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.