Metal Ion Nanosystems for Targeted siRNA Delivery and Coordinated Macrophage Polarization Modulation for Liver Fibrosis Reversal

RNA therapeutics represent a promising avenue for liver fibrosis treatment, owing to their ability to downregulate cytokine levels in key effector cells. However, targeted delivery of RNA to hepatic macrophages remains a critical hurdle. Here, the metal ion-based nanosystem is designed for the efficient loading of RNA and its targeted delivery to macrophages. This system effectively inhibits TNF-α production and regulates macrophage polarization through a metal ion-mediated NF-κB pathway, offering a strategy for liver fibrosis therapy. Additionally, the incorporation of perfluorocarbon has endowed the nanocarriers with the ability to store oxygen, thereby enhancing gene delivery efficiency in hypoxic environments. In mouse models, TNF-α levels are reduced to levels comparable to those in healthy mice. Furthermore, metal ion-mediated NF-κB pathway inhibition balances macrophage polarization, suppresses hepatic stellate cell (HSC) activation, and ultimately leads to the reversal of liver fibrosis. Our findings demonstrate that concurrent reduction of TNF-α and regulation of macrophage polarization can synergistically promote fibrosis reversal. This work presents a strategy for the preparation of nanocarriers capable of efficiently delivering siRNA to regulate macrophages and promote low-oxygen adaptation, thereby reversing liver fibrosis.