Hydroxyl-radical-specific cascade photogeneration for oxygen-chain photocatalytic therapy

The hydroxyl radical (˙OH), the most potent reactive oxygen species, plays a crucial role in photodynamic therapy (PDT). However, conventional photosensitizers (PSs) that produce ˙OH through the classical Haber-Weiss pathway suffer from multistep/side reactions, short-lived intermediates, and O₂ dependence, underscoring the demand for direct and selective ˙OH photogeneration in biological tissues. Here, we report a de novo LQM scaffold core allowing the evolution of H₂O into ˙OH through an unprecedented "H₂O-O₂-˙OH" oxygen-chain cascade photochemical pathway. The acceptor relocation in D-π-A featured PSs with long-range intramolecular charge transfer can regulate individual oxidation/reduction potentials and fully amplify the electron-hole separation, for the first time achieving ˙OH-specific photogeneration independent of ambient O₂. This generalizable molecular engineering method yields a palette of oxygen-chain PSs that spans the visible and second near-infrared ranges. Our LQM-based oxygen-chain photocatalytic therapy successfully improves therapeutic efficiency in living mice and addresses the long-standing hypoxic challenge of PDT. This study provides a full demonstration of our strategy for the rational design and streamlined PS discovery for ˙OH-specific generation to push the limits of phototherapy in personalized treatment.