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 Cu_2-S 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.