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Standard treatment consists of antibiotics to eliminate bacteria and dexamethasone to reduce inflammation. Despite this, mortality reaches 20% in treated individuals, and half of the survivors suffer long\u2010term neurological sequelae. This is largely due to the poor capacity of antibiotics to reach the brain and the lack of antimicrobial treatment capable of neutralizing the pneumococcal toxin pneumolysin (Ply). To address these limitations, we isolated extracellular vesicles (EVs) derived from human HEK293T cells and evaluated their therapeutic potential in pneumococcal meningitis. Alongside wild\u2010type EVs (WT.EVs), we bioengineered EVs to express RVG peptides (RVG.EV) for targeting neuronal acetylcholine receptors, signal incompetent IL\u20106 signal transducer (IL\u20106ST) decoy receptors (IL\u20106.EV) to block the pro\u2010inflammatory signalling of IL\u20106, or EVs expressing both RVG peptides and IL\u20106ST (DB.EV).\n                    <jats:italic>In vitro<\/jats:italic>\n                    , all EVs reduced pneumococcal adhesion to neurons and mitigated cytotoxicity by binding and sequestering Ply. In a bacteremia\u2010derived pneumococcal meningitis model, EV treatment significantly increased the survival of the mice without affecting bacterial load in the brain or the periphery. Among all groups, RVG.EV treatment was most effective in reducing pro\u2010inflammatory cytokine release in the periphery and brain. These findings highlight the therapeutic potential of bioengineered EVs, particularly RVG peptides expressing EVs, as an adjunctive treatment for pneumococcal meningitis thanks to their (i) sequestration and neutralization of Ply, (ii) increased blood\u2010brain barrier crossing, and (iii) dampening of inflammation.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70369","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T07:22:04Z","timestamp":1789111324000},"source":"Crossref","is-referenced-by-count":1,"title":["Bioengineered Extracellular Vesicles Mitigate Neuroinflammation by Neutralizing Pneumolysin and Delaying Disease Onset in Experimental Pneumococcal Meningitis"],"prefix":"10.1002","volume":"15","author":[{"given":"Kristine","family":"Farmen","sequence":"first","affiliation":[{"name":"Department of Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4785-0796","authenticated-orcid":false,"given":"Doste R.","family":"Mamand","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet  Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet  Stockholm Sweden"},{"name":"Breast Center Karolinska Comprehensive Cancer Center Karolinska University Hospital  Stockholm Sweden"},{"name":"Biology Research Center, Research Center University of Zakho  Zakho, Duhok Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Tofi\u00f1o\u2010Vian","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Yfanti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuming","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet  Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houze","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine Karolinska Institutet  Stockholm Sweden"},{"name":"Karolinska ATMP Center Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky W. 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