Liver fibrosis therapy based on biomimetic nanoparticles which deplete activated hepatic stellate cells

Liver fibrosis is one of the most common liver diseases with substantial morbidity and mortality. However, effective therapy for liver fibrosis is still lacking. Considering the key fibrogenic role of activated hepatic stellate cells (aHSCs), here we reported a strategy to deplete aHSCs by inducing apoptosis as well as quiescence. Therefore, we engineered biomimetic all-trans retinoic acid (ATRA) loaded PLGA nanoparticles (NPs). HSC (LX2 cells) membranes, presenting the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were coated on the surface of the nanoparticles, while the clinically approved agent ATRA with anti-fibrosis ability was encapsulated in the inner core. The biomimetic coating of TRAIL-expressing HSC membranes does not only provide homologous targeting to HSCs, but also effectively triggers apoptosis of aHSCs. ATRA could induce quiescence of activated fibroblasts. While TM-NPs (i.e. membrane coated NPs without ATRA) and ATRA/NPs (i.e. non-coated NPs loaded with ATRA) only showed the ability to induce apoptosis and decrease the alpha-SMA expression in aHSCs, respectively, TM-ATRA/NPs induced both apoptosis and quiescence in aHSCs, ultimately leading to improved fibrosis amelioration in both carbon tetrachloride-induced and methionine and choline deficient L-amino acid diet induced liver fibrosis mouse models. We conclude that biomimetic TM-ATRA/NPs may provide a novel strategy for effective antifibrosis therapy.

Automated summary

Liver fibrosis is a common liver disease with significant morbidity and mortality. However, there is still a lack of effective therapy for liver fibrosis. In this study, biomimetic all-trans retinoic acid (ATRA) loaded PLGA nanoparticles (NPs) were developed to deplete activated hepatic stellate cells (aHSCs) by inducing apoptosis and quiescence. The NPs were coated with HSC membranes expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and ATRA was encapsulated in the core. The biomimetic TM-ATRA/NPs showed the ability to induce both apoptosis and quiescence in aHSCs, leading to improved fibrosis amelioration in mouse models.