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Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    \u2010induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage\u2010released apoEVs, which bound iron\u2010containing proteins and neutralized \u03b1\u2010toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti\u2010inflammatory agents (microRNA\u2010146a). These engineered apoEVs can capture iron and neutralize \u03b1\u2010toxin with their natural membrane while also regulating inflammation by releasing microRNA\u2010146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes\u2010driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron\u2010loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202306884","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T01:21:51Z","timestamp":1705886511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Engineered Extracellular Vesicles Driven by Erythrocytes Ameliorate Bacterial Sepsis by Iron Recycling, Toxin Clearing and Inflammation Regulation"],"prefix":"10.1002","volume":"11","author":[{"given":"Yan","family":"Li","sequence":"first","affiliation":[{"name":"National Center for Stomatology National Clinical Research Center for Oral Diseases Shanghai Key Laboratory of Stomatology Research Unit of Oral and Maxillofacial Regenerative Medicine Chinese Academy of Medical Sciences Department of Oral Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine College of Stomatology Shanghai Jiao Tong University  Shanghai 200011 China"},{"name":"State Key Laboratory of Oral &amp; 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