Hyaluronan-decorated CuO2-doxorubicin nanodot clusters for targetedly sensitizing cuproptosis in breast cancer via a three-pronged strategy

Cuproptosis shows great prospects in cancer treatments. However, insufficient intracellular copper amount, low-level redox homeostasis, and hypoxic tumor microenvironment severely restrict cuproptosis efficacy. Herein, hydrazided hyaluronan-templated decorated CuO 2 -doxorubicin (CuDT) nanodot clusters (NCs) are developed for efficient doxorubicin (DOX)-sensitized cuproptosis therapy in breast cancer via a three-pronged strategy. The CuDT NCs with an average size of 56.2 nm are fabricated from 3,3′-dithiobis(propionohydrazide)-conjugated hyaluronan, Cu 2+ , and DOX through a one-pot mineralization process. The CuDT nanoparticles exhibit pH-responsive H 2 O 2 , Cu 2+ , and DOX release profiles and catalytic activity. Upon entrance into tumor cells, CuO 2 -based exogenous H 2 O 2 supply and DOX-augmented endogenous H 2 O 2 generation jointly elevate intracellular H 2 O 2 level, which can further be transformed into hydroxyl radicals and O 2 through Fenton-like reaction to achieve oxidative stress amplification and hypoxia relief, respectively. Moreover, the CuDT NCs can efficiently deplete intracellular overexpressed glutathione via Cu 2+ /Cu + cycle and abundant disulfide bonds, further enhancing cellular oxidative stress. These results demonstrate that the novel CuDT NCs achieve DOX-sensitized cuproptosis in breast cancer cells through elevating copper level, amplifying oxidative stress and alleviating hypoxia, and display prominent in vivo antitumor efficacy. Such a three-pronged strategy of targetedly boosting cuproptosis in cancer cells represents a novel approach for antitumor treatments.