Substrate-free generation of photosensitizer radical-ion pairs enables multipath photoredox for hypoxia-tolerant photodynamic therapy

Photodynamic therapy (PDT) is fundamentally limited by inefficient conversion of photoexcited energy into reactive oxygen species (ROS), especially in hypoxic pathological tissues. Photogenerated radical-ion pairs (PS⁺•/PS⁻•) from photosensitizer could overcome this limitation by broadening photoredox diversity for hypoxia-tolerant ROS production. However, conventional substrate-dependent mechanism typically generates only one radical species, limiting both photoredox diversity and overall ROS production. Here we demonstrate a substrate-free mechanism via noncovalent homodimer fission for efficient generation of PS⁺•/PS⁻• pairs from water-soluble DB-Py, unlocking multipath photoredox for hypoxia-tolerant PDT. Spectroscopic studies and calculations provide experimental evidence for homodimer formation via noncovalent interactions between a photoexcited triplet-state and a ground-state molecule, followed by fission into abundant PS⁺•/PS⁻• pairs. The resulting PS⁺• oxidizes water to generate O 2 in situ, which is subsequently reduced by PS⁻• to produce •OH and O 2 ⁻•, thereby establishing a self‑oxygen‑supplying ROS generation cycle. Consequently, DB-Py achieves 4.9‑fold higher •OH and 2.7‑fold higher O 2 ⁻• compared to commercial Rose Bengal, resulting in 7.9-fold enhanced antibacterial efficacy and 2.2-fold accelerated wound epithelialization. This work establishes a substrate-free radical generation mechanism with broad implications for the development of photodynamic, photocatalytic, and photoredox systems.