Metal–Organic Framework for Hypoxia/ROS/pH Triple‐Responsive Cargo Release

Abstract Nanoparticulate antitumor photodynamic therapy (PDT) is suffering from a very short lifetime, limited diffusion distance of reactive oxygen species (ROS). Herein, a hypoxia/ROS/pH triple‐responsive metal–organic framework (MOF) is designed to facilitate the on‐demand release of photosensitizers and hence enhanced PDT efficacy. Tailored azo‐containing imidazole ligand is coordinated with zinc to form MOF where photosensitizer (Chlorin e6/Ce6) is encapsulated. Azo can be reduced by overexpressed azoreductase in hypoxic tumor cells, resulting in depletion of glutathione (GSH) and thioredoxin (Trx) which are major antioxidants against ROS oxidative damage in PDT, resulting in rapid cargo release and additional efficacy amplification. The imidazole ionization causes a proton sponge effect to ensure the disintegration of the nanocarriers in acidic organelles, allowing the rapid release of Ce6 through lysosome escape. Under light irradiation, ROS produced by Ce6 may oxidize imidazole to urea, resulting in rapid cargo release. All of the triggers are expected to show interactive synergism. The pH‐ and hypoxia‐responsiveness can improve the release rate of Ce6 for enhanced PDT therapy, whereas the consumption of oxygen by PDT may induce elevated hypoxia and hence in turn enhanced cargo release. This work highlights the role of triple‐responsive nanocarriers for triggered photosensitizer release and improved antitumor PDT efficacy.