Controllable Synthesis of Self-Assembled Nitroimidazole-Based Nanocomplexes for Enhanced Chemodynamic Therapy by Dual-Channel Modulation of Glutathione

Chemodynamic therapy (CDT) offers an effective in situ activation therapy for cancer treatments. However, the efficiency of CDT is limited by the antioxidant system within tumor cells, including antioxidative niacinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH). Zeolitic imidazolate framework-8 (ZIF-8) is widely used in tumor therapies due to its tunable structure and properties, but ZIF-8 itself lacks CDT application. In order to meet the application demand of CDT, we select Cu 2+ ions that can catalyze a Fenton-like reaction and 2-nitroimidazole (2-NI) that can consume NADPH as new inorganic–organic connection components. Based on the reasonable coordination mode of ZIF-8, a CDT nanoplatform with an adjustable size is constructed. The synthesized Cu-NI NPs are triple responsive to hypoxia, GSH, and hydrogen peroxide (H 2 O 2 ), which selectively enhance Cu + /Cu 2+ -mediated CDT and induce tumor apoptosis/ferroptosis. This work will promote the diversification of ZIF-8 structures and properties, and provide good implications for the realization of enhanced CDT.