De novo design of nitrobenzoselenadiazole-based activatable photosensitizers for fluorescence imaging-guided photodynamic therapy

In recent years, numerous photosensitizers (PSs) have been developed toward clinical translation, yet off-target toxicity remains a major limitation. Activatable photosensitizers (aPSs) capable of on-demand photodynamic therapy (PDT) offer a promising solution. Herein, we report that oxygen (O)-substitution at the 4-position of nitrobenzoselenadiazole (NBSe) effectively quenches both fluorescence and PDT efficiency, whereas subsequent intramolecular Smiles rearrangement to the corresponding nitrogen (N)-substituted product leads to efficient recovery of both functionalities. Leveraging this mechanism, we established an NBSe-based molecular platform for the rational design of aPSs. Using this platform, we successfully constructed three aPSs (NBSe-H₂O₂, NBSe-Thiol and NBSe-NQO1) responsive to tumor-associated biomarkers (H₂O₂, thiols, and NQO1), enabling tumor-targeted activation and fluorescence imaging-guided PDT. This strategy provides a robust and versatile approach to overcome nonspecific activation issues in conventional PDT, presenting a valuable platform for the development of high-selectivity phototheranostic agents. Copyright © 2026. Published by Elsevier B.V.