Cancer cells show unique redox homeostasis. Glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play essential roles as coenzymes of multiple key antioxidant enzymes. Coenzyme depletion offers a unique opportunity for cancer treatment by inducing oxidative stress. Here, we report an innovative hybrid nanocarrier for cancer redox therapy via selective depletion of GSH and NADPH. The nanocarrier core is a sorafenib-loaded porous zeolitic imidazole framework (ZIF-65), and the shell is epigallocatechin gallate (EGCG)-Fe complex (EF). The nitroimidazole ligand in ZIF-65 could selectively deplete NADPH under hypoxia. Sorafenib diminished GSH by inhibiting cystine import and GSH biosynthesis. EGCG can reduce Fe to Fe, which aids the generation of hydroxyl radicals via the Fenton reaction. The reversible coordination between nitroimidazole and Zn, EGCG, and Fe enables triggered cargo release in acidic lysosomes. Tailored nanocarriers induced the depletion of both coenzymes (GSH and NADPH) and boosted reactive oxygen species in a 4T1 murine cancer cell line. The altered redox balance eventually resulted in efficient apoptotic cell death. The current work offers a novel means of redox cancer therapy via the selective depletion of key antioxidant enzymes in hypoxic cells.