Journal Article

An Autologous Macrophage‐Based Phenotypic Transformation‐Collagen Degradation System Treating Advanced Liver Fibrosis

Duan, Bo‐Wen, Zhang, Ling‐Feng, Jiang, Hu‐Lin, Li, Xue‐Na, Hong, He‐Yuan, Liu, Yan‐Jun, Han, Meng‐Meng, Yu, Hao‐Yuan, Xing, Lei

2024

Overview

In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug‐loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG‐E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG‐E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti‐inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage‐focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF. AC73 and siUSP1 dual drug‐loaded lipid nanoparticle carrying milk fat globule epidermal growth factor 8 (MFG‐E8) (named MUA/Y) can significantly induce the macrophages phenotype transformation and effectively inhibit the source of inflammatory cytokines. Meanwhile, MUA/Y inhibits the HSCs proliferation and activation and ablates the deposited ECM to treat advanced liver fibrosis.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: advanced hepatic fibrosis / Bone marrow / Collagen / Cytokines / Flow cytometry / Genotype & phenotype / hepatic stellate cells / Homeostasis / Humans / in situ collagen degradation / Inflammation / lipid nanoparticle / Lipids / Liver cirrhosis / Liver Cirrhosis - therapy / macrophages / Macrophages - metabolism / Nanoparticles / Phenotype / Tumor necrosis factor-TNF