Excited-State Structural Distortion of Pentamethine Chains Enhances Singlet Oxygen Generation as a Photoimmunotherapeutic Agent.

The structural design of photosensitizers (PSs) has a significant impact on the intersystem crossing (ISC) and reactive oxygen species (ROS) generation and photodynamic performance. However, current studies of PSs for increasing ROS yield mainly focus on the ground-state configuration, ignoring the influence of the excited-state distorted configuration. In this work, we designed a distorted pentamethine chain structure in the excited state with a rotatable, large steric hindrance electron-withdrawing group (ethylbenzothiazole) in the meso-position (Cy-S-Y). Due to a new strategy of structural distortion-enhanced intersystem crossing (SDE-ISC), Cy-S-Y exhibited a superior capacity for singlet oxygen (1O2) generation (1O2 quantum yield (ΦΔ) = 44.7%) with low light power (3 mW/cm2) in H2O, outperforming the Cy-Br modified with heavy atoms (8.4-fold). Theoretical calculations confirmed that Cy-S-Y had a distorted pentamethine chain structure in the T2 state, resulting in a small energy gap (ΔES1-T2 = -0.002 eV) and a large spin-orbit coupling constant (SOC = 0.29 cm-1), thereby promoting efficient ISC. In addition, Cy-S-Y-mediated photoimmunotherapy promoted damage-associated molecular patterns (DAMPs) and released immune-stimulating factors in vitro. As a result, Cy-S-Y not only inhibited tumor growth but also improved the immune microenvironment and significantly prolonged survival in a tumor-bearing mouse model.