Defect-Engineered photothermal nanozyme with NIR-II absorption induces Cuproptosis-Apoptosis for synergized cancer immunotherapy and fast wound healing

Cuproptosis is a newly recognized copper-dependent nonapoptotic form of cell death, which stimulate studies exploring copper-based nanomaterials to treat cancer through distinct mechanistic action. However, it remains a challenge to completely eradicate tumors via monotherapy. Herein, a copper-doped BiSex (CBS) nanozyme was developed to boost alpha PD-L1-mediated immune checkpoint blocking (ICB) via synergetic apoptosis/cuproptosisinduced immunogenic cell death (ICD). The defect-engineered CBS nanozyme exhibits strong peroxidasemimicking activities and generates abundant reactive oxygen species (ROS) production causing cell apoptosis, which could be further augmented by NIR photoirradiation. Meanwhile, the CBS could cause mitochondrial lipoylated protein aggregation, leading to cell cuproptosis. The photothermal/catalytic/cuproprosis synergistic therapy triggered by CBS nanozyme combined with alpha PD-L1 antibody effectively inhibits the growth of primary tumors and distant tumors in prostate cancer model. Furthermore, CBS nanozyme exhibited significant germicidal effect in wound infection. Collectively, this work provides a new insight into cancer treatment of copperbased nanozyme based on cuproptosis/apoptosis-related combined therapy.