Molecularly engineering a dual-drug nanoassembly for self-sensitized photodynamic therapy via thioredoxin impairment and glutathione depletion

Photodynamic therapy (PDT) has been extensively investigated as a spatiotemporally noninvasive and controllable modality for cancer treatment. However, the intracellular antioxidant systems mainly consisting of thioredoxin (Trx) and glutathione (GSH) significantly counteract and prevent reactive oxygen species (ROS) accumulation, resulting in a serious loss of PDT efficiency. To address this challenge, we propose that PDT can be improved by precisely blocking antioxidant systems. After molecular engineering and synergistic cytotoxic optimization, a DSPE-PEG2K-modified dual-drug nanoassembly (PPa@GA/DSPE-PEG2K NPs) of pyropheophorbide a (PPa) and gambogic acid (GA) is successfully constructed. Interestingly, GA can effectively destroy intracellular antioxidant systems by simultaneously inhibiting Trx and GSH. Under laser irradiation, the cell-killing effects of PPa is significantly enhanced by GA-induced inhibition of the antioxidant systems. As expected, PPa@GA/DSPE-PEG2K nanoparticles demonstrate potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Such a carrier-free self-sensitized nanotherapeutic offers a novel co-delivery strategy for effective PDT.