Regio-isomerization Optimization Strategy for Photosensitizers: Achieving Ultrahigh Type I Reactive Oxygen Species...

Phototherapy, renowned for its noninvasiveness, is widely employed in tumor treatment. However, the tumor microenvironment is usually hypoxic, with insufficient reactive oxygen species (ROS) production, severely limiting its application. Herein, we introduce a regio-isomerization optimization strategy and have synthesized four regio-isomeric photosensitizers featuring a donor-acceptor (D-A) configuration by tactically varying the linkage sites between D and A. Among them, TAF-3 with excellent photostability has an ultrahigh type I ROS production efficiency (4.79 times that of methylene blue) and a photothermal conversion efficiency of 41.7%. TAF-3 improves the conjugation degree; produces an appropriate intramolecular charge transfer effect, which enhances its optical properties and phototherapeutic efficiency; and promotes a stronger immune cell death effect, reducing postoperative melanoma recurrence by 60%. Overall, the optical attributes of D-A type photosensitizers can be tailored through the precision modulation of regio-isomerization, offering a promising avenue for the advancement of clinical photosensitizers suitable for phototherapy.