Tetrahedral Framework Nucleic Acid-Based Delivery of miR-34a Inhibitor for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH), a metabolic liver disorder with severe complications, features hepatic inflammation and oxidative stress. MiR-34a dysregulation is a critical contributor to MASH progression, making it a promising therapeutic target. However, clinical translation of miR-34a-targeted interventions remains limited by poor stability and cellular uptake. Here, we developed a miRNA-binding tetrahedral framework nucleic acids (TDN)-based system, termed Tm to deliver miR-34a inhibitor, overcoming these limitations. Tm exhibited enhanced structural stability and cellular uptake compared to free miR-34a inhibitor. Mechanistically, Tm inactivated the nuclear factor-κB (NF-κB) cascade and upregulated the Nrf2/HO-1 pathway, effectively reducing the production of pro-inflammatory cytokine and reactive oxygen species (ROS). In a methionine-restricted and choline-deficient (MRCD)-induced MASH mouse model, Tm treatment markedly attenuated hepatic steatosis, inflammation, and fibrosis and restored liver function more effectively than free miR-34a inhibitor. In summary, this study presents a robust nanomedicine strategy that leverages multifunctional pathway modulation to counteract MASH progression and offers a promising therapeutic avenue for MASH treatment.