Glutathione responsive nitric oxide release for enhanced photodynamic therapy by a porphyrinic MOF nanosystem

In photodynamic therapy (PDT), the concentration of reactive oxygen species (ROS) generated in cells directly determines the therapeutic effect. However, excessive glutathione (GSH) concentration at the tumor site and hypoxic environment strongly reduce the production of ROS. Nitric oxide (NO) has a variety of anti-tumor activities, including the induction of cell apoptosis and sensitization to PDT, so it is in the spotlight in the area of cancer intervention. Therefore, it is very innovative to combine NO therapy with PDT and simultaneously reduce GSH content and relieve hypoxia. Metal-organic framework (MOF) is an emerging drug delivery vehicle that can exert photodynamic effects when a photosensitizer is used as its organic ligand. In this study, we constructed a GSH-responsive NO producing nanosystem to enhance ROS production through GSH depletion and hypoxia alleviation. Briefly, nicorandil (Nic) is encapsulated into porous porphyrinic MOF nanoparticles, and hyaluronic acid (HA) is electrostatically adsorbed on the surface of the MOF nanoparticles for CD44 receptor-targeting and prevention of Nic leakage. Notably, the Nic reacts with GSH to produce NO gas with vasodilation and GSH reduction, thus improving oxygen supply for efficient ROS generation. Moreover, the generated NO can further react with superoxide radical anion to produce highly reactive peroxynitrite (ONOO-) molecules with higher cytotoxicity. Overall, the Nic-MOF@HA nanosystem combines NO gas therapy with PDT, resulting in a significant increase in ROS production and greatly enhancing the efficacy of PDT.