Bioinspired nanocatalysts as hydrogen peroxide homeostasis regulators for tumor-specific synergistic therapy

Tailored to the special tumor microenvironment (TME), chemodynamic therapy (CDT) has been introduced to generate hydroxyl radicals (˙OH) primarily for the tumor via Fenton and Fenton-like reactions. However, deficient hydrogen peroxide (H2O2) levels and low reaction efficiency severely limit the development of CDT, which have attracted tremendous efforts to alleviate. Inspired by the H2O2 homeostasis in cancer cells, here, hollow Cu2-xS nanocatalysts (CS NCs) loaded with doxorubicin (DOX) (named CSD NCs) are engineered. As biometric enzyme-like reactive oxygen species (ROS) regulators, the CS NCs were fabricated to cyclically take advantage of H2O2 for enhanced CDT and synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). According to the conception here, CDT is strengthened due to the H2O2 generation step, which is dependent on superoxide radical (O2˙-) conversion by the superoxide dismutase-mimicking activity of the nanoparticles. Meanwhile, catalase-like activity promotes O2 levels, which overcome the hypoxia limitation in the TME and further promote ˙OH and O2˙- creation and augmentation through PDT/PTT under NIR II laser stimulation. Moreover, DOX released in the acidic environment can activate nicotinamide adenine dinucleotide phosphate oxidases (NOXs), which increase O2˙- generation and successively participates in the next H2O2 supply in the cycle. Overall, this work paves the way to construct synergistic therapy agents with H2O2 cyclic utilization ability for PDT/PTT/chemotherapy and intensive CDT.