Azobenzene-cyanine hybrids with enhanced photostability and non-radiative transitions for multimodal tumor therapy

Photothermal and photodynamic therapies (PTT/PDT) have emerged as promising noninvasive tumor treatments. Effective regulation of excited-state properties in near-infrared (NIR) photosensitizers (PSs) is crucial for enhancing therapeutic efficacy by minimizing photobleaching and optimizing energy dissipation pathways. Rational molecular design of NIR PSs to simultaneously improve photostability and favor non-radiative decay mechanism holds significant potential for revolutionizing tumor treatment. In this work, a series of NIR photosensitizer isomers (<i>o</i>2CyO-AB and <i>p</i>2CyO-AB) were designed and synthesized by combining azobenzene group and a cyanine dye (Cy-Cl). Compared with Cy-Cl, both isomers exhibited significantly improved photostability and non-radiative transitions. For the first time, single-crystal structural analysis revealed that azobenzene incorporation shortened the conjugated double-bond system in the cyanine dye, leading to a dramatic enhancement in photostability. Different substitution positions exerted a significant influence on the non-radiative transition process. Notably, the non-radiative transition of <i>o</i>2CyO-AB was dominated by intersystem crossing with a remarkable 15-fold increase in the yield of ¹O₂ compared with the clinical NIR PS Indocyanine green, while the non-radiative decay of <i>p</i>2CyO-AB mainly proceeded via thermal deactivation with a high photothermal conversion efficiency of 51.02%. In a proof-of-concept study using oral squamous cell carcinoma HN6 as a model, <i>o</i>2CyO-AB mediated potent combined PTT/PDT effects, achieving a high tumor growth inhibition rate of 95.41% <i>in vivo</i> within 14 days. Therefore, modifying PSs with azobenzene groups holds promise for enhancing their phototherapeutic performance, offering new strategies and approaches for developing efficient and precise tumor PSs.