State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
ACS Appl Mater Interfaces. 2023 Mar 1;15(8):10492-10505. doi: 10.1021/acsami.2c22579. Epub 2023 Feb 17.
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.
肝硬化是慢性肝病的终末期阶段，目前尚无批准的临床药物。在这项研究中，建立了一种新的策略，即通过装载多价 siCcr2 的四面体框架 DNA 纳米结构（tFNA）载体（tFNA-siCcr2），使用 C-C 趋化因子受体 2（CCR2）小干扰 RNA 沉默（siCcr2）疗法来减轻肝纤维化。tFNA-siCcr2 成功合成，而不改变 tFNA 的物理化学性质。与裸 siCcr2 分子相比，tFNA-siCcr2 复合物在腹腔注射后改变了从肾脏到肝脏的积累。tFNA-siCcr2 复合物还延长了肝脏的保留时间，主要在巨噬细胞和内皮细胞内共定位。tFNA-siCcr2 有效地沉默了 CCR2，并显著改善了预防和治疗干预中的肝纤维化。单细胞 RNA 测序和实验验证表明，tFNA-siCcr2 可以通过抑制致纤维化巨噬细胞和中性粒细胞在纤维化肝脏中的积累，恢复免疫细胞景观并构建抗纤维化生态位。从分子水平上讲，tFNA-siCcr2 复合物通过使 NF-κB 信号通路失活来减少炎症介质的产生。总之，基于 tFNA 的肝靶向 tFNA-siCcr2 递药复合物通过恢复免疫细胞景观和构建抗纤维化生态位，有效地改善了肝纤维化，这使得 tFNA-siCcr2 复合物成为治疗肝硬化的潜在治疗候选物。
