Liver-Targeted siRNA Lipid Nanoparticles Treat Hepatic Cirrhosis by Dual Antifibrotic and Anti-inflammatory Activities

Abstract

Previous studies on the treatment of hepatic cirrhosis have been focusing on how to inhibit liver fibrosis, while ignoring liver inflammation, a key and underlying factor that promotes cirrhosis. High mobility group box-1 (HMGB1) protein, a pro-inflammatory factor and fibroblast chemokine, can promote the proliferation of hepatic stellate cells (HSCs) and the development of hepatic inflammation and fibrosis, playing a key role in cirrhosis formation. In this study, we prepared pPB peptide (C*SRNLIDC*)-modified and HMGB1-siRNA-loaded stable nucleic acid lipid nanoparticles (HMGB1-siRNA@SNALP-pPB) to effectively treat hepatic cirrhosis by their dual antifibrotic and anti-inflammatory activities. The pPB peptide-modified and heat shock protein 47 (HSP47)-siRNA-loaded stable nucleic acid lipid nanoparticles (HSP47-siRNA@SNALP-pPB), which have only an antifibrotic effect without an anti-inflammatory effect, was used as control. The results demonstrated that HMGB1-siRNA@SNALP-pPB were actively targeted to HSCs by the mediation of pPB peptide, effectively silenced the HMGB1 gene, inhibited the activation and proliferation of HSCs, reduced the release of HMGB1 protein, inhibited collagen deposition and fibrosis formation in the liver, and significantly prolonged the survival time of cirrhotic mice models. HMGB1-siRNA@SNALP-pPB showed a stronger therapeutic effect on liver cirrhosis than HSP47-siRNA@SNALP-pPB. This study provides an actively targeted siRNA delivery system for cirrhosis treatment based on the dual antifibrotic and anti-inflammatory effects. In addition, this study clarified the role of inflammatory problems in cirrhosis treatment in addition to liver fibrosis, providing a useful idea and scientific basis for the development of cirrhosis treatment strategies in the future.

Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice

“…This study did not dwell deep into the mechanistic aspects, and we could not analyze the direct effect of this peptide against hepatic stellate cells (HSCs). Recently, Zhang et al reported that HSC-targeted lipid nanoparticles loaded with HMGB1-siRNA attenuated liver fibrosis and inflammation [ 36 ]. The difference between this study and ours is that while Zhang et al used HMGB1 knockdown, we used the modified HMGB1 peptide lacking box B lesion for the treatment.…”

Nanotechnology in Drug Delivery for Liver Fibrosis

“…The drug delievery system prolonged circulation half-life of IFNγ and decreased its side effects in fibrotic livers. Recently, Zhang et al (2020) constructed pPB peptide-modified stable nucleic acid lipid NPs loading HMGB1 (High mobility group box-1)-siRNA (HMGB1-siRNA@SNALP-pPB) to effectively treat liver cirrhosis by their dual antifibrotic and anti-inflammatory abilities ( Figure 3 ). HMGB1 protein is known as a fibroblast chemokine and pro-inflammatory factor, which promotes the proliferation of HSCs and facilitates hepatic inflammation and fibrosis.…”

“…FIGURE 3 | Schematic diagram of the HMGB1-siRNA@SNALP-pPB nanoparticle targeting HSCs to silence HMGB1 to show antifibrotic and antiinflammatory effects for hepatic cirrhosis(Zhang et al, 2020).…”

Performance of High Mobility Protein Group 1 and Interleukin-6 as Predictors of Outcomes Resulting from Variceal Bleeding in Patients with Advanced Chronic Liver Disease

“…HMG1, a non-histone protein discovered years ago, is widely distributed in tissues such as the liver, brain and lymphatic system. With the discovery of its pro-inflammatory effect, HMG1 has become important in critical medical research in recent years [8]. IL-6 performs a large variety of functions and is mainly produced by immune cells but can also be expressed by hepatocytes.…”