Sequential system based on ferritin delivery system and cell therapy for modulating the pathological microenvironment...

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.