Engineering Nanomedicine with Oxidative Stress Amplification and Antioxidant Defense Disruption for Enhanced Cancer Treatment

Photodynamic therapy (PDT) faces limitations due to tumor
hypoxia
and antioxidant defenses. Herein, a modular drug delivery system (P@Ce6/PTX)
that integrates photosensitizer (Ce6), metal ion (Cu2+),
and hypoxia-activated paclitaxel prodrugs (PTX-MTZ) was developed
by a one-step coassembly strategy to amplify oxidative stress-induced
ferroptosis while enabling hypoxia-triggered chemotherapy. The Cu2+-imidazole coordination not only stabilizes the nanostructure
but also facilitates controllable size modulation by varying the polymer-to-metal
ratio. Upon laser irradiation, Ce6 generates cytotoxic ROS to induce
DNA damage while exacerbating hypoxia, which triggers PTX-MTZ reduction
and PTX/MTZ release. MTZ consumes NADPH or GSH to sensitize PDT via
inhibiting DNA repair and aggravates the antioxidant system. The reported
multimodulating nanomedicine exhibits spatiotemporal controllable
PDT, Cu2+-amplified ferroptosis through lipid peroxidation,
and hypoxia-activated chemotherapy, achieving 92.3% tumor regression
rate with minimal off-target toxicity.