肝窦内皮细胞（LSEC）毛细血管化、肝星状细胞（aHSC）激活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疗法，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亚基脱铁铁蛋白（铁蛋白）负载桔梗蛋白D（PLD）和MnO2，形成铁蛋白@MnO2/PLD（FMP）纳米颗粒，利用铁蛋白与高表达的转铁蛋白受体1（TfR1）的高亲和力，实现FMP在肝脏的精准靶向递送。在 PLD 干预后，通过在体外和体内调节磷脂酰肌醇 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 LSEC 开窗孔的恢复，从而实现高效FMP 进入 Disse 空间。随后，FMP NPs 通过调节 TLR2/TLR4/NF-κB-p65 信号通路有效抑制 HSC 活化。此外，FMP NPs 有效清除活性氧（ROS）并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，使用骨髓间充质干细胞（BMMSCs）来促进受损肝细胞的再生和功能恢复。总之，FMP 和 BMMSC 联合序贯疗法可有效减轻 CCl4 诱导的肝纤维化，从而显着改善纤维化状况。本研究概述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，从而为肝纤维化的临床干预提供了一条有前途的途径。版权所有 © 2024。由 Elsevier B.V. 出版。

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 MnO2, forming ferritin@MnO2/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 CCl4 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.Copyright © 2024. Published by Elsevier B.V.