Leveraging an Electron-Acceptor Engineering Strategy to Regulate Excitation Dynamics of Dyes for Devising Ideal Phototherapeutic Agents in Synergistic Photodynamic/ Mild-Photothermal Tumor Therapy

Despite the individual merits of photodynamic or photothermal therapy (PTT) for clinical cancer treatment, the inherent shortcomings of single-modal therapy significantly hinder therapeutic outcomes in tumors. Therefore, integrating multimodal therapeutic functions into a smart dye can address the drawbacks of single-modal therapy, albeit with significant challenges. By employing an electron-acceptor engineering strategy to regulate the excitation dynamics processes of dyes, we designed a series of near-infrared (NIR) dyes (Hcy-OO, Hcy-ON, and Hcy-NN). Among these dyes, Hcy-ON demonstrated the best photodynamic/ mild-photothermal performances by optimizing the energy release pathway of the excited state of dyes, which is attributed to the synergistic effects of the lowest difference in gap between S₁ and T₁ energy levels of 0.678 eV, a large spin–orbit coupling matrix element value of 0.725 cm⁻¹, a high root mean squared displacement value of 1.662 Å, and a Huang–Rhys factor of >70. Importantly, upon irradiation at 760 nm, through mild-photothermal therapy (MPTT) in synergy with the photodynamic therapy, Hcy-ON successfully ablated tumors in the mouse model with a single treatment under a safe light dose of 300 mW/cm². Overall, we hope that this work will provide practical guidance to enhance the phototherapeutic performance of NIR dyes for clinical multimodal treatment of tumors.