Tailoring NIR‐II Fluorescence and Photothermal Properties via Side‐Chain Engineering for Vascular Imaging and Image‐Guided Tumor Therapy

Second near-infrared (NIR-II, 1000-1700 nm) fluorescence imaging (FLI)-guided photothermal therapy is a promising non-invasive strategy for tumor theranostics. However, existing photothermal agents struggle to balance high photothermal conversion efficiency (PCE) with strong fluorescence quantum yield (QY). Herein, an alkoxyl side chain engineering strategy was proposed to construct a series of donor-π bridge-acceptor-π bridge-donor (D-π-A-π-D) structured organic photothermal agents (TTQ1-TTQ6) enabling simultaneous NIR-II FLI-guided photothermal therapy. By introducing different alkoxyl side chains on triphenylamine donor or thiophene π-bridge, the photophysical properties including aggregation-induced emission (AIE) property, QY and PCE were regulated. TTQ2 NPs and TTQ6 NPs featured superior resolution and low background in in vivo NIR-II fluorescence imaging of the mouse blood vessels with high signal-to-noise ratio. Four alkoxyl chains attached to the donor moiety enhanced the intramolecular donor-acceptor interaction and effectively suppressed aggregation-caused quenching (ACQ), enabling TTQ6 NPs to exhibit desirable NIR-II fluorescence and a high PCE of 46.5%. Encouragingly, TTQ6 NPs could effectively ablate both subcutaneous and orthotopic breast tumors and stimulate adaptive immune responses, which collectively reduced the risk of tumor recurrence. This study illustrates the potential of alkoxyl side chain engineering strategy in developing advanced photothermal agents for NIR-II FLI-guided theranostics.