Pyrrolopyrrole Cyanine J-Aggregates with Amplified Superoxide Radical Generation, GSH Depletion, and Photothermal Action for Hypoxic Cancer Phototherapy

The elevated glutathione (GSH) level and hypoxia in tumor cells are two key obstacles to realizing the high performance of phototherapy. Herein, the electron-donating rotors are introduced to wings of electron-withdrawing pyrrolopyrrole cyanine (PPCy) to form donor-acceptor-donor structure J-aggregates for amplified superoxide radical generation, GSH depletion, and photothermal action for hypoxic cancer phototherapy to tackle this challenge. Three PPCy photosensitizers (PPCy-H, PPCy-Br, and PPCy-TPE) produce hydroxyl radicals (•OH) and superoxide radicals (O₂^•-) in hypoxia tumors exclusively as well as excellent photothermal performances under light irradiation. More importantly, GSH as an "electron reservoir" could effectively participate in photoredox processes, continuously consuming GSH and simultaneously generating more superoxide radicals. Notably, the structure-function relationship results reveal that PPCy-TPE nanoparticles (NPs) possess a high molar extinction coefficient (8.5 × 10⁴ M^-1 cm^-1 at 778 nm) with the broadest absorption band in the near-infrared region, the most significant type I total ROS enhancement, and the highest photothermal conversion efficiency (41.3%). Furthermore, PPCy-TPE NPs have been successfully applied for in vitro and in vivo hypoxic cancer phototherapy under an 808 nm laser with outstanding specificity and biological safety. This work provides a promising single phototherapy agent against hypoxic tumors with efficient type I PDT/PTT synergistic therapy.