Homeostatic remodeling platform for reprogramming Iron Intraspatial orientation to reverse liver fibrosis

Chronic alcohol consumption disrupts iron homeostasis, leading to iron overload in liver parenchymal cells and activation of hepatic stellate cells, ultimately contributing to the development of alcoholic liver fibrosis. Due to the differing iron requirements of these two cell types, current treatment strategies often fail to effectively restore iron balance in the liver and may even exacerbate disease progression. To address this challenge, we developed a targeting-intelligent regulation platform composed of iron-depleting micelles (Met/Gal) and iron-redirecting micelles (Sor/DVA) for the treatment of alcoholic liver fibrosis and other disorders associated with iron dysregulation. Specifically, the Met/Gal micelles suppressed iron excretion in liver parenchymal cells and reduced inflammatory cell infiltration. Concurrently, the Sor/DVA micelles captured iron and directed it toward hepatic stellate cells, leading to their selective elimination through ferroptosis. This dual strategy successfully restored iron homeostasis in the liver and significantly alleviated fibrosis. Notably, the platform also demonstrated therapeutic potential in other iron-related conditions, including pulmonary fibrosis. These findings highlight a novel and broadly applicable approach for the treatment of diseases driven by iron imbalance.