Microglia‐Targeted Biomimetic Tetrahedral Framework Nucleic Acid Nanovesicles for Synergistic Treatment of Sepsis‐Associated Encephalopathy

ABSTRACT Sepsis‐associated encephalopathy (SAE), the most prevalent and severe complication of sepsis, is a leading cause of long‐term cognitive deficits and increased mortality. Although anti‐inflammatory and antioxidant therapies have advanced, single‐target drugs cannot disrupt the complex inflammatory cascade in SAE. Therefore, multi‐target 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 (siTNFα) to target TNF‐α. It is also loaded with disulfiram (DSF) to inhibit pyroptosis. The resulting FDsi was encapsulated in erythrocyte membrane vesicles modified with the M1 microglia‐targeting MG1 peptide. ME@FDsi exhibits a nanovesicle structure, prolonged circulation, stability, and biocompatibility. In SAE mice, it crosses the compromised blood‐brain barrier and targets M1 microglia via MG1, releasing DSF and siTNF‐α intracellularly. DSF blocks pyroptosis and IL‐1β release, while siTNFα silences TNF‐α 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‐organ damage, and increased survival in SAE mice. This multi‐mechanism synergistic approach offers a promising therapeutic strategy for clinical SAE and sepsis.