Abstract Hypoxia and hydrogen peroxide (H 2 O 2 ) accumulation form the profibrogenic liver environment, which involves fibrogenesis and chronic stimulation of hepatic stellate cells (HSCs). Catalase (CAT) is the major antioxidant enzyme that catalyzes H 2 O 2 into oxygen and water, which loses its activity in different liver diseases, especially in liver fibrosis. Clinical specimens of cirrhosis patients and liver fibrotic mice are collected in this work, and results show that CAT decrease is closely correlated with hypoxia-induced transforminmg growth factor β1 (TGF-β1). A multifunctional nanosystem combining CAT-like MnO 2 and anti-fibrosis Saikosaponin b1 (Ssb1) is subsequently constructed for antifibrotic therapy. MnO 2 catalyzes the accumulated H 2 O 2 into oxygen, thereby ameliorating the hypoxic and oxidative stress to prevent activation of HSCs, and assists to enhance the antifibrotic pharmaceutical effect of Ssb1. This work suggests that TGF-β1 is responsible for the diminished CAT in liver fibrosis, and our designed MnO 2 @PLGA/Ssb1 nanosystem displays enhanced antifibrotic efficiency through removing excess H 2 O 2 and hypoxic stress, which may be a promising therapeutic approach for liver fibrosis treatment.