Photocatalytic Depletion of GSH/NADH and O ₂ -Adaptive Pathway Switching in Producing ROS: Overcoming Treatment Resistances of Cancer Cells to Photodynamic Therapy and Inducing Ferroptotic Cell Death

Photosensitizers (PSs), capable of overcoming the treatment resistances caused by the elevated levels of glutathione (GSH) and nicotinamide adenine dinucleotide (NADH) within cancer cells as well as the hypoxic microenvironment of solid tumors, are highly desirable for photodynamic therapy (PDT) of tumors. Herein, leveraging the redox activity and heavy atom effect of selenium (Se), we develop a cancer-cell-targetable, enzyme/light dual-activatable PS based on a Se-rhodamine platform. Upon encountering cancer cells, the dual-activatable PS can be enzymatically cleaved by aminopeptidase N (APN, overexpressed on the outer membrane of cancer cells) to release a cytomembrane-permeable prodrug PS, which, after being internalized by cancer cells, can be further activated by light to produce an active PS. The resulting active PS features not only dual photocatalytic activities in depleting GSH and NADH but also O₂-adaptive type-II (under normoxia) → type-I (under hypoxia) pathway switching in producing reactive oxygen species (ROS), thereby effectively potentiating the sensitivity of cancer cells to PDT and overcoming the treatment resistances. Due to interrupting the GSH/NADH-dependent antioxidant systems, the active PS almost exclusively induces cancer cell ferroptosis. The study provides an all-in-one strategy in overcoming the treatment resistances of tumors to PDT, paving the way for developing high-performance PSs in the future.