Glutathione depletion and dual-model oxygen balance disruption for photodynamic therapy enhancement

Photodynamic therapy (PDT) is a prospective approach to cure tumor diseases. However, tumor micro-environment is notably characterized with severe hypoxia and high expression of glutathione (GSH), which seriously limit its clinical application. Here, based on the characteristics of perfluorocarbon (PFC) to dissolve substantial oxygen (O 2 ) and the sensitivity of reductive GSH to S-NO group, we designed GSH depletion and dual-model O 2 supply strategies to promote PDT enhancement. The PFC nanoliposomes ( [email protected] ) and biocompatible NO donor S-nitrosated human serum albumin (HSA-SNO) were combined to synergistically combat the obstacle of tumor micro-environment, reducing GSH concentration and increasing singlet oxygen ( 1 O 2 ) generation. In vitro , after irradiation with NIR laser, the PFC in [email protected] dissolved more O 2 to increase 1 O 2 generation. In addition, with co-delivery of HSA-SNO, it can effectively promote GSH depletion to recover 1 O 2 level and release NO concurrently to inhibit mitochondrial respiration. This combination strategy of [email protected] and HSA-SNO obviously relieved intracellular hypoxia and decreased GSH to increase more toxic 1 O 2 generation for PDT enhancement. The present work will play as an enlightening role in PDT design and clinical application in the near future.