Biomimetic Nanomedicines With Anti-inflammatory And Anti-fibrosis Properties Ameliorate Liver Fibrosis

Liver fibrosis is a common feature of chronic liver disease characterized by excessive deposition of the extracellular matrix.As the main driver of liver fibrosis,activated hepatic stellate cells synthesize and secret a large amount of collagen.Therefore inhibiting the proliferation and activation of hepatic stellate cells is an effective strategy to ameliorate liver progression.Apart from this,the persistent inflammatory response also aggravates the process of liver fibrosis.Multifunctional drugs with anti-inflammatory and inhibiting hepatic stellate cells activation may show better anti-fibrotic effects in liver fibrosis.Studies have shown that NF-κB inhibitors could inhibit liver inflammation,promote apoptosis of hepatic stellate cells,and delay the progression of liver fibrosis.However,several undesirable properties of BAY 117082,such as low water insolubility and systematic side effects on normal tissue,have limited its further application.Therefore,the targeted delivery of BAY 11-7082 to hepatic stellate cells with nanotechnology is a promising strategy to solve the problems mentioned above.Cell membrane-coating nanomaterial acquires a variety of unique advantages,such as decreased non-specific uptake of nanomedicine by the reticuloendothelial system,prolonged blood circulation lifetimes.In addition,cell membrane-coating nanomaterial can be enriched in specific sites.Using this property can increase the concentration of nanomedicine in the diseased site and improve the bioavailability of the drug.In this study,we synthesized hepatic stellate cells membrane-modified HSCPLGA-BAY nanomedicine to treat liver fibrosis.We successfully separated hepatic stellate cells via gradient density centrifugation and extracted hepatic stellate cells membranes using ultracentrifugation.We prepared HSC-PLGA-BAY nanomedicine via double emulsion and extrusion.The morphology,size,and surface potential were characterized via transmission electron microscopy,dynamic light scattering.We also evaluated the encapsulation efficiency of BAY 11-7082 using HPLC.Laser confocal and flow cytometry was used to detect the uptake of HSC-PLGA nanoparticles by hepatic stellate cells and macrophages;Living animal image was used to evaluate the distribution of nanoparticles in mice;CCK-8,flow cytometry,and western blot were used to analyze anti-fibrotic effects on hepatic stellate cells and macrophages;In vivo anti-fibrotic effect of nanomedicine was evaluated in a bile duct ligation mice model.Results showed that HSC-PLGA-BAY had a uniform diameter of about 100 nm with negative zeta potential(-23.4 mV).HSC-PLGA had a high encapsulation efficiency and drug loading rate.HSC-PLGA can efficiently accumulate in the liver,especially in the hepatic stellate cells.In vitro study results validated that HSC-PLGABAY can significantly suppress the inflammatory response,increase HSC apoptosis.In the bile duct ligation model,HSC-PLGA nanomedicine effectively ameliorated the progression of liver fibrosis.Therefore,the biomimetic nanomedicine targeting hepatic stellate cells can effectively deliver NF-κB inhibitor to HSCs,enhance the anti-fibrotic effect of BAY 11-7082.It is expected to provide a new strategy for the treatment of liver fibrosis.