Tetrahedral framework nucleic acids ameliorate cholestatic liver disease by activating Wnt/β-catenin signaling and promoting ERK1/2 phosphorylation

Cholestatic liver disease (CLD) is characterized by disruptions in bile formation, secretion and excretion, leading to progressive liver injury, inflammation and fibrosis. Effective treatments to halt or reverse the progression of CLD remain limited. The Wnt/β-catenin signaling pathway has been implicated in the regulation of bile acid homeostasis and liver regeneration, playing a complex role in CLD pathophysiology. Tetrahedral framework nucleic acids (TFNAs), a class of anti-inflammatory and antioxidant DNA nanomaterials, have shown potential in promoting mammalian cell proliferation through activation of cell cycle and proliferation-related signaling pathways. However, their therapeutic potential in CLD has not been fully explored. In this study, we investigated the effects of TFNAs in an α-naphthyl isothiocyanate (ANIT)-induced mouse model of CLD. TFNAs demonstrated the ability to enter hepatocytes, where they activated the Wnt/β-catenin signaling pathway and enhanced ERK1/2 phosphorylation. These molecular changes resulted in significant improvements in liver injury markers, bile acid metabolism and liver regeneration. Complementary <i>in vitro</i> experiments revealed that TFNAs reduced hepatocyte apoptosis and oxidative stress, while promoting cell viability and proliferation. Histological analysis confirmed that TFNAs treatment mitigated liver necrosis, reduced ductular reactions and decreased neutrophil infiltration, highlighting their anti-inflammatory and tissue-protective effects. These findings provide compelling evidence that TFNAs can ameliorate CLD by modulating key signaling pathways involved in hepatocyte survival, regeneration and bile acid homeostasis. Collectively, our findings highlight the therapeutic potential of TFNAs as a novel treatment for CLD and paves the way for further exploration of nanomaterials in liver disease therapy.