Molecular Engineering to Boost AIE‐Active Free Radical Photogenerators and Enable High‐Performance Photodynamic Therapy under Hypoxia

Abstract The severe hypoxia in solid tumors and the vicious aggregation‐caused fluorescence quenching (ACQ) of conventional photosensitizers (PSs) have limited the application of fluorescence imaging‐guided photodynamic therapy (PDT), although this therapy has obvious advantages in terms of its precise spatial–temporal control and noninvasive character. PSs featuring type I reactive oxygen species (ROS) based on free radicals and novel aggregation‐induced emission (AIE) characteristics (AIE‐PSs) could offer valuable opportunities to resolve the above problems, but molecular engineering methods are rare in previous reports. Herein, a strategy is proposed for generating stronger intramolecular charge transfer in electron‐rich anion‐π + AIE‐active luminogens (AIEgens) to help suppress nonradiative internal conversion and to promote radiative and intersystem crossing to boost free radical generation. Systematic and detailed experimental and theoretical calculations prove the proposal herein: the electron‐donating abilities are enhanced in collaborative donors, and the AIE‐PSs exhibit higher performance in near‐infrared fluorescence imaging‐guided cancer PDT in vitro / vivo. This work serves as an important reference for the design of AIE‐active free radical generators to overcome the ACQ and tumor hypoxia challenges in PDT.