Redox homeostasis disruptors enhanced cuproptosis effect for synergistic photothermal/chemodynamic therapy.

The combination of chemodynamic therapy (CDT) with photothermal therapy (PTT) is a promising approach to enhance antitumor efficacy of chemotherapeutics. In this paper, we developed novel copper-chelated polydopamine (PDA) nanoparticles (NPs) functionalized with hyaluronic acid (HA) (Cu-PDA-HA NPs) to induce apoptosis and cuproptosis-induced cell death, synergistically combining PTT and CDT. Experimental results revealed that Cu-PDA-HA NPs can respond to excessive glutathione (GSH) and hydrogen peroxide (HO) in the tumor microenvironment (TME), which will enable their specific degradation, thereby leading to efficient accumulation of Cu within tumor cells. The released Cu ions were reduced by GSH to generate Cu, which catalyzed in situ Fenton-like reactions to produce cytotoxic hydroxyl radicals (·OH), disrupting cellular redox homeostasis and promoting apoptosis-related CDT. Meanwhile, the photothermal effect of the Cu-PDA-HA NPs could enhance oxidative stress within the tumor by elevating the temperature and subsequent ·OH production. The enhanced oxidative stress made tumor cells more vulnerable to cuproptosis-induced toxicity. Furthermore, in vivo experiments demonstrated that Cu-PDA-HA NPs can still undergo a temperature increase of 18.9°C following 808 nm near-infrared irradiation (1.0 W/cm, 5 min). Meanwhile, Cu-PDA-HA NPs were able to induce oligomerization of dihydrolipoamide S-acetyltransferase (DLAT) and down-regulate Fe-S cluster proteins such as ferredoxin (FDX1), thereby activating cuproptosis. Therefore, this study provides a novel approach for designing multifunctional nanoparticles with on-demand Cu release and offers a fresh perspective for exploring synergistic therapeutic strategies involving CDT/PTT/apoptosis/cuproptosis.