Molecular Engineeringof Asymmetric Cyanines withHybridized Local and Charge-Transfer Characteristics for NIR-II Imaging-GuidedType I/II Photodynamic Therapy

Conventional cyanine photosensitizers face challenges in photodynamic therapy (PDT) due to poor intersystem crossing (ISC), hypoxia sensitivity, and low tumor retention. Herein, we report the first asymmetric D-π-A-D' cyanine dyes with hybridized local and charge-transfer (HLCT) characteristics to address these limitations. By precisely regulating triplet excitons of the T2 state, these dyes facilitate enhanced ISC from the S1 to T2 state and boost reactive oxygen species (ROS) generation. These HLCT-type cyanine dyes integrate the charge-transfer state to promote oxygen-independent Type I PDT for hypoxic tumor environments and the locally excited state to maintain high photoluminescence quantum yield (PLQY) for visualized tumor therapy. Among them, CyTY-3 exhibits exceptional dual Type I/II PDT performance, with a singlet oxygen yield outperforming ICG by 27.8-fold, while simultaneously delivering a high NIR-II PLQY of 11.4% for high-contrast imaging. Unique delocalized charge distribution enables excellent tumor targeting and an ultralong retention time of up to 12 days. In vivo, CyTY-3 nanoparticles achieve 99.01% tumor inhibition under 808 nm irradiation with good biosafety. This HLCT strategy provides a robust platform for developing next-generation photosensitizers to overcome the intrinsic limitations of hypoxic tumor therapy.