“Kupffer Cell Teleportation” Strategy for Liver Fibrosis Alleviation Based on Hybrid Polymer‐ Bimetallic Sequential Delivery System

Abstract Although direct hepatic stellate cell (HSC) inhibition is considered a promising strategy for alleviating liver fibrosis, traditional therapies struggle with off‐target effects due to limited penetration of liver sinusoidal endothelial cell barriers. This study reports on the development of a “Kupffer cell (KC) teleportation” strategy to treat liver fibrosis by fabricating a hybrid polymer‐bimetallic sequential delivery system, CF@BPPM (baicalin prodrug polymer [BP]/mannose derivative polymer [PM] encapsulated copper [Cu]‐iron [Fe] ultrasmall nanoparticles [CFs]). The nanosystems exhibit KCs targeting and acidic response sequential release properties by a hybrid polymer, which first releases CFs in lysosome after being internalized by KCs through a PM targeting effect. The exposed CFs efficiently scavenge reactive oxygen species in KCs and subsequently degrade Cu 2+ / Fe 2+ to upregulate the heme oxygenase expression for suppressing interleukin 1β, interleukin 6, tumor necrosis factor‐alpha, and platelet‐derived growth factors. Second, baicalin, released from BP in lysosome, further inhibits transforming growth factor beta secretion. These results suggest that CF@BPPM inhibits the inclusive cytokine secretion of KCs, which play a vital conductive role in liver fibrosis progression. Subsequently, CF@BPPM achieves protection against HSCs activation, migration, and collagen production, enriching anti‐liver fibrosis therapeutic methods by exploiting messaging between KCs and HSCs.