Exo/endogenous dual-augmented chemodynamic therapy based on bio-reducible and bio-breakable copper (Ⅱ)-based truncated octahedron

•Stable in vitro and bio-reducible in vivo of Cu (II).•GSH-depletion/photothermal dual-augmented chemodynamic therapy.•Excellent mitochondrial targeting and amplified the oxidative stress.•CuO@AuCu-TPP possesses bio-breakable capacity in vivo. Recently, chemodynamic therapy (CDT) has become an outstanding cancer treatment because of its high specificity for tumor microenvironment (TME). Nevertheless, lower reactive oxygen species production efficiency and cellular antioxidant defense system are still the main obstacles in CDT. To this end, we propose a highly efficient nanoplatform for exogenous and endogenous dual-augmented mitochondrial targeted CDT based on bio-reducible and bio-breakable copper (II) truncated octahedron (CuO@AuCu-TPP). In vitro, copper exists in the form of bio-reducible Cu (II) without Fenton-like reaction. After entering the tumor cells, however, Cu (II) was converted into Cu (I) to trigger rapid Fenton-like reaction because of the special exposed surface and morphology of truncated octahedron in the presence of endogenous glutathione, thus generating ROS as well as consuming GSH to disrupt the redox homeostasis. Moreover, exogenous near-infrared light induces hyperthermia of tumor site, which significantly improves the production efficiency of hydroxyl radicals, thus achieving the effect of dual-augmented CDT (4.6 times). Importantly, using triphenylphosphonium (TPP) as a targeted component, Fenton catalyst is localized into the mitochondrial site of tumor, which plays an important role in cell apoptosis through cytochrome c pathway. In addition, the truncated octahedron framework could be collapsed to small-sized nanoparticles under overexpressed GSH and acidic environment, thereby avoiding accumulation of nanocarriers in the body. Overall, both cellular and animal experiments show that CuO@AuCu-TPP nanocarriers exhibit excellent therapeutic efficacy and low systemic toxicity, which may hold great application prospects in dual-augmented chemodynamic cancer treatment.