Hepatocellular injury is the pathological hallmark of hepatitis and a crucial driver for the progression of liver diseases, while the treatment options are commonly restricted. Interleukin-22 (IL-22) has attracted special attention as a potent survival factor for hepatocytes that both prevents and repairs the injury of hepatocytes through activation of STAT3 signaling pathway. We hypothesized that the ability to generate potent expression of IL-22 locally for the treatment of severe hepatocellular injury in hepatitis was a promising strategy to enhance efficacy and overcome off-target effects. Accordingly, we developed a polypeptide penetratin-based hybrid nanoparticle system (PDPIA) carrying IL-22 gene by a self-assembly process. This nanocomplex modified with penetratin featured direct translocation across the cellular or endosomal membrane but mild zeta-potential to facilitate the high cellular internalization and endosomal escape of the gene cargos as well as scarcely Kupffer cells uptake. More importantly, PDPIA afforded preferential liver accumulation and predominant hepatocytes internalization following systemic administration, which showed pharmacologically suitable organ and sub-organ-selective properties. Subsequent studies confirmed a considerable protective role of PDPIA in a model of severe hepatitis induced by concanavalin A, evidenced by reduced hepatocellular injury and evaded immune response. The locally expressed IL-22 by PDPIA activated STAT3/Erk signal transduction, and thus promoted hepatocyte regeneration, inhibited reactive oxygen species (ROS) accumulation as well as prevented the dysfunction of mitochondrial. In addition, this system did not manifest side effects or systemic toxicity in mice. Collectively, the high versatility of PDPIA rendered its promising applications might be an effective agent to treat various hepatic disorders.

肝细胞损伤是肝炎的病理标志，是肝病进展的关键驱动器，而治疗选择通常受到限制。白介素22（IL-22）作为肝细胞的有效存活因子已引起了特别关注，该因子通过激活STAT3信号通路来预防和修复肝细胞的损伤。我们假设能够在本地产生有效的IL-22表达以治疗肝炎中严重的肝细胞损伤的能力是增强疗效和克服脱靶效应的一种有前途的策略。因此，我们通过自组装过程开发了携带IL-22基因的基于多肽穿透素的杂合纳米颗粒系统（PDPIA）。这种用渗透素修饰的纳米复合物具有跨细胞膜或内体膜直接易位的特点，但具有适度的ζ电位，以促进基因货物的高细胞内在化和内体逃逸以及几乎没有库普弗细胞的吸收。更重要的是，在全身性给药后，PDPIA提供了优先的肝脏蓄积和主要的肝细胞内在化，这显示出药理学上合适的器官和亚器官选择性特性。随后的研究证实了PDPIA在伴刀豆球蛋白A诱发的严重肝炎模型中的重要保护作用，这可通过减少肝细胞损伤和逃避免疫反应来证明。PDPIA局部表达的IL-22激活STAT3 / Erk信号转导，从而促进肝细胞再生，抑制活性氧（ROS）的积累以及预防线粒体功能障碍。另外，该系统在小鼠中没有表现出副作用或全身毒性。总体而言，PDPIA的高度多功能性使其有希望的应用可能是治疗各种肝病的有效药物。