Abstract

During chronic liver injury, danger signals released by damaged hepatocytes are known to sequentially promote the polarization of monocyte-derived macrophages (Mo-Macs) toward a pro-fibrotic phenotype and activate hepatic stellate cells (HSCs), ultimately leading to hepatic fibrosis (HF). Intracellular endoplasmic reticulum (ER) stress, tightly associated with dysregulated calcium ion (Ca 2+ ) flux and excessive reactive oxygen species (ROS) production, is recognized as a key driver of this pro-fibrotic polarization process. Recently, metal-polyphenolic networks (MPNs) have garnered significant attention as a versatile class of nanomedicines for treating various diseases, with their potential for tailored design and functional modification, as well as the stimuli-responsive delivery of natural polyphenols and metal ions. In this study, exploiting the ability of magnesium ions (Mg 2+ ) to suppress ER Ca 2+ release and tannic acid (TA) to scavenge ROS, we fabricated Mg-TA MPN-based nanomedicines aimed at restoring ER homeostasis for the treatment of HF. The resulting PEGylated formulation, Mg-TA-PEG (MTP), exhibited excellent biocompatibility, pH-responsive dissociation, and efficient hepatic accumulation. Intravenous MTP administration significantly attenuated carbon tetrachloride induced HF in mice, as evidenced by reduced collagen deposition, normalized liver architecture, and improved metabolic function. Single-nucleus RNA sequencing analysis revealed that MTP inhibits the induction of Mo-Macs by damaged hepatocytes, alleviates ER stress in Mo-Macs, and shifts their polarization from a fibrosis-promoting phenotype to immuno-suppressing and regeneration-promoting phenotypes. This reprogramming further modulates paracrine signaling from Mo-Macs to HSCs, reverting HSCs from an activated to a quiescent state. Moreover, in vitro cell coculture experiments confirmed that MTP primarily targets Mo-Macs rather than directly inhibiting HSC activation, underscoring the cen