pPB Peptide-Mediated siRNA-Loaded Stable Nucleic Acid Lipid Nanoparticles on Targeting Therapy of Hepatic Fibrosis.

Hepatic fibrosis is a necessary process in the development of liver diseases such as hepatic cirrhosis and its complications, which has become a serious threat to human health. Currently, antifibrotic drug treatment is ineffective, and one reason should be the lack of liver targeting ability. In this report, polypeptide pPB-modified stable nucleic acid lipid nanoparticles (pPB-SNALPs) were prepared to selectively deliver siRNAs against heat shock protein 47 to the liver for targeted therapy of hepatic fibrosis. First, siRNA sequences with high silencing efficiency were screened based on siRNA transfection efficacy. Then, pPB-SNALPs were prepared, which showed a narrow size distribution with a diameter in the range of 110-130 nm and a neutral z-potential of 0 mV. As evidenced by the in vitro and in vivo targeting study, compared with unmodified SNALP, pPB-SNALP showed increased uptake by LX-2 cells and primary hepatic stellate cells (HSC) of mice in vitro and showed increased liver distribution and HSC uptake in vivo. In addition, pPB-SNALP also exhibited an enhanced inhibitory effect on TAA-induced hepatic fibrosis mice with high gp46 mRNA expression in vivo. In summary, our results demonstrated that pPB-SNALP is an effective liver-targeted delivery system. This study could lay a good foundation for the targeted gene therapy of hepatic fibrosis.