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Oral Administration of a Tetrahedral Framework DNA-Based Nanoshot Attenuates Liver Fibrosis via Targeting Galectin-3
Zhiqiang Liu1,2, Bowen Wang3,4, Songhang Li1
1State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P. R. China.
Abstract:
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.
Insights
Oral administration of a novel DNA nanoshot (DNS@cap) effectively treats liver fibrosis by delivering Galectin-3 siRNA to liver cells, offering a promising alternative to injectable medications for liver cirrhosis.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Hepatology
Background:
- Liver cirrhosis is a significant global health problem with limited treatment options, often due to poor patient adherence to injectable therapies.
- Uncontrolled hepatic inflammation is a key target for liver cirrhosis treatment.
- Oral administration of tetrahedral framework nucleic acid (tFNA) shows potential for liver-targeted drug delivery and inflammation control.
Purpose of the Study:
- To develop an orally administrable therapeutic agent for liver fibrosis.
- To evaluate the efficacy and mechanism of a novel DNA nanoshot (DNS@cap) for treating liver fibrosis.
Main Methods:
- Development of a DNA nanoshot (DNS) combining tFNA and Galectin-3-targeted siRNA, encapsulated in an enteric-coated capsule (DNS@cap).
- Assessment of DNS@cap's stability, intestinal penetration, and therapeutic effect on liver fibrosis in a mouse model.
- Investigation of the underlying molecular mechanisms, including Galectin-3 silencing and inflammatory pathway inhibition (ERK, NF-κB, STAT1).
Main Results:
- DNS@cap demonstrated excellent gastric stability and intestinal absorption following oral administration.
- Oral administration of DNS@cap significantly ameliorated liver fibrosis in mice.
- The therapeutic effect was attributed to targeted silencing of Galectin-3 and inhibition of M1 polarization via key signaling pathways.
Conclusions:
- DNS@cap provides an effective strategy for oral siRNA delivery to the liver, attenuating liver fibrosis.
- This approach offers a promising therapeutic avenue for hepatic diseases, overcoming limitations of injectable treatments.
