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 (H₂O₂) in the tumor microenvironment (TME), which will enable their specific degradation, thereby leading to efficient accumulation of Cu²⁺ within tumor cells. The released Cu²⁺ 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/cm², 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 Cu²⁺ release and offers a fresh perspective for exploring synergistic therapeutic strategies involving CDT/PTT/apoptosis/cuproptosis.