2. Academic Validation
  3. Tetrahedral Framework Nucleic Acid-Based Delivery of miR-34a Inhibitor for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

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

  • ACS Appl Mater Interfaces. 2025 Dec 10;17(49):66460-66474. doi: 10.1021/acsami.5c18832.
Ruiqing Wang 1,  Yichen Yang 1,  Jiale Liang 1,  Yutian He 1,  Lan Yao 1,  Wenjuan Ma 1,  Yao He 2,  Taoran Tian 1,  Yunfeng Lin 1 3 4
Affiliations

Affiliations

  • 1 State 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, China.
  • 2 Macao Translational Medicine Center, Macau University of Science and Technology, Taipa 999078, Macau SAR, China.
  • 3 Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China.
  • 4 National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 41307917 DOI: 10.1021/acsami.5c18832
Abstract

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.

Keywords

MASH; NF-κB; Nrf2/HO-1; inflammation; miRNA; tetrahedral DNA nanostructure.

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