Flexible-Structured Cyanine–Cyanine Conjugate Affords Highly Efficient Photothermal Therapy via Enhanced Tumor Accumulation and Heating Performance

Simultaneous optimization of tumor accumulation and photothermal conversion efficiency (PCE) remains a major challenge in photothermal agent (PTA) development. Here, benzene-thiol/-dithio/-trithiol was introduced at the meso-position of heptamethine cyanine (Cy7) via sulfhydryl substitution. The obtained derivatives, denoted as M-Cy7, D-Cy7, and T-Cy7, conferred enhanced molecular flexibility, promoting self-assembly and passive tumor accumulation. Although increasing the number of Cy7 units reduced molecular flexibility in the D- and T-derivatives, the central phenyl linker enabled covalent coupling of intramolecular Cy7 moieties, resulting in a "covalent aggregation" effect and boosting PCE to 77%─nearly seven times higher than that of the prototypic Cy7. Among them, D-Cy7 demonstrated the most favorable balance of tumor accumulation and photothermal efficiency, achieving optimal in vivo PTT efficacy. This novel molecular design strategy successfully integrated high PCE and tumor-targeting capability into a single PTA, offering new insights for advancing photothermal therapy.