Liver-Targeted Delivery of Small Interfering RNA of C–C Chemokine Receptor 2 with Tetrahedral Framework Nucleic Acid Attenuates Liver Cirrhosis

• Published in: ACS applied materials & interfaces Vol. 15; no. 8; pp. 10492 - 10505
• Main Authors: Tian, Taoran, Zhao, Chong, Li, Songhang, Huang, Zhiyin, Guo, Yangkun, Dai, Wenting, Bai, Ruqiang, Tang, Chengwei, Lin, Yunfeng, Gao, Jinhang
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.2023
• Subjects: Animals; Biological and Medical Applications of Materials and Interfaces; Chemokines, CC; Endothelial Cells; Humans; Liver - pathology; Liver Cirrhosis; Mice; Nucleic Acids; Receptors, Chemokine; RNA, Small Interfering; immune cell landscape; macrophage; liver fibrosis; single-cell RNA sequence; neutrophil; NF-κB signaling pathway
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.2c22579

Liver cirrhosis is the end stage of chronic liver diseases without approved clinical drugs. In this study, a new strategy that uses a C–C chemokine receptor 2 (CCR2) small interfering RNA silencing (siCcr2)-based therapy by loading multivalent siCcr2 with tetrahedron framework DNA nanostructure (tFNA) vehicle (tFNA-siCcr2) was established to attenuate liver fibrosis. tFNA-siCcr2 was successfully synthesized without changing the physiochemical properties of tFNA. Compared to the naked siCcr2 molecule, the tFNA-siCcr2 complex altered the accumulation from the kidney to the liver after the intraperitoneal injection. The tFNA-siCcr2 complex also prolonged hepatic retention and mainly colocalized within macrophages and endothelial cells. tFNA-siCcr2 efficiently silenced CCR2 and significantly ameliorated liver fibrosis in prevention and treatment interventions. Single-cell RNA sequencing followed by experimental validation suggested that tFNA-siCcr2 can restore the immune cell landscape and construct an antifibrotic niche by inhibiting profibrotic macrophage and neutrophil accumulation in the murine fibrotic liver. Molecularly, the tFNA-siCcr2 complex reduced inflammatory mediator production by inactivating the NF-κB signaling pathway. In conclusion, the tFNA-based liver-targeted tFNA-siCcr2 delivery complex efficiently ameliorated liver fibrosis by restoring the immune cell landscape and constructing an antifibrotic niche, which makes the tFNA-siCcr2 complex a potential therapeutic candidate for the clinical treatment of liver cirrhosis.