A Type-I/II Photosensitizer with Cell Death Self-Reporting for Ferroptosis-Potentiated Photodynamic Theranostics against Large Tumors

Abstract Photodynamic therapy (PDT) with ferroptosis induction is a promising antitumor strategy, yet its efficacy is compromised by conventional photosensitizers limited to single-pathway ROS generation, particularly in large tumors. Herein, a series of D−A−D AIE photosensitizers integrating Type I/II ROS generation, ferroptosis induction, and cell death self-reporting is developed, with TPBI standing out for its strong D−A architecture and narrow bandgap, which jointly drive exceptional ROS production. Upon irradiation, TPBI yields type-I ROS (depleting GSH/inactivating GPX4) and type-II ROS (inducing lipid peroxidation), which with SLC7A11/GPX4 downregulation collapse redox homeostasis and drive ferroptosis-boosted PDT in large tumors. Furthermore, TPBI shuttles to nucleus upon cell death initiation, triggering bright fluorescence that enables real-time therapeutic tracking. In vivo studies demonstrate that TPBI efficiently arrests large tumor progression and enables precise early of therapeutic responses monitoring, guiding the development of multifunctional AIE photosensitizers for ferroptosis-potentiated photodynamic theranostics.