Engineering 2D Cu-composed metal–organic framework nanosheets for augmented nanocatalytic tumor therapy

• Published in: Journal of nanobiotechnology Vol. 20; no. 1; pp. 66 - 13
• Main Authors: Zhuang, Shangwen, Xiang, Huijing, Chen, Yixin, Wang, Lulu, Chen, Yu, Zhang, Jun
• Format: Journal Article
• Language: English
• Published: London BioMed Central 04.02.2022; BioMed Central Ltd; BMC
• Subjects: Analysis; Apoptosis; Biosafety; Biotechnology; Cancer therapies; Care and treatment; Cell Line, Tumor; Chemistry; Chemistry and Materials Science; Copper; Depletion; Diagnosis; Fenton reaction; Ferroptosis; Free radicals; Glutathione; Humans; Hydrogen Peroxide; Hydroxyl radicals; Internalization; Iron; Logic circuits; Metal-organic frameworks; Metal-Organic Frameworks - pharmacology; Metal–organic framework; Methods; Microscopy; Molecular Medicine; Morphology; Nanocatalytic therapy; Nanomedicine; Nanosheets; Nanotechnology; Neoplasms - drug therapy; Nucleotide sequence; Reactive oxygen species; Risk factors; Spectrum analysis; Tumor cells; Tumor Microenvironment; Tumor suppression; Tumor therapy; Tumors; China; Metal–organic framework; Fenton reaction; Nanocatalytic therapy; Tumor therapy; Nanomedicine
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-022-01250-x

The engineered nanoformulation that can be activated by intracellular tumor microenvironment, including acidic pH, overexpressed H 2 O 2 , and high concentration of glutathione (GSH), features high efficacy to eradicate tumor cells with the intrinsic specificity and therapeutic biosafety. However, the relatively slow reaction rate of traditional Fe 2+ -mediated Fenton reaction induces the low production amount of reactive oxygen species (ROS) and subsequently the limited therapeutic outcome against tumors. Here, we established Cu (II)-based two-dimensional (2D) metal–organic framework (MOF) nanosheets as a distinct chemoreactive nanocatalyst for GSH-triggered and H 2 O 2 -augmented chemodynamic therapy (CDT), depending on the “AND” logic gate, for significant tumor suppression. After internalization by tumor cells, the MOF catalytic nanosheets reacted with local GSH for inducing GSH consumption and reducing the Cu 2+ into Cu + . Subsequently, abundant hydroxyl radicals (·OH) generation was achieved via Cu + -mediated Fenton-like catalytic reaction. The dual effects of ·OH production and GSH depletion thus enhanced ROS production and accumulation in tumor cells, leading to significant cellular apoptosis and tumor inhibition, which was systematically demonstrated in both 4T1 and MDA-MB-231 tumor models. Therefore, GSH and H 2 O 2 , serve as an “AND” logic gate to trigger the Cu + -mediated Fenton-like reaction and reduce GSH level for augmented CDT with high therapeutic specificity and efficacy, thus inducing cellular apoptosis primarily through ferroptosis at the RNA sequence level. Graphical Abstract