Carbon Nitride‐Based siRNA Vectors with Self‐Produced O2 Effects for Targeting Combination Therapy of Liver Fibrosis via HIF‐1α‐Mediated TGF‐β1/Smad Pathway

Abstract Hypoxia is an important feature, which can upregulate the hypoxia‐inducible factor‐1α (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, a safe and effective method is established 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 can be promoted to complete the transfection process. Simultaneously, VA‐PEG‐CN@GQD nanosheets enable 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 can 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 proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF‐1α at lesion site.