Silicon-Xanthenium Scaffold for pH- and Far-Red Light Dual-Responsive Photocage

The development of far-red light-activatable photolabile protecting groups (PPGs) is crucial for precision medicine applications, yet remains challenging due to the low energy of far-red light photons and the frequent compromise of aqueous solubility. While conditional PPGs activated by specific biochemical conditions offer enhanced spatial control, their scope is limited by the need for external triggers or heterogeneous enzyme expression. Here, we report a new class of dual-responsive PPGs based on a silicon-xanthenium scaffold that are activated by both acidic pH and far-red light. Through systematic structural modification, we developed pcSiR718-OH, a photocage with a low molecular weight (<500 Da) and a red-shifted absorption maximum at 718 nm. pcSiR718 CO2H exhibits efficient uncaging (ε × Φ uncaging rel = 184 M –1 cm –1 ) under mildly acidic conditions (pH 5.5–6.7) while remaining stable at physiological pH. Mechanistic studies reveal that photolysis can proceed via both homolytic and heterolytic pathways. We demonstrate the utility of this platform through the precise release of bioactive molecules─pomalidomide and gambogic acid─achieving spatiotemporal control over protein degradation in cellular models and tumor growth inhibition in a murine model. This work establishes a versatile strategy for designing environmentally responsive photocages for targeted therapy.