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 (H 2 O 2 ) levels and low reaction efficiency severely limit the development of CDT, which have attracted tremendous efforts to alleviate. Inspired by the H 2 O 2 homeostasis in cancer cells, here, hollow Cu 2- x 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 H 2 O 2 for enhanced CDT and synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). According to the conception here, CDT is strengthened due to the H 2 O 2 generation step, which is dependent on superoxide radical (O 2 ˙ - ) conversion by the superoxide dismutase-mimicking activity of the nanoparticles. Meanwhile, catalase-like activity promotes O 2 levels, which overcome the hypoxia limitation in the TME and further promote ˙OH and O 2 ˙ - 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 O 2 ˙ - generation and successively participates in the next H 2 O 2 supply in the cycle. Overall, this work paves the way to construct synergistic therapy agents with H 2 O 2 cyclic utilization ability for PDT/PTT/chemotherapy and intensive CDT.