Gold/Prussian Blue-Based Nanocomposites with Dual Nanozyme Activities Exert a Synergistic Effect of Starvation Therapy and Sonodynamic Therapy in the Treatment of Liver Cancer

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 (H 2 O 2 ) 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 H 2 O 2 , decompose H 2 O 2 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 H 2 O 2 , 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.