Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.

中文翻译：

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磷酸肌醇 3-激酶 γ 抑制剂的靶向递送可恢复脓毒症患者的器官功能

黄疸是感染相关肝功能障碍的临床标志，反映了肝细胞小管极膜组织的改变，预示着不良后果。缺乏磷酸肌醇 3-激酶-γ (PI3Kγ) 的小鼠可以免受膜崩解和肝排泄功能障碍的影响。然而，它们表现出严重的免疫缺陷，阻碍中性粒细胞募集到感染部位。为了开发 PI3Kγ 抑制在脓毒症中的治疗潜力，似乎有必要采用一种有针对性的方法，将药物输送到肝实质细胞而不损害其他细胞，特别是免疫细胞。在这里，我们证明通过 DY-635（一种荧光聚次甲基染料）和有机阴离子转运蛋白配体功能化的纳米载体可以选择性地将治疗药物递送至肝实质细胞。将此策略应用于脓毒症小鼠模型，我们观察到 PI3Kγ 依赖性胆管结构的恢复，维持排泄性肝功能，并在不损害宿主防御机制的情况下提高生存率。该策略有可能将靶向纳米药物扩展到具有全身炎症并伴随屏障功能受损的疾病实体。