Molecular Tailoring Based on Forster Resonance Energy Transfer for Initiating Two-Photon Theranostics with Amplified Reactive Oxygen Species.

The fabrication of multifunctional photosensitizers (PSs) with abundant Type I/II ROS for efficient theranostics in the "therapeutic window" (700-900 nm) is an appealing yet significantly challenging task. We herein report a molecular tailoring strategy based on intramolecular two-photon Forster Resonance Energy Transfer (TP-FRET) to obtain a novel theranostic agent (<b>Lyso-FRET</b>), featuring the amplified advantage of energy donor (<b>NH</b>) and acceptor (<b>COOH</b>), because of the reuse of fluorescence energy with high efficiency of FRET (∼83%). Importantly, under the excitation by the near-infrared (840 nm) window, <b>Lyso-FRET</b> can not only penetrate the deeper tissue with a higher resolution for fluorescence imaging due to the nonlinear optical (NLO) nature, but also generate more Type I (superoxide anion) and Type II (singlet oxygen) reactive oxygen species for hypoxic PDT. Moreover, <b>Lyso-FRET</b> targeting lysosomes further promotes the effect of treatment. The experiments <i>in vitro</i> and <i>in vivo</i> also verify that the developed TP-FRET PS is conducive to treating deep hypoxic tumors. This strategy provides new and significant insights into the design and fabrication of advanced multifunctional PSs.