Acid-Labile Liver-Targeted Unimolecular Micelles Based on Hyperbranched Polyprodrug Amphiphiles for Targeted Therapy of Hepatic Fibrosis.

Liver fibrosis is a chronic liver disease driven by sustained inflammation, highlighting the need for targeted delivery of anti-inflammatory agents. We report the design of an acid-sensitive, liver-targeted hyperbranched polyprodrug (PPOG) that forms stable unimolecular micelles. Prednisone is conjugated to the hydrophobic core through acid-labile linkers, and glycyrrhetinic acid on the micelle surface enables hepatocyte targeting. PPOG demonstrates excellent colloidal stability under dilution, ionic stress, and long-term storage. In vitro, the micelles show low cytotoxicity and rapid prednisone release under acidic conditions. GA-mediated targeting enhances cellular uptake in hepatocytes, while in vivo imaging in a CCl4-induced mouse fibrosis model confirms higher liver accumulation than nontargeted micelles. PPOG treatment markedly reduces liver injury biomarkers, inflammatory cytokines, and collagen deposition, outperforming free prednisone and nontargeted formulations. These results indicate that PPOG unimolecular micelles offer a promising strategy for targeted anti-inflammatory therapy in liver fibrosis.