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. 2023 Apr;35(17):e2212206.
doi: 10.1002/adma.202212206. Epub 2023 Mar 14.

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis

Fenfen Li  1   2   3   4 , Ying Zhao  2   3 , Zhaoxia Cheng  2   3 , Yazhou Wang  2   3 , Yale Yue  1   2   3   4 , Xiaoyu Cheng  2   3 , Jingyi Sun  2   3 , Mona Atabakhshi-Kashi  2   3 , Jundong Yao  5 , Jianping Dou  5 , Jie Yu  5 , Xiuping Zhang  2   3   6   7   8 , Yingqiu Qi  1 , Xiaotian Li  9 , Xiaolong Qi  10 , Guangjun Nie  1   2   3   4   11
Affiliations

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis

Fenfen Li et al. Adv Mater. 2023 Apr.

Abstract

During the onset of liver fibrosis, capillarized liver sinusoidal endothelial cells (LSECs) limit substance exchange between the blood and the Disse space, further accelerating hepatic stellate cell (HSCs) activation and fibrosis progression. Limited accessibility of therapeutics to the Disse space is often overlooked and remains a major bottleneck for HSCs-targeted therapy in liver fibrosis. Here, an integrated systemic strategy for liver fibrosis treatment is reported, utilizing pretreatment with the soluble guanylate cyclase stimulator, riociguat, followed by insulin growth factor 2 receptor-mediated targeted delivery of the anti-fibrosis agent, JQ1, via peptide-nanoparticles (IGNP-JQ1). The riociguat reversed the liver sinusoid capillarization to maintain a relatively normal LSECs porosity, thus facilitating the transport of IGNP-JQ1 through the liver sinusoid endothelium wall and enhancing the accumulation of IGNP-JQ1 in the Disse space. IGNP-JQ1 is then selectively taken up by activated HSCs, inhibiting their proliferation and decreasing collagen deposition in the liver. The combined strategy results in significant fibrosis resolution in carbon tetrachloride-induced fibrotic mice as well as methionine-choline-deficient-diet-induced nonalcoholic steatohepatitis (NASH) mice. The work highlights the key role of LSECs in therapeutics transport through the liver sinusoid. The strategy of restoring LSECs fenestrae by riociguat represents a promising approach for liver fibrosis treatment.

Keywords: HSCs-targeted therapy; LSECs fenestrae; drug delivery; liver fibrosis; liver sinusoid barrier; nonalcoholic steatohepatitis.

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