Targeted Interleukin-22 Gene Delivery in the Liver by Polymetformin and Penetratin-Based Hybrid Nanoparticles to Treat Nonalcoholic Fatty Liver Disease
Targeted Interleukin-22 Gene Delivery in the Liver by Polymetformin and Penetratin-Based Hybrid Nanoparticles to Treat Nonalcoholic Fatty Liver Disease
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通过聚二甲双胍和基于渗透素的混合纳米颗粒将白细胞介素 22 基因靶向递送至肝脏以治疗非酒精性脂肪肝
DOI：
10.1021/acsami.8b19717
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发表时间：
2019
影响因子：
9.5
通讯作者：
Ju Dianwen
中科院分区：
文献类型：
--
作者：
Zai Wenjing;Chen Wei;Wu Zimei;Jin Xin;Fan Jiajun;Zhang Xuyao;Luan Jingyun;Tang Shijie;Mei Xiaobin;Hao Bang;Liu Hongrui;Ju Dianwen
非酒精性脂肪肝（NAFLD）现在是慢性肝脏疾病的主要原因，目前尚无可用的治疗策略。白细胞介素-22（IL-22）被认为是一种很有前途的治疗NAFLD的药物，但其疗效远不能令人满意，因为安全剂量的IL-22引起的改善有限，而更高浓度的IL-22可能引起严重的副作用和脱靶毒性。因此，IL-22在肝脏中的靶向和持续表达是必要的。为了应对这一挑战，我们精心开发了一种新型的聚二甲双胍载体，将双胍与壳聚糖偶联，称为壳聚糖-二甲双胍（chitosan-metformin，CM），其可以发挥先进的基因递送效率，并具有二甲双胍对NAFLD的内在治疗效果。CM与penetratin和DSPE-PEG 2000通过静电相互作用可以与IL-22基因自组装形成稳定的纳米复合物。这种纳米颗粒（CDPIA）发挥了理想的粒径在100 nm，精细的形态，和有效的细胞内化。此外，CDPIA还表现出内体逃逸能力和令人满意的生物相容性以及主要的肝脏蓄积方面的独特优势。最重要的是，CDPIA在高脂饮食喂养的小鼠模型中明显减轻肝脏脂肪变性，恢复胰岛素敏感性，并改善代谢综合征。这种IL-22的肝脏靶向递送激活了STAT 3/Erk 1/2和Nrf 2/SOD 1信号转导，并调节了脂质代谢相关的基因表达。这些发现共同表明，基于聚二甲双胍和渗透素的混合纳米颗粒可以被开发为用于改善NAFLD的新的安全且有效的策略。
Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan–metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient cellular internalization. Furthermore, CDPIA also demonstrated a unique superiority in endosomal escape capacity and satisfactory biocompatibility as well as predominant liver accumulation. Most importantly, CDPIA distinctly alleviated hepatic steatosis, restored insulin sensitivity, and improved metabolic syndrome in high-fat-diet-fed mice model. This liver-targeted delivery of IL-22 activated STAT3/Erk1/2 and Nrf2/SOD1 signaling transductions as well as modulated lipid-metabolism-related gene expression. These findings altogether demonstrated that the polymetformin and penetratin-based hybrid nanoparticles could be exploited as a novel safe and efficient strategy for the improvement of NAFLD.