Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China.
Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China; Department of Pharmacy, Haimen People's Hospital, Nantong 226100, China.
Int J Pharm. 2024 Oct 25;664:124607. doi: 10.1016/j.ijpharm.2024.124607. Epub 2024 Aug 17.
The vicious crosstalk among capillarization of hepatic sinusoidal endothelial cells (LSECs), activation of hepatic stellate cells (aHSCs), and hepatocyte damage poses a significant impediment to the successful treatment of liver fibrosis. In this study, we propose a sequential combination therapy aimed at disrupting the malignant crosstalk and reshaping the benign microenvironment while repairing damaged hepatocytes to achieve effective treatment of liver fibrosis. Firstly, H-subunit apoferrin (Ferritin) was adopted to load platycodonin D (PLD) and MnO, forming ferritin@MnO/PLD (FMP) nanoparticles, which exploited the high affinity of ferritin for the highly expressed transferrin receptor 1 (TfR1) to achieve the precise targeted delivery of FMP in the liver. Upon PLD intervention, restoration of the fenestration pores in capillarized LSECs was facilitated by modulating the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) and Kruppel Like Factor 2 (KLF2) signaling pathways both in vitro and in vivo, enabling efficient entry of FMP into the Disse space. Subsequently, FMP NPs effectively inhibited HSC activation by modulating the TLR2/TLR4/NF-κB-p65 signaling pathway. Moreover, FMP NPs efficiently scavenged reactive oxygen species (ROS) and mitigated the expression of inflammatory mediators, thereby reshaping the microenvironment to support hepatocyte repair. Finally, administration of bone marrow mesenchymal stem cells (BMMSCs) was employed to promote the regeneration and functional recovery of damaged hepatocytes. In conclusion, the combined sequential therapy involving FMP and BMMSCs effectively attenuated liver fibrosis induced by CCl administration, resulting in significant amelioration of the fibrotic condition. The therapeutic strategy outlined in this study underscores the significance of disrupting the deleterious cellular interactions and remodeling the microenvironment, thereby presenting a promising avenue for clinical intervention in liver fibrosis.
肝窦内皮细胞（LSEC）毛细血管化、肝星状细胞（aHSCs）活化和肝细胞损伤之间的恶性串扰对肝纤维化的成功治疗构成了重大障碍。在本研究中，我们提出了一种序贯联合治疗策略，旨在破坏恶性串扰，重塑良性微环境，同时修复受损的肝细胞，以实现肝纤维化的有效治疗。首先，采用 H 亚基脱铁蛋白（铁蛋白）负载远志皂苷 D（PLD）和 MnO，形成铁蛋白@MnO/PLD（FMP）纳米颗粒，利用铁蛋白对高表达转铁蛋白受体 1（TfR1）的高亲和力，实现 FMP 在肝脏中的精确靶向递送。在 PLD 干预下，通过调节体外和体内的磷脂酰肌醇 3-激酶/蛋白激酶 B（PI3K/AKT）和 Kruppel 样因子 2（KLF2）信号通路，促进毛细血管化的 LSEC 中窗孔的恢复，使 FMP 能够有效地进入 Disse 间隙。随后，FMP NPs 通过调节 TLR2/TLR4/NF-κB-p65 信号通路有效地抑制 HSC 激活。此外，FMP NPs 还能有效地清除活性氧（ROS），减轻炎症介质的表达，从而重塑微环境以支持肝细胞修复。最后，给予骨髓间充质干细胞（BMMSCs）以促进受损肝细胞的再生和功能恢复。总之，FMP 和 BMMSCs 的联合序贯治疗有效减轻了 CCl 给药引起的肝纤维化，显著改善了纤维化状况。本研究中提出的治疗策略强调了破坏有害细胞相互作用和重塑微环境的重要性，为肝纤维化的临床干预提供了有前途的途径。
