Ultrasound-triggered self-assembled cascade nanozymes for ROS-mediated synergistic chemodynamic therapy

Chemodynamic therapy (CDT) is severely limited by insufficient reactive oxygen species (ROS) generation and high glutathione (GSH)-mediated antioxidant defense in the tumor microenvironment. To address these challenges, we developed an ultrasound-triggered self-assembled cascade nanozyme (HSA-GOx-CuO) that amplifies ROS production through triple synergy: glucose oxidase (GOx)-mediated glucose depletion (starvation therapy) and hydrogen peroxide self-supply, CuO-driven GSH depletion, and synergistic CDT. In vitro studies using 4T1 breast cancer cells showed that under US stimulation, HSA-GOx-CuO significantly elevated intracellular ROS levels, induced potent apoptosis (late apoptotic rate: 85.1%), and promoted dendritic cell maturation (97.9% CD80⁺CD86⁺ DCs). In vivo, the nanozyme efficiently accumulated in tumors via the enhanced permeability and retention effect, achieving a 92.6% tumor inhibition rate with strong growth suppression. This US-activatable cascade nanoplatform integrates starvation therapy and GSH depletion, offering a safe and novel strategy for precision synergistic CDT of tumors.