Ultrasmall Cu2-xS nanodots as photothermal-enhanced Fenton nanocatalysts for synergistic tumor therapy at NIR-II biowindow

Reactive oxygen species (ROS)-mediated nanocatalytic therapy, as conducted by the tumor microenvironment to generate toxic hydroxyl (%OH) radicals with the assistant of Fenton nanocatalysts, exhibits high tumor-ther- apeutic promise due to its high therapeutic selectivity and desirable therapeutic outcome. The mostly explored Fe-based Fenton nanocatalysts-enabled nanocatalytic cancer therapy substantially suffers from lowed pH con- dition and the corresponding therapeutic effect is still far from satisfactory for further clinic application. In this work, we report, for the first time, that copper (Cu)-based nanocatalysts have the intrinsic capability to catalyze hydrogen peroxide (H2O2) into hydroxyl radicals in a wide range pH condition with the comparable and even better performance as compared to mostly explored Fe-based nanocatalysts. Especially, ultrasmall (≤5 nm) PEGylated Cu2-xS nanodots (Cu2-xS-PEG) were fabricated to serve as the novel Fenton nanocatalysts for nano- catalytic tumor therapy. Importantly, taking the unique advantage of high near infrared (NIR) light absorbance at NIR-II biowindow (1000–1350 nm), light-activated photonic theranostic modality, i.e. photoacoustic imaging and photothermal therapy at both NIR-II biowindows was introduced, which could efficiently delineate/monitor the tumor regions and synergistically enhance Fenton-mediated therapeutic efficacy by photonic hyperthermia, respectively. Both systematic in vitro and in vivo experiments have demonstrated the high therapeutic efficacy of Cu2-xS-enabled synergistic photothermal hyperthermia-enhanced nanocatalytic therapy. This work not only provides a nanoparticle-augmented synergistic cancer-therapeutic modality, but also enriches the totally new nanocatalyst types for catalytic Fenton reaction-based nanocatalytic tumor therapy.