Challenges in copper ion delivery and intracellular copper balance hinder effective cuproptosis in tumor cells.
T-T@Cu utilizes a carrier-free metal-polyphenolic platform for targeted copper delivery to tumor mitochondria.
Exposure to a 1064 nm laser with T-T@Cu leads to reduced ATP levels and down-regulates copper ion efflux proteins ATP7A/7B.
T-T@Cu demonstrates significant glutathione depletion and responsive degradation in tumor microenvironments.
In vitro and in vivo evaluations show strong tumor inhibition with T-T@Cu, alongside absence of significant systemic toxicity.
Simplified
Inducing 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 , 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.
Key numbers
100%
Tumor Inhibition Rate
Observed in 4T1 breast cancer models treated with T-T@Cu.
5.4-fold
Copper Ion Concentration Increase
Measured in 4T1 cells treated with T-T@Cu and mild photothermal irradiation.
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Declarations. Ethics approval and consent to participate: All animal experiments were conducted following the protocols approved by the Laboratory Animal Ethics Committee of Wenzhou Institute, University of Chinese Academy of Sciences (WIUCAS23070701). All participants consented to publish the paper. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
