A Novel Protein‐Polysaccharide Oral Nanoemulsion Targeting Activated Hepatic Stellate Cells to Enhance the Therapeutic Effect of Pirfenidone on Fibrosis After Transarterial Chemoembolization for Liver Cancer

Abstract Transarterial chemoembolization (TACE) is considered the main treatment for intermediate and advanced liver cancer. Nevertheless, TACE may aggravate liver fibrosis in these patients, which could affect the therapeutic effect after TACE. Pirfenidone (PFD) exhibits significant antifibrotic effects in the liver, primarily via inhibition of hepatic stellate cells (HSCs) activation. However, owing to the high dose required for effective treatment, oral administration of PFD is associated with several side effects. This study introduces an oral folic acid (FA)‐modified protein‐polysaccharide PFD nanoemulsion designed to treat post‐TACE liver fibrosis via liver targeting. This novel PFD oral nanoemulsion withstands gastrointestinal digestion and ensures the gastrointestinal stability of PFD. Furthermore, this nanoemulsion improves the intestinal permeability and antifibrotic efficacy of PFD at a lower dose via folate receptors expressed on both intestinal epithelial cells and activated HSCs. In conclusion, this FA‐modified protein‐polysaccharide nanoemulsion presents a promising approach for oral PFD delivery to effectively ameliorate fibrosis after TACE for liver cancer.