Self‐Adaptive Charge Transfer States in Aqueous Solutions Promote Fast Intersystem Crossing in a Photosensitizer for Tumor Inhibition

ABSTRACT Although conventional design strategies of photosensitizers (PSs) have enabled control of their excited‐state evolution in organic solvents, their distinct photophysical evolution pathways in aqueous solutions severely reduce their intersystem crossing (ISC) rates and reactive oxygen species (ROS) yields. Thus, the design of high‐performance PSs with high ISC rates and ROS yields in aqueous solutions remains a challenge for photodynamic therapy (PDT). In this study, we utilized the ability of aqueous solvents to promote charge transfer to construct Cy5‐PCZ, a PS that can self‐adaptively generate charge transfer singlet states ( 1 CT) and charge transfer triplet states ( 3 CT) in aqueous solutions, thereby promoting ISC. Transient absorption spectroscopy and theoretical calculations demonstrated that the ISC time (∼5 ps) of Cy5‐PCZ was two orders of magnitude faster than Cy5 without PCZ (∼580 ps). Thus, Cy5‐PCZ exhibited markedly increased yields of both type I and type II ROS in aqueous solutions. Consequently, Cy5‐PCZ–mediated PDT induced cancer cell apoptosis and pyroptosis at low concentrations, and markedly suppressed subcutaneous tumor growth and lung metastasis in mouse models. Therefore, this study offers a rational design principle for optimizing the excited‐state processes of high‐performance PSs in aqueous media, thereby enhancing their efficacy in biological applications.