Norcantharidin/Cu²⁺ dual-depleting GSH nanocatalyst with pH-responsive for CT/CDT synergistic cancer therapy

The high level of glutathione (GSH) in tumor cells can consume reactive oxygen species (ROS), seriously affecting the efficacy of chemodynamic therapy (CDT). Although it took a great deal of effort, developing a tumor-specific CDT that efficiently depletes GSH remains a formidable challenge. Herein, we propose a pH-responsive nanocatalyst containing the active molecule norcantharidin (NCTD) and Cu²⁺ for dual GSH depletion, achieving efficient GSH depletion. Due to the weakly acidic tumor microenvironment (TME), the catalyst releases NCTD and Cu²⁺ in a pH-responsive manner for the synergistic therapy of chemotherapy (CT) and CDT. Both components consume GSH and subsequently produce ROS, reducing the antioxidant capacity of cancer cells while increasing oxidative stress. This disrupts cellular redox homeostasis, leading to mitochondrial dysfunction and inducing tumor cell apoptosis. This work not only develops nanomaterials with dual GSH depletion capabilities for high-efficiency CDT but also achieves synergistic CT and CDT tumor therapy with the addition of NCTD, an active ingredient of traditional Chinese medicine.