aHSCs-targeted bimetallic nanozymes and luteolin-loaded liposomes: Synergistic reversal of liver fibrosis via antioxidant, cellular senescence, and cellular apoptotic mechanisms

Liver fibrosis is a prevalent pathological process in the development of a range of chronic liver diseases. Hepatic stellate cells (HSCs) are known to be highly activated in the Liver fbrosis environment, and the proliferation of activated HSCs (aHSCs) and the secretion of associated extracellular matrix are crucial in the process of Liver fibrosis, which in turn promotes the development of Liver fibrosis. Concurrently, the inhibition of HSCs activation and the induction of aHSCs senescence/apoptosis have been identified as a therapeutic strategy that exhibits numerous synergistic mechanisms. In addition, the efficacy of clinical treatment is constrained by a number of factors, including the limited selectivity of pharmaceuticals and the inefficiency of drug delivery mechanisms. Consequently, the present study proposes a Luteolin-loaded liposome (LUT@LIP-BSA) and Ce/Mn bimetallic nanozyme (CMB) dual nanodelivery system, which has been modified by BSA to target aHSCs. The results of both in vitro and in vivo experiments demonstrated that the aHSCs-targeted dual delivery system combining LUT@LIP-BSA with CMB exhibited effective targeting delivery capacity to aHSCs. In vitro, LUT@LIP-BSA effectively induced senescence, apoptosis, and counteracted oxidative stress in aHSCs. These effects were confirmed in vivo. Consequently, this combination reduced extracellular matrix production and deposition, thereby inhibiting liver fibrosis. This combinatorial strategy provides a promising foundation for the construction and clinical application of hybrid delivery systems that synergize metal nanoenzymes with natural drugs as an effective targeted therapeutic approach for liver fibrosis.