Carbon Nitride-Based Sirna Vectors with Self-Produced O 2 Effects for Targeting Combination Therapy of Liver Fibrosis via HIF-1α-mediated TGF-β1/Smad Pathway.

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor HIF-1α expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, we established a safe and effective method to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA could be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enabled trigger the water splitting process to produce O 2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy could inhibit the activation of HSCs via HIF-1α-mediated TGF-β1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposed a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site. This article is protected by copyright. All rights reserved.