Self-Delivery Nanomedicine for Selective Mitochondrial Copper Depletion and Oxidative Stress Amplification

Amplifying cellular oxidative stress damage is of great significance for triple-negative breast cancer (TNBC) treatment. However, high levels of mitochondrial copper metabolism effectively reverse oxidative damage and suppress TNBC apoptosis. Herein, we reported a copper depletion moiety (CDM) composed of a copper chelator and near-infrared heptamethine cyanine agent (IR780) for selective mitochondrial copper depletion and oxidative stress amplification. The as-prepared CDM could assemble with distearoyl phosphoethanolamine-PEG₂₀₀₀-COOH into self-delivery nanomedicine (CDM NPs) with improved hydrophilicity and excellent dispersion. Furthermore, compared to free CDM, these obtained CDM NPs display 9.26-fold, 1.16-fold, and 14.5-fold enhancement in cellular internalization, mitochondria targeting, and tumor accumulation, respectively. And they could efficiently induce mitochondrial copper depletion and burst production of reactive oxygen species under 808 nm laser irradiation, leading to powerful mitochondrial damage, oxidative stress imbalance, and upgraded immunogenic cell death. Apart from these, this synergistic mitochondrial copper depletion and oxidative stress elevation strategy significantly reverses the immunosuppressive microenvironment (promotes dendritic cell maturation and T cell vivification, regulates macrophage polarization and myeloid-derived suppressor cell infiltration), activates T cells in the spleen, and accelerates TNBC death with almost negligible systemic toxicity and is expected to provide perspective for the treatment of TNBC.