Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly (ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.

脓毒症是感染的潜在致命并发症，目前尚无有效的治疗严重脓毒症的方法。在这项研究中，我们揭示了最近被确定为败血症治疗靶点的转化生长因子β诱导蛋白（TGFBIp）的分泌机制，并设计了抑制TGFBIp中赖氨酸676乙酰化的TGFBIp乙酰化抑制肽（TAIP）。为了提高肽的生物利用度和生物降解性，将TAIP与聚酰胺酰胺（PAMAM）树状聚合物偶联。此外，将细胞穿透肽（CPP）与TAIP修饰的PAMAM树状聚合物偶联，以进行TGFBIp的细胞内递送。所得的纳米结构通过聚（乙二醇）键用TAIP和CPP装饰，改善败血性小鼠模型的死亡率和器官损伤，并抑制脂多糖激活的内皮细胞严重血管炎性反应。因此，使用CPP递送TAIP的基于树状聚合物的纳米结构在脓毒症治疗的实际应用中显示出巨大的希望。