Nintedanib-amplified effects of HSP47 siRNA on liver fibrosis therapy by inhibiting collagen secretion.

Liver fibrosis is characterized by an excessive deposition of extracellular matrix, especially collagen type I and type III, which were produced by activated hepatic stellate cells (HSCs). In our study, the lipid nanoparticles co-delivering nintedanib (NDNB) and HSP47 siRNA (LNP-siHSP47/NDNB) were developed for inhibiting collagen secretion by siHSP47-mediated downregulation of collagen-specific molecular chaperone (HSP47) and NDNB-mediated inhibition of procollagen production. Surprisingly, a significantly higher gene silencing efficiency on the mRNA level of HSP47 (at least 1.41-fold) was observed in HSCs treated with LNP-siHSP47/NDNB than that treated with LNP-siHSP47. Meanwhile, NDNB-amplified effects of siHSP47 on inhibiting collagen I and collagen III secretion were demonstrated in HSCs after treated with LNP-siHSP47/NDNB compared to LNP-siHSP47 and LNP-siNC/NDNB. Also, LNP-siHSP47/NDNB treatment effectively inhibited TGF-β secretion, thereby suppressing HSC activation, proliferation, and migration. Furthermore, in the bile duct ligation-induced model and the carbon tetrachloride-induced mouse liver fibrosis model, the results revealed that LNP-siHSP47/NDNB treatment effectively ameliorated collagen deposition, HSCs activation, and liver damage, which were near to those in sham and healthy groups. Therefore, the nanomedicine co-delivering siHSP47 and NDNB would provide a potential and promising approach for enhancing liver fibrosis therapy.