A Glutathione-activatable Nanoplatform For Enhanced Photodynamic Therapy with Simultaneous Hypoxia Relief and Glutathione Depletion

Abstract Inspired by unique selectivity and irreversible destruction toward treated tissues or cells, photodynamic therapy (PDT) has gained increasing attention in cancer treatment. However, PDT-induced hypoxia and elevated glutathione (GSH) levels in cancer cells are still great challenges which can significantly reduce treatment outcomes. Herein, we designed a GSH-activatable nitric oxide (NO) generating mannan nanoparticles (NO-mannan), an “All in One” therapy nanoplatform with enhanced reactive oxygen species (ROS) generation through GSH depletion and hypoxia relief. Upon reaching the reductive hypoxic tumor microenvironment, the nanoplatform could undergo a GSH-triggered hydrophobic to hydrophilic transition and simultaneously generate NO gas with vessel-relaxing and GSH scavenging for efficient ROS production. Notably, the NO induced hypoxia relief and redox-responsive cellular antioxidant defense system destruction endowed the NO-mannan with the ability of enhanced photodynamic therapy both in vitro and in vivo. Overall, our work demonstrated a simple strategy to combine the GSH responsive NO-based gas therapy with PDT to greatly improve the PDT efficacy especially for hypoxic solid tumors, which may provide a practical paradigm for effective PDT cancer treatment.