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Although anti\u2010inflammatory and antioxidant therapies have advanced, single\u2010target drugs cannot disrupt the complex inflammatory cascade in SAE. Therefore, multi\u2010target synergistic strategies are urgently needed. This study developed a multifunctional biomimetic nanodrug, ME@FDsi, for precise SAE therapy. The system uses a tetrahedral framework nucleic acid (tFNA) as a carrier, connected via base complementary pairing with small interfering RNA (siTNF\u03b1) to target TNF\u2010\u03b1. It is also loaded with disulfiram (DSF) to inhibit pyroptosis. The resulting FDsi was encapsulated in erythrocyte membrane vesicles modified with the M1 microglia\u2010targeting MG1 peptide. ME@FDsi exhibits a nanovesicle structure, prolonged circulation, stability, and biocompatibility. In SAE mice, it crosses the compromised blood\u2010brain barrier and targets M1 microglia via MG1, releasing DSF and siTNF\u2010\u03b1 intracellularly. DSF blocks pyroptosis and IL\u20101\u03b2 release, while siTNF\u03b1 silences TNF\u2010\u03b1 expression. Additionally, tFNA scavenges reactive oxygen species. Together, these actions shift microglia from the M1 to the M2 phenotype. ME@FDsi treatment improved cognitive function, reduced multi\u2010organ damage, and increased survival in SAE mice. This multi\u2010mechanism synergistic approach offers a promising therapeutic strategy for clinical SAE and sepsis.<\/jats:p>","DOI":"10.1002\/advs.202523716","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T07:48:28Z","timestamp":1777276108000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglia\u2010Targeted Biomimetic Tetrahedral Framework Nucleic Acid Nanovesicles for Synergistic Treatment of Sepsis\u2010Associated Encephalopathy"],"prefix":"10.1002","volume":"13","author":[{"given":"Huimin","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Shenzhen Clinical College (Longgang Central Hospital of Shenzhen) Guangzhou University of Chinese Medicine Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxia","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute for Engineering 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