Glycyrrhetinic acid-albumin nanoparticles with bimodal pharmacological activities for time-dependent restoration of acute liver injury

Acute liver injury (ALI) represents a critical initiating event for deterioration into severe hepatitis or fatal acute liver failure. Glycyrrhizin acid has shown clinical effectiveness in managing liver injury and hepatitis, but it requires metabolic conversion to glycyrrhetinic acid (GA) to be effective. However, the application of GA is impeded by poor solubility and rapid clearance. Given the ultra-high albumin affinity of GA, three GA-human serum albumin nanoparticles (GA@HSA NPs) with optimized mass ratios (1:0.5, 1:1, and 1:2) were reported. Molecular dynamics simulations revealed that GA predominantly occupied structural domain IIA within Sudlow site I of HSA. Upon administration, the hepatic retention of GA@HSA NPs was significantly increased, especially for 1:2 GA@HSA NPs. Notably, GA@HSA NPs exhibited bimodal pharmacological activities, including time-dependent prophylactic and therapeutic effects on ALI, which were achieved by decreasing intracellular nitric oxide (NO), reactive oxygen species (ROS), and restoring pro-inflammatory macrophages to normal macrophages. In preventive mode, 1:2 GA@HSA NPs even restored liver function indicators involved in ALI to normal levels while ensuring safety, displaying potent therapeutic benefits. These findings established a paradigm for liver targeting therapy, offering mechanistic insights and translational potential for ALI management.