Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity
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Huaqing Jing1, Yingzi Ren1, Yue Zhou1
1Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Abstract:
Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.
Insights
Nilotinib-loaded nanozymes effectively target liver fibrosis by inhibiting hepatic stellate cell activation and remodeling the fibrotic microenvironment. This novel approach shows significant antifibrotic effects in vivo with minimal toxicity.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Hepatology
Background:
- Liver fibrosis, a precursor to liver cancer, involves complex microenvironmental factors like extracellular matrix deposition and hypoxia.
- Hepatic stellate cell (HSC) activation is a key therapeutic target, but current strategies face limitations due to the fibrotic microenvironment.
Purpose of the Study:
- To develop nilotinib-loaded hyaluronic acid-coated Ag@Pt nanotriangular nanozymes (APNH NTs) for inhibiting HSC activation and remodeling the liver fibrosis microenvironment.
- To investigate the synergistic effects of nanozymes and nilotinib in combating liver fibrosis.
Main Methods:
- Synthesis of APNH NTs with inherent superoxide dismutase (SOD) and catalase (CAT) activities.
- Evaluation of APNH NTs' ability to eliminate reactive oxygen species (ROS) and alleviate hypoxia.
- Assessment of nilotinib's role in collagen depletion via tissue inhibitor of metalloproteinase-1 (TIMP-1) suppression.
- In vivo study using CCl4-induced fibrotic mice to determine antifibrogenic efficacy and toxicity.
Main Results:
- APNH NTs effectively scavenged ROS, downregulated NADPH oxidase-4 (NOX-4), and inhibited HSC activation.
- Nanozyme-produced oxygen alleviated the hypoxic microenvironment.
- Released nilotinib promoted collagen depletion by suppressing TIMP-1.
- APNH NTs demonstrated significant antifibrogenic effects in vivo without notable long-term toxicity.
Conclusions:
- APNH NTs offer a promising strategy for liver fibrosis treatment by simultaneously targeting HSC activation and remodeling the fibrotic microenvironment.
- The developed nanozyme system exhibits potent antifibrogenic activity and a favorable safety profile, paving the way for new therapeutic interventions.
