The dynamic modulation of the aggregation process of small molecules represents an important research objective for scientists. However, the complex and dynamic nature of internal environments in vivo impedes controllable aggregation processes of single molecules. In this study, we successfully achieved tumor-targeted aggregation of an aggregation-induced emission photosensitizer (AIE-PS), TBmA, with the catalysis of a tumor-overexpressed enzyme, γ-Glutamyl Transferase (GGT). Mechanistic investigations revealed that TBmA-Glu could be activated by GGT through cleavage of the -glutamyl bond and releasing TBmA. The poor water solubility of TBmA induced its aggregation, leading to an aggregation-enhanced emission and photodynamic activities of AIE-PS. The TBmA-Glu not only induced glutathione (GSH) depletion through GGT inhibition, but also triggered lipid peroxidation accumulation and ferroptosis in cancer cells through photodynamic therapy. The exceptional cancer-targeting ability and therapeutic efficiency demonstrated by this GGT activatable AIE-PS highlighted enzymatic-mediated modulation as an effective approach for regulating small molecule aggregation intracellularly, thereby advancing innovative therapeutic strategies for various diseases.
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