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

Area of Science:

• Biomedical Engineering
• Hepatology
• Nanomedicine

Background:

• Liver fibrosis is exacerbated by crosstalk between capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (aHSCs), and damaged hepatocytes.
• Existing treatments face challenges due to this complex cellular crosstalk and the damaged liver microenvironment.

Purpose of the Study:

• To develop and evaluate a sequential combination therapy to disrupt cellular crosstalk and promote liver repair in liver fibrosis.
• To investigate the efficacy of ferritin@MnO2/PLD (FMP) nanoparticles combined with bone marrow mesenchymal stem cells (BMMSCs) for treating liver fibrosis.

Main Methods:

• Fabrication of FMP nanoparticles utilizing H-subunit apoferrin for targeted delivery via transferrin receptor 1 (TfR1).
• In vitro and in vivo assessment of FMP's effect on LSEC fenestration via PI3K/AKT and KLF2 pathways.
• Evaluation of FMP's impact on HSC activation (TLR2/TLR4/NF-κB-p65 pathway), ROS scavenging, and inflammation.
• Assessment of BMMSC administration for promoting hepatocyte regeneration and functional recovery.

Main Results:

• FMP nanoparticles successfully targeted the liver and restored LSEC fenestration, facilitating Disse space entry.
• FMP inhibited HSC activation, scavenged ROS, reduced inflammation, and reshaped the microenvironment.
• The sequential FMP and BMMSC therapy significantly attenuated CCl4-induced liver fibrosis, improving the fibrotic condition.

Conclusions:

• The combined sequential therapy effectively treats liver fibrosis by disrupting detrimental cellular interactions and remodeling the liver microenvironment.
• This strategy presents a promising therapeutic approach for clinical intervention in liver fibrosis.