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Active miRNA sorting into sEVs depends on RNA\u2011binding proteins (RBPs), sequence determinants, and RNA modifications. Here, a functional interplay between the RBP SYNCRIP and N6\u2011methyladenosine (m6A) RNA methylation controlling miRNA loading into hepatocellular carcinoma (HCC)\u2011derived sEVs has been disclosed. It is reported that (i) METTL3 (Methyltransferase-like-3)\u2011dependent m6A modification is required for efficient binding of SYNCRIP to specific miRNAs, thereby enabling their selective incorporation into sEVs; (ii) silencing of SYNCRIP markedly reshapes the sEV miRNA-cargo and impairs the ability of HCC\u2011derived sEVs to induce epithelial-to-mesenchymal transition (EMT) in non\u2011tumorigenic hepatocytes. Notably, (iii) depletion of METTL3 produces an even stronger effect, indicating that m6A methylation represents an upstream and essential determinant of SYNCRIP\u2011mediated miRNA export. Mechanistically, the data identify SYNCRIP as an m6A\u2011dependent miRNA reader, adding epitranscriptomic regulation to sequence\u2011based miRNA sorting into sEVs. Functionally, disruption of this interaction attenuates sEV\u2011driven EMT and pro\u2011tumorigenic signaling. Collectively, these findings uncover a novel regulatory axis governing sEV miRNA cargo selection and highlight the m6A\u2013SYNCRIP interplay as a potential therapeutic target to interfere with sEV\u2011mediated tumor progression and metastasis.<\/jats:p>","DOI":"10.1038\/s41419-026-08991-9","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:39:15Z","timestamp":1781527155000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interplay between the RBP SYNCRIP and RNA methylation in determining sEV miRNA-cargo and function in cell-to-cell communication"],"prefix":"10.1038","volume":"17","author":[{"given":"Luca","family":"Quattrocchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Garbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4836-057X","authenticated-orcid":false,"given":"Francesco","family":"Marocco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Matilde","family":"Renne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3910-3298","authenticated-orcid":false,"given":"Marco","family":"Loria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Pucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Costanzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0944-6992","authenticated-orcid":false,"given":"Maria Felice","family":"Brizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4681-2170","authenticated-orcid":false,"given":"Simona","family":"Fontana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5611-7377","authenticated-orcid":false,"given":"Cecilia","family":"Battistelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-971X","authenticated-orcid":false,"given":"Marco","family":"Tripodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"8991_CR1","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1631\/jzus.B2300566","volume":"25","author":"H Xiang","year":"2024","unstructured":"Xiang H, Bao C, Chen Q, Gao Q, Wang N, Gao Q, et al. 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