Antioxidative Hyaluronic Acid–Bilirubin Nanomedicine Targeting Activated Hepatic Stellate Cells for Anti-Hepatic-Fibrosis Therapy,ACS Nano

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Antioxidative Hyaluronic Acid–Bilirubin Nanomedicine Targeting Activated Hepatic Stellate Cells for Anti-Hepatic-Fibrosis Therapy
ACS Nano ( IF 15.8 ) Pub Date : 2024-01-30 , DOI: 10.1021/acsnano.3c06107
Jongyoon Shinn ₁ , Seojeong Park ₁ , Seonju Lee ₁ , Nayoon Park ₁ , Seojeong Kim ₁ , Seohui Hwang ₁ , James J Moon _{2,

3,

4,

5} , Youngjoo Kwon ₁ , Yonghyun Lee ₁

Affiliation

Liver fibrosis is a life-threatening and irreversible disease. The fibrosis process is largely driven by hepatic stellate cells (HSCs), which undergo transdifferentiation from an inactivated state to an activated one during persistent liver damage. This activated state is responsible for collagen deposition in liver tissue and is accompanied by increased CD44 expression on the surfaces of HSCs and amplified intracellular oxidative stress, which contributes to the fibrosis process. To address this problem, we have developed a strategy that combines CD44-targeting of activated HSCs with an antioxidative approach. We developed hyaluronic acid–bilirubin nanoparticles (HABNs), composed of endogenous bilirubin, an antioxidant and anti-inflammatory bile acid, and hyaluronic acid, an endogenous CD44-targeting glycosaminoglycan biopolymer. Our findings demonstrate that intravenously administered HABNs effectively targeted the liver, particularly activated HSCs, in fibrotic mice with choline-deficient l-amino acid-defined high-fat diet (CD-HFD)-induced nonalcoholic steatohepatitis (NASH). HABNs were able to inhibit HSC activation and proliferation and collagen production. Furthermore, in a murine CD-HFD-induced NASH fibrosis model, intravenously administered HABNs showed potent fibrotic modulation activity. Our study suggests that HABNs have the potential to serve as a targeted anti-hepatic-fibrosis therapy by modulating activated HSCs via CD44-targeting and antioxidant strategies. This strategy could also be applied to various ROS-related diseases in which CD44-overexpressing cells play a pivotal role.

中文翻译：

抗氧化透明质酸-胆红素纳米药物靶向激活肝星状细胞进行抗肝纤维化治疗

肝纤维化是一种危及生命且不可逆转的疾病。纤维化过程很大程度上是由肝星状细胞（HSC）驱动的，在持续性肝损伤期间，肝星状细胞经历从失活状态到激活状态的转分化。这种激活状态导致肝组织中的胶原沉积，并伴随着 HSC 表面 CD44 表达的增加和细胞内氧化应激的放大，从而促进纤维化过程。为了解决这个问题，我们开发了一种策略，将激活的 HSC 的 CD44 靶向与抗氧化方法相结合。我们开发了透明质酸胆红素纳米颗粒 (HABN)，由内源性胆红素（一种抗氧化剂和抗炎胆汁酸）和透明质酸（一种内源性 CD44 靶向糖胺聚糖生物聚合物）组成。我们的研究结果表明，在缺乏胆碱的l-氨基酸高脂饮食（CD-HFD）诱导的非酒精性脂肪性肝炎（NASH）的纤维化小鼠中，静脉注射HABN可以有效地靶向肝脏，特别是活化的HSC。 HABN 能够抑制 HSC 活化和增殖以及胶原蛋白的产生。此外，在小鼠 CD-HFD 诱导的 NASH 纤维化模型中，静脉注射 HABN 显示出有效的纤维化调节活性。我们的研究表明，HABN 有可能通过 CD44 靶向和抗氧化策略来调节活化的 HSC，从而成为一种靶向抗肝纤维化疗法。该策略还可应用于各种 ROS 相关疾病，其中 CD44 过表达细胞发挥关键作用。

更新日期：2024-01-30

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