Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China; State Key Laboratory of Systems Medicine for Cancer, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200090, China.
Department of Gastroenterology, Minhang hospital of Fudan University, China.
Int J Biol Macromol. 2023 Sep 1;248:125906. doi: 10.1016/j.ijbiomac.2023.125906. Epub 2023 Jul 21.
Early intervention of liver fibrosis can prevent its further irreversible progression. Both excess reactive oxygen species (ROS) and transforming growth factor beta(TGF-β)/drosophila mothers against decapentaplegic protein (SMADS) pathway balance disorder promote the progression of hepatic stellate cell (HSC) activation, but existing therapeutic strategies failed to focus on those two problems. A new biomimetic mesoporous polydopamine nandrug (MPO) was constructed for liver fibrosis therapy with multiple targets and reliable biosafety. The MPO was formed by mesoporous polydopamine (mPDA) which has the effect of ROS elimination and encapsulated with anti-fibrotic drug -oxymatrine (OMT) which can intervene liver fibrosis targeting TGF-β/SMADSpathway. Particularly, the nanodrug was completed by macrophage-derived exosome covering. The MPO was confirmed to possess a desired size distribution with negative zeta potential and exhibite strong ROS scavenger ability. Besides, in vitro studies, MPO showed efficient endocytosis and superior intracellular ROS scavenging without cytotoxicity; in vivo studies, MPO effectively cleared the excessive ROS in liver tissue and balanced the TGF-β/SMADS pathways, which in turn inhibited HSC activation and showed superior anti-liver fibrosis therapeutic efficiency with good biological safety. Taken together, this work showed highlights the great potential of the MPO for ameliorating liver fibrosis via ROS elimination and TGF-β/SMADS balancing.
早期干预肝纤维化可以防止其进一步不可逆转的进展。过量的活性氧（ROS）和转化生长因子β（TGF-β）/果蝇母亲对抗 decapentaplegic 蛋白（SMADS）途径平衡障碍都促进肝星状细胞（HSC）激活的进展，但现有的治疗策略未能集中在这两个问题上。一种新的仿生介孔聚多巴胺纳米药物（MPO）被构建用于具有多种靶点和可靠生物安全性的肝纤维化治疗。MPO 由具有 ROS 消除作用的介孔聚多巴胺（mPDA）形成，并封装有抗纤维化药物氧化苦参碱（OMT），可以靶向 TGF-β/SMADS 途径干预肝纤维化。特别是，纳米药物是通过巨噬细胞衍生的外泌体覆盖完成的。MPO 被证实具有理想的粒径分布和负 zeta 电位，并表现出很强的 ROS 清除能力。此外，体外研究表明，MPO 具有高效的内吞作用和优异的细胞内 ROS 清除能力，同时没有细胞毒性；体内研究表明，MPO 能有效清除肝组织中过多的 ROS，并平衡 TGF-β/SMADS 途径，从而抑制 HSC 激活，并表现出优异的抗肝纤维化治疗效果，具有良好的生物安全性。总之，这项工作表明，MPO 通过清除 ROS 和平衡 TGF-β/SMADS 具有改善肝纤维化的巨大潜力。
