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

• Published in: ACS nano Vol. 18; no. 6; pp. 4704 - 4716
• Main Authors: Shinn, Jongyoon, Park, Seojeong, Lee, Seonju, Park, Nayoon, Kim, Seojeong, Hwang, Seohui, Moon, James J., Kwon, Youngjoo, Lee, Yonghyun
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.02.2024
• Subjects: Animals; Antioxidants - metabolism; Antioxidants - pharmacology; Bilirubin - pharmacology; Collagen - metabolism; Fibrosis; Hepatic Stellate Cells - metabolism; Hyaluronic Acid - pharmacology; Liver - metabolism; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Mice; Mice, Inbred C57BL; Nanomedicine; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Activated hepatic stellate cells; Nonalcoholic steatohepatitis; Antioxidative therapy; Bilirubin; Hyaluronic acid; NASH; Nanomedicine; Anti-liver-fibrosis therapy
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.3c06107

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.