The Dual‐Target Nanoparticles with ROS Sensitivity Inhibit the Hedgehog Signaling Pathway and Decrease Oxidative Stress in Activated Hepatic Stellate Cells to Alleviate Liver Fibrosis

Abstract Liver fibrosis is characterized by excess reactive oxygen species (ROS) production, hepatic stellate cell (HSC) activation, and subsequent extracellular matrix deposition. Since complex pathways regulate HSC activation, the single‐drug therapy efficacy for live fibrosis often falls short of expectations. To address this issue, an HSC‐targeted multifunctional nanoparticle (NP) delivery system co‐loaded with cyclopamine (Cyc; hedgehog inhibitor) and bilirubin (BR; ROS‐scavenger) is designed. The NP, termed RHB, is constructed via chemically conjugating hydrophobic bilirubin to hyaluronic acid (HA), followed by inserting into a cRGDyK peptide modified‐PEG shell. RHB can effectively target activated HSCs in the fibrotic liver by recognizing of the cRGDyK peptide and HA with integrin αvβ3 and CD44 due to their high expression on HSCs. During liver fibrosis, RHB NPs intelligently released Cyc in response to elevated ROS, inhibiting hedgehog signaling and subsequent HSC activation. Meanwhile, RHB NPs exhibited ROS scavenging capability and activated nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling in stimulated HSCs, deactivating HSC. Cyc‐loaded RHB NPs significantly reversed the inflammatory and fibrotic phenotypes in liver fibrotic mice without evident toxicity. In summary, the multifunctional NPs dual‐targeted activated HSCs and deactivated HSC via multiple signaling, effectively ameliorating liver fibrosis, showing great promise for hepatic fibrosis treatment.