Liver-Targeted Delivery of Small Interfering RNA of C–C Chemokine Receptor 2 with Tetrahedral Framework Nucleic Acid Attenuates Liver Cirrhosis
Taoran Tian, Chong Zhao, Songhang Li, Zhiyin Huang, Yangkun Guo, Wenting Dai, Ruqiang Bai, Chengwei Tang, Yunfeng Lin, Jinhang Gao
Abstract
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.