Engineering Cu-CuFe2O4 nanoenzyme for hypoxia-relief and GSH-depletion enhanced chemodynamic/sonodynamic therapy

Specific hypoxia and overexpressed glutathione (GSH) in the tumor microenvironment (TME) are bottleneck for reactive oxygen species (ROS)-involved therapy performance. Herein, we report a novel Cu-CuFe2O4 nanoenzyme enables simultaneous hypoxia relief and GSH depletion for efficiently augmenting ROS-involved chemodynamic (CDT)/sonodynamic (SDT) therapy. The nanoenzyme exhibited both catalase-like and GSH peroxidase-like catalytic activities, which can persistently catalyze tumor-overexpressed hydrogen peroxide (H2O2) to generate oxygen (O2) to facilitate singlet oxygen (1O2) production under an external ultrasound, achieving hypoxia-relieved SDT. Meanwhile, the Cu-CuFe2O4 NPs reacted with GSH to deplete GSH and release Fenton-like Cu+ and Fe2+ ions to mediate abundant hydroxyl radical (OH) production for CDT. Highly efficient anticancer ability of the Cu-CuFe2O4 NPs was demonstrated from the efficient MCF-7 cells killing and multicellular tumor spheroids (MCTS) elimination. This work provides a useful strategy to design multi-mode TME-responsive nanosonosensitizer for enhancing therapeutic effect of cancer therapy via persistent and simultaneous regulatory of TME, showing a great potential for clinical cancer therapy.