Bidirectionally H₂O₂-suppliable and antioxidant-consumable copper peroxide nanoparticles for photochemodynamic immunotherapy

Reactive oxygen species (ROS)-based antitumor compounds show great promise in cancer treatments such as chemodynamic therapy (CDT) and photodynamic therapy (PDT), but are severely restricted by both endogenous antioxidants and hydrogen peroxide (H₂O₂). Here, we synthesize bidirectionally H₂O₂-suppliable and antioxidant-consumable copper peroxide (CuO₂) nanoparticles for CDT/PDT-synergized immunotherapy against aggressive triple-negative breast cancers (TNBCs). The CuO₂ nanoparticles are established to afford pH-responsive decomposition into H₂O₂ and Cu²⁺, followed by the reduction into Cu⁺ by glutathione and subsequent catalysis reaction of H₂O₂ into highly reactive ·OH, thus yielding CDT-mediated cell injury. Meanwhile, the glutathione consumption from the nanoparticles attenuates their ROS scavenging to promote singlet oxygen generation of co-assembled indocyanine green upon light exposure, thereby amplifying PDT-based cell damage. Moreover, the dully enhanced CDT/PDT damages of the nanoparticles provoke potent immunogenic cell death that further synergizes with immune checkpoint inhibitor via relieving indoleamine 2,3-dioxygenase 1-mediated immunosuppression, thus amplifying immunotherapeutic efficacy against primary, distant and metastatic TNBCs. This work provides valuable insights into nanomedicines for synergistic cancer therapy.