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 CuO₂-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, Cu²⁺, and DOX through a one-pot mineralization process. The CuDT nanoparticles exhibit pH-responsive H₂O₂, Cu²⁺, and DOX release profiles and catalytic activity. Upon entrance into tumor cells, CuO₂-based exogenous H₂O₂ supply and DOX-augmented endogenous H₂O₂ generation jointly elevate intracellular H₂O₂ level, which can further be transformed into hydroxyl radicals and O₂ through Fenton-like reaction to achieve oxidative stress amplification and hypoxia relief, respectively. Moreover, the CuDT NCs can efficiently deplete intracellular overexpressed glutathione via Cu²⁺/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, thus displaying prominent in vivo antitumor efficacy. Such a three-pronged strategy of targetedly boosting cuproptosis in cancer cells represents a novel approach for antitumor treatments.