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While Bacillus Calmette\u2013Gu\u00e9rin (BCG) is the most widely used vaccine for tuberculosis prevention, its broader use as an inducer of trained immunity is limited by adverse reactions. Here, it is reported that BCG\u2010derived outer membrane vesicles (B\u2010OMVs) effectively trigger trained immunity to protect against experimental polymicrobial sepsis. Comprehensive characterization and safety assessments confirmed that B\u2010OMVs exhibited no significant toxicity or pathological effects, positioning them as a promising alternative to conventional BCG vaccines and\n                    <jats:italic>E. coli<\/jats:italic>\n                    \u2010derived outer membrane vesicles (E\u2010OMVs) in terms of both efficacy and safety. Mechanistically, B\u2010OMVs enhanced trained immunity by promoting hematopoietic stem cell expansion and myelopoiesis via toll like receptor 2 (TLR2)\u2010dependent activation of aerobic glycolysis and epigenetic reprogramming. 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Together, these findings establish B\u2010OMVs as a novel immunomodulatory agent against sepsis\u2010induced immune dysfunction, with translational potential.\n                  <\/jats:p>","DOI":"10.1002\/advs.202504101","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T04:30:52Z","timestamp":1750739452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["BCG\u2010Derived Outer Membrane Vesicles Induce TLR2\u2010Dependent Trained Immunity to Protect Against Polymicrobial Sepsis"],"prefix":"10.1002","volume":"12","author":[{"given":"Yuan","family":"Gong","sequence":"first","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"},{"name":"Department of Pediatric Surgery Affiliated Hospital of Zunyi Medical University  Zunyi Guizhou 563000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Hao","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyi","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"},{"name":"Department of Surgery UT Southwestern Medical Center  Dallas TX 75235 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Pan","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenjiang","family":"Bai","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research Children's Hospital of Soochow University  Suzhou 215025 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaidi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Affiliated Hospital of Zunyi Medical University  Zunyi Guizhou 563000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Affiliated Hospital of Zunyi Medical University  Zunyi Guizhou 563000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Surgery UT Southwestern Medical Center  Dallas TX 75235 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Shan","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Immunity and Inflammation Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; 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