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Given that inflammation is central to many acute and chronic diseases, understanding EV biodistribution under inflammatory conditions is essential for therapeutic optimisation. This study examines how acute systemic inflammation influences EV biodistribution, clearance and plasma half\u2010life, with a focus on the role of macrophages and their polarisation states. Using a lipopolysaccharide (LPS)\u2010induced inflammation model in wild\u2010type mice and bioluminescent and fluorescent labelling of EVs, we observed that inflammation extends the plasma half\u2010life of EVs by over 600\u2010fold within 2 h and 900\u2010fold at 24 h post\u2010administration, leading to significant enrichment in inflamed organs, particularly the liver and spleen. Enhanced accumulation in specific tissues translated to increased targeting of immune\u2010 and epithelial cells within those organs, with notable uptake by hepatocytes in the liver. To probe the mechanism, we profiled the EV protein corona, revealing inflammation\u2010driven remodelling with enrichment of acute\u2010phase proteins, complement factors and cytoskeletal regulators\u2014linking corona composition to altered biodistribution. Yet, despite increased uptake and tissue accumulation, functional EV cargo delivery in vivo remained limited. These findings underscore the complex dynamics between EVs and immune cells under inflammatory conditions and provide critical insights for advancing EV\u2010based therapies in chronic inflammatory diseases.<\/jats:p>","DOI":"10.1002\/jev2.70256","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:12:11Z","timestamp":1775560331000},"source":"Crossref","is-referenced-by-count":7,"title":["Systemic Inflammation Modulates Clearance and Drives Extra\u2010Hepatic Distribution of Extracellular Vesicles"],"prefix":"10.1002","volume":"15","author":[{"given":"Svetlana","family":"Pavlova","sequence":"first","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Huddinge Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doste R.","family":"Mamand","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Breast Center Karolinska Comprehensive Cancer Center Karolinska University Hospital  Solna Stockholm Sweden"},{"name":"Biology Research Center Research Center University of Zakho, Zakho Duhok Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9198-0857","authenticated-orcid":false,"given":"Andr\u00e9","family":"G\u00f6rgens","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Huddinge Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje M.","family":"Zickler","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Huddinge Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2416-5822","authenticated-orcid":false,"given":"Wenyi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Huddinge Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0202-1211","authenticated-orcid":false,"given":"Xiuming","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Huddinge Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet, ANA Futura, Alfred\u2010Nobels\u2010All\u00e9 8  Huddinge Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar P. 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