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.