Type-I Supramolecular Photosensitizer Enables GSH Depletion by Hydrogen Atom Transfer

Abstract

Photodynamic therapy (PDT) induces oxidative stress that triggers a compensatory upregulation of intracellular glutathione (GSH), thereby diminishing PDT efficacy. The simultaneous generation of reactive oxygen species and depletion of GSH holds promise for amplifying oxidative damage and enhancing therapeutic outcomes yet remains a challenge. In this work, we present a Type-I supramolecular photosensitizer designed to deplete GSH through a hydrogen atom transfer mechanism while concurrently generating superoxide radicals. This photosensitizer is constructed through the supramolecular host–guest assembly of cyclodextrin-conjugated N-hydroxyphthalimide (CD-NHPI) and a BODIPY-based photosensitizer (BDP). Upon light irradiation, electron transfer from CD-NHPI to BDP forms a radical ion pair: CD-NHPI^+• and BDP^–•. CD-NHPI^+• undergoes deprotonation to yield an oxygen-centered radical that oxidizes GSH by directly abstracts hydrogen atoms from GSH, while BDP^–• concurrently reduces molecular oxygen to superoxide radicals. As a result, this photosensitizer exhibits remarkable photocytotoxicity and significant antitumor efficacy in mouse models. This work offers a strategy for synergistically photocatalytic oxidation of antioxidants and generation of reactive oxygen species for PDT.