Magnesium-tannic acid nanomedicines reprogram pro-fibrotic macrophages for hepatic fibrosis treatment via restoring endoplasmic reticulum homeostasis

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 central role of Mo-Macs in MTP mediated fibrosis resolution. Together, these findings elucidate the anti-fibrotic mechanism of MTP nanomedicines and highlight a promising strategy for reprogramming Mo-Mac phenotypes to treat HF.