Sorafenib, encapsulated within Gal-SLPs, initiates a ROS cascade, enabling the rapid release of shUSP22, which inhibits downstream SIRT1/AKT/MRP1 and ABCC1 pathways, increases intracellular sorafenib accumulation, and disrupts glycolysis in HCC cells. Here, ABCC1 is linked to hepatocellular carcinoma.