Coenzyme-depleting nanocarriers for enhanced redox cancer therapy under hypoxia

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 3+ 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 3+ to Fe 2+ , which aids the generation of hydroxyl radicals via the Fenton reaction . The reversible coordination between nitroimidazole and Zn 2+ , EGCG, and Fe 3+ 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.