Cascade-targeting copper homeostasis nano-regulators for mild-photothermal boosted cuproptosis/ferroptosis mediated breast cancer therapy

Inducing cuproptosis in tumor cells is significantly impeded by the challenges of arduous copper ion delivery in vivo and the unbreakable intracellular copper homeostasis, which leads to insufficient mitochondrial copper accumulation. Here, a carrier-free metal-polyphenolic (CF-MPs) based nanoplatform (T-T@Cu) that features tumor-mitochondria cascade-targeting, glutathione (GSH) depletion and near-infrared Ⅱ photothermal performance is designed to induce mitochondria copper-overload and exacerbate cuproptosis in tumor cells. By leveraging the enhanced permeability and retention (EPR) effects and the mitochondria-targeting capabilities of tannic acid, T-T@Cu effectively increases mitochondrial copper accumulation in tumor cells. Upon exposure to a 1064 nm laser, T-T@Cu triggers mild photothermal-boosted ferroptosis, which down-regulates intracellular ATP levels. This reduction dramatically impacts the expression of copper-ion efflux proteins ATP7A/7B, ultimately inhibiting copper ion efflux. Additionally, T-T@Cu exhibits robust GSH consumption and dual-responsive degradation in tumor microenvironments characterized by overexpressed cysteine (Cys) and GSH. This results in alleviated GSH-induced inactivation of copper ions and specific copper release within the tumor microenvironment. In vitro and in vivo therapeutic evaluations demonstrate the outstanding tumor inhibition of T-T@Cu in 4T1-breast-cancer models, with no significant systemic toxicity observed. This novel mild photothermal-boosted ferroptosis strategy for exacerbating tumor cell cuproptosis holds great promise for future clinical applications in oncotherapy.