Oral Administration of a Tetrahedral Framework DNA-Based Nanoshot Attenuates Liver Fibrosis via Targeting Galectin-3

Liver cirrhosis is a prevalent global health issue that has imposed a significant economic burden. Currently, there is a lack of effective treatment for liver cirrhosis due to poor patient compliance with injectable medications. Hepatic uncontrolled inflammation is the primary therapeutic target for liver cirrhosis. The oral administration of tetrahedral framework nucleic acid (tFNA) presents a promising approach due to its low hepatic toxicity and the ability to control inflammation, target the liver, and deliver small interfering RNAs (siRNAs). Here, we reported that tFNA could be effectively delivered to the liver. Then, a DNA nanoshot (DNS) combining tFNA and Galectin-3-targeted siRNA was developed and encapsulated in an enteric-coated capsule (DNS@cap) to protect it from gastric acid and enhance intestinal absorption. Functionally, the oral administration of DNS@cap showed excellent gastric stability and intestinal penetration to ameliorate mouse liver fibrosis. Mechanistically, DNS@cap attenuated liver fibrosis via targeted silencing of Galectin-3 and M1 polarization inhibition by inhibiting ERK, NF-κB, and STAT1 pathways. In conclusion, DNS@cap attenuated liver fibrosis by efficiently delivering Galectin-3 siRNA into hepatic macrophages, providing a potential therapeutic strategy with oral siRNA delivery for hepatic diseases.