Shengnan Huang,1,2,* Chengzhi Song,3,* Tengyue Zhao,4,* Yefei Yang,4 Zhiwei Yao,4 Shaofeng Duan,5 Wanyi Chen,6 Lixian Li,6 Xiaogang Hu,6 Chunming Li,6 Yurong Hu4 

1Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China; 2Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China; 3Center for Quantitative Biology, Peking University, Beijing, 100871, People’s Republic of China; 4School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China; 5School of Pharmaceutical Sciences, Henan University, Zhengzhou, 450046, People’s Republic of China; 6Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chunming Li, Email lchm@cqu.edu.cn Yurong Hu, Email huyr@zzu.edu.cn

Purpose: This study aimed to develop a composite nanozyme system (Au/PB-Ce6-HA) based on gold nanoparticles (AuNPs) and Prussian blue nanoparticles (PBNPs) to combat tumor hypoxia and insufficient endogenous hydrogen peroxide (H2O2) deficiency, thus enhancing the efficacy of sonodynamic therapy (SDT) and starvation therapy for liver cancer.
Methods: The Au/PB-Ce6-HA system was constructed by in situ embedding AuNPs on PBNPs, loading the sonosensitizer Chlorin e6 (Ce6), and surface-coating with thiolated hyaluronic acid (HA-SH). The system was evaluated both in vitro and in vivo to assess its ability to catalyze glucose to generate H2O2, decompose H2O2 to produce oxygen, and generate highly toxic reactive oxygen species (ROS) under ultrasound irradiation.
Results: The Au/PB-Ce6-HA nanozymes demonstrated high catalytic activity, thus significantly improving SDT and starvation therapy. Specifically, the system effectively deprived tumors of their energy supply by generating H2O2, while simultaneously producing oxygen to enhance cytotoxic ROS generation under ultrasound irradiation. Both in vivo and in vitro studies further demonstrated a synergistic effect in inhibiting tumor growth while enhancing therapeutic efficacy.
Conclusion: An intelligent composite nanomaterial was successfully developed, combining starvation therapy and sonodynamic therapy to significantly enhance the treatment of liver cancer. The Au/PB-Ce6-HA nanozyme system demonstrated excellent synergy in both in vitro and in vivo settings, offering a promising strategy for cancer therapy.

Keywords: gold nanoparticles, Prussian blue nanoparticles, composite nanozyme, sonodynamic therapy, starvation therapy