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Photodynamic therapy (PDT) is a promising non-invasive and selective cancer treatment. However, its efficacy is curtailed by tumor hypoxia and high levels of glutathione (GSH) in the tumor and addressing both limitations simultaneously remain challenging. Here, an all-in-one nanoplatform was designed using a GSH-responsive nitric oxide (NO) nano-prodrug that synchronously depletes GSH and relieves hypoxia in tumors, enhancing PDT efficacy. The nano-prodrug PEG-PAMAM-PA/SNO was prepared by integrating the GSH-sensitive NO and pheophorbide A (PA) prodrugs N-acetyl-d-penicillamine thiolactone and PAMAM-PA into polyethylene glycol (PEG), and the NPPA/NOand NPPAwere then obtained through nanoprecipitation method. This nanoplatform depletes the intracellular antioxidant, GSH, by integrating GSH-responsive NO prodrug and generating NO that relaxes blood vessels, thereby relieving tumor hypoxia and defeating antioxidant defense system in tumor, while PEGylated PAMAM dendrimers have abundant surface functional groups and can greatly prolong their circulation lifetime in the bloodstream. These effects make this GSH-activatable NO nano-prodrug platform an appealing strategy for enhancing PDT's antitumor effects.