posted on 2024-01-30, 12:36authored byJongyoon Shinn, Seojeong Park, Seonju Lee, Nayoon Park, Seojeong Kim, Seohui Hwang, James J. Moon, Youngjoo Kwon, Yonghyun Lee
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.