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Interfering with the mechanisms regulating this cellular process might find application particularly in oncology where cancer cell\u2010derived <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content>s play a role in tumour microenvironment transformation. Although several mechanisms were ascribed to explain the internalization of <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content>s, little is our knowledge about the fate of their cargos, which are crucial to mediate their function. We recently demonstrated a new intracellular pathway in which a fraction of endocytosed <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content>\u2010associated proteins is transported into the nucleoplasm of the host cell via a subpopulation of late endosomes penetrating into the nucleoplasmic reticulum. Silencing tetraspanin <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9 both in <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content>s and recipient cells strongly decreased the endocytosis of <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content>s and abolished the nuclear transfer of their cargos. Here, we investigated whether monovalent Fab fragments derived from 5H9 anti\u2010<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9 monoclonal antibody (referred hereafter as <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9 Fab) interfered with these cellular processes. To monitor the intracellular transport of proteins, we used fluorescent <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content>s containing <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9\u2010green fluorescent protein fusion protein and various melanoma cell lines and bone marrow\u2010derived mesenchymal stromal cells as recipient cells. Interestingly, <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9 Fab considerably reduced <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content> uptake and the nuclear transfer of their proteins in all examined cells. In contrast, the divalent <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9 antibody stimulated both events. By impeding intercellular communication in the tumour microenvironment, <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>9 Fab\u2010mediated inhibition of <jats:styled-content style=\"fixed-case\">EV<\/jats:styled-content> uptake, combined with direct targeting of cancerous cells could lead to the development of novel anti\u2010melanoma therapeutic strategies.<\/jats:p>","DOI":"10.1111\/jcmm.14334","type":"journal-article","created":{"date-parts":[[2019,4,14]],"date-time":"2019-04-14T04:10:28Z","timestamp":1555215028000},"page":"4408-4421","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Anti\u2010human <scp>CD<\/scp>9 antibody Fab fragment impairs the internalization of extracellular vesicles and the nuclear transfer of their cargo proteins"],"prefix":"10.1111","volume":"23","author":[{"given":"Mark F.","family":"Santos","sequence":"first","affiliation":[{"name":"College of Medicine Touro 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