Biodegradable copper telluride nanosheets for redox-homeostasis breaking-assisted chemodynamic cancer therapy boosted by mild-photothermal effect

• Glutathione-degradable PEGylated Cu 2-x Te nanosheets (bioCu 2-x Te NSs) are reported. • The bioCu 2-x Te NSs display remarkable cancer therapeutic efficacy. • The bioCu 2-x Te NSs exhibit excellent near-infrared II plasmonic and photothermal properties. • High-efficiency ·OH production and effective glutathione depletion can be achieved. Chemodynamic therapy (CDT) holds great promise for cancer treatment through employing the Fenton or Fenton-like effects for highly toxic ·OH production exclusively in the tumor microenvironment. Herein, glutathione (GSH)-degradable Cu 2-x Te nanosheets modified with polyethylene glycol (bioCu 2-x Te NSs) as a multifunctional CDT agent are reported for effective cancer treatment via mild-photothermally enhanced CDT. The resulting bioCu 2-x Te NSs exhibit excellent near-infrared II (NIR-II) plasmonic absorption and photothermal properties. Upon endocytosis by cancer cells, bioCu 2-x Te NSs are degraded into Cu + and elemental Te by GSH overexpressed in cancer cells. The generated Cu + and Te together exhibit efficient catalytic decomposition of endogenous H 2 O 2 into ·OH with effective GSH depletion and redox homeostasis breaking of cancer cells. The mild-photothermal effect from the NIR-II irradiation is confirmed to promote intracellular ·OH production and tumor accumulation of bioCu 2-x Te NSs. Owing to all these prominent features, our results on both in vitro and in vivo studies verify the remarkable therapeutic efficacy via mild-photothermally enhanced CDT on a MCF-7 tumor mouse model with intravenous administration of bioCu 2-x Te NSs under NIR-II irradiation. This study demonstrates the potential of bioCu 2-x Te NSs as a potent CDT agent, which features GSH-triggered degradability and excellent therapeutic functions, for efficient cancer treatment.