenticated-orcid":false,"given":"Ivy AW","family":"Ho","sequence":"additional","affiliation":[{"name":"Molecular Neurotherapeutics Laboratory National Neuroscience Institute  Singapore Singapore"},{"name":"Duke\u2010NUS Medical School  Singapore Singapore"},{"name":"Department of Physiology, Yong Loo Lin School of Medicine National University of Singapore  Singapore 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