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

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.