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.