Near‐Infrared Self‐Assembled Hydroxyl Radical Generator Based on Photoinduced Cascade Electron Transfer for Hypoxic Tumor Phototherapy

Abstract The hydroxyl radical (•OH) is an extremely potent reactive oxygen species that plays a crucial role in photooxidations within the realm of hypoxic tumor therapy. However, the current methods for •OH photogeneration typically rely on inorganic materials that require UV/vis light excitation. Consequently, photogenerators based on organic molecules, especially those utilizing near‐infrared (NIR) light excitation, are rare. In this study, the concept of photoinduced cascade charge transfer (PICET), which utilizes NIR heavy‐atom‐free photosensitizers (ANOR‐Cy5) to generate •OH is introduced. The ANOR‐Cy5 photosensitizer, with its flexible hydrophobic structure, enables the formation of nanoparticles in aqueous solutions through molecular assembly. PICET involves a symmetry‐breaking charge separation‐induced localized charge‐separated state, transitioning to a delocalized charge‐separated state, which governs the efficiency of •OH generation. Thanks to the oxygen‐independent nature of •OH generation and its robust oxidative properties, the ANOR‐Cy5‐based photosensitizer demonstrates highly effective photoinduced anti‐cancer effects, even under severely hypoxic conditions. This discovery emphasizes the potential for achieving •OH photogeneration using a single organic molecule through the engineering of molecular self‐assembly, thereby opening up new possibilities for phototherapy and beyond.