Hyaluronan-decorated CuO-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-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, and DOX through a one-pot mineralization process. The CuDT nanoparticles exhibit pH-responsive HO, Cu, and DOX release profiles and catalytic activity. Upon entrance into tumor cells, CuO-based exogenous HO supply and DOX-augmented endogenous HO generation jointly elevate intracellular HO level, which can further be transformed into hydroxyl radicals and O 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/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.