Li Fenfen, Zhao Ying, Cheng Zhaoxia, Wang Yazhou, Yue Yale, Cheng Xiaoyu, Sun Jingyi, Atabakhshi-Kashi Mona, Yao Jundong, Dou Jianping, Yu Jie, Zhang Xiuping, Qi Yingqiu, Li Xiaotian, Qi Xiaolong, Nie Guangjun
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, P. R. China.
CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China.
Adv Mater. 2023 Apr;35(17):e2212206. doi: 10.1002/adma.202212206. Epub 2023 Mar 14.
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.
在肝纤维化发生过程中，肝窦内皮细胞（LSECs）毛细血管化限制了血液与狄氏间隙之间的物质交换，进一步加速肝星状细胞（HSCs）活化和纤维化进展。治疗药物难以到达狄氏间隙这一问题常常被忽视，并且仍然是肝纤维化靶向治疗HSCs的主要瓶颈。在此，报告了一种综合的肝纤维化系统性治疗策略，即先用可溶性鸟苷酸环化酶刺激剂利奥西呱进行预处理，然后通过肽纳米颗粒（IGNP-JQ1）实现胰岛素生长因子2受体介导的抗纤维化药物JQ1的靶向递送。利奥西呱可逆转肝血窦毛细血管化，以维持相对正常的LSECs孔隙率，从而促进IGNP-JQ1穿过肝血窦内皮细胞壁的转运，并增强IGNP-JQ1在狄氏间隙的蓄积。然后，活化的HSCs选择性摄取IGNP-JQ1，抑制其增殖并减少肝脏中的胶原沉积。联合策略在四氯化碳诱导的纤维化小鼠以及蛋氨酸-胆碱缺乏饮食诱导的非酒精性脂肪性肝炎（NASH）小鼠中均能显著减轻纤维化。这项工作突出了LSECs在治疗药物通过肝血窦转运中的关键作用。利奥西呱恢复LSECs窗孔的策略代表了一种有前景的肝纤维化治疗方法。
