Targeted Immune Modulation for Primary Biliary Cholangitis using Glycyrrhetinic Acid Liposomal Nanoparticles Loaded with Itaconic Acid

Abstract Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by intrahepatic bile duct destruction, cholestasis, and progressive liver fibrosis, and currently lacks effective therapeutic strategies targeting immune dysregulation. In this study, we designed and constructed glycyrrhetinic acid (GA)-modified liposomal nanoparticles loaded with itaconic acid (IA) (LNP-GA@IA) to achieve targeted delivery to diseased liver tissue and precise immune modulation. Both in vitro and in vivo experiments demonstrated that LNP-GA@IA exhibited favorable biosafety and hepatic targeting properties, significantly alleviating hepatobiliary pathological injury and inflammatory responses in PBC mice. Mechanistically, LNP-GA@IA downregulated the expression of methionine adenosyltransferase 2α (Mat2a), thereby promoting metabolic and epigenetic reprogramming. This effectively suppressed the differentiation of pro-inflammatory Th17 cells while enhancing the function of regulatory Treg cells, resulting in attenuated inflammation and improved PBC-related hepatobiliary injury. These findings not only highlight the pivotal role of Mat2a in regulating Th17/Treg balance but also provide a novel therapeutic strategy and target for PBC and other autoimmune diseases.