Engineering a Universal Scaffold for Activatable Near-Infrared Photosensitizers

The efficacy of photodynamic therapy (PDT) critically depends on the intrinsic properties of the employed photosensitizer (PS). Conventional PSs often suffer from an “always-on” characteristic, which leads to poor selectivity and undesirable phototoxicity in nontarget tissues. To address this limitation, activatable photosensitizers (aPSs) that respond selectively to disease-associated stimuli are highly desirable. Herein, we report a universal near-infrared (NIR) photosensitizing scaffold, Rho-I, for the construction of stimulus-responsive aPSs. Rho-I exhibits strong NIR absorption and high phototoxicity upon illumination, enabling efficient tumor ablation. Notably, its photodynamic activity can be effectively suppressed through phenolate donor caging. Leveraging this feature, we developed two aPSs, Rho−I-H₂O₂ and Rho-I-ALP, which are specifically activated by hydrogen peroxide (H₂O₂) and alkaline phosphatase (ALP), respectively. These aPSs demonstrated selective activation and efficient photoablation of tumor cells in response to their respective stimuli. This work establishes Rho-I as a versatile scaffold for the development of precision aPSs, offering a promising strategy for targeted and safe PDT applications.