End Group Engineering for Constructing A−D−A Fused‐Ring Photosensitizers with Balanced Phototheranostics Performance

Abstract Phototheranostics continues to flourish in cancer treatment. Due to the competitive relationships between these photophysical processes of fluorescence emission, photothermal conversion, and photodynamic action, it is critical to balance them through subtle photosensitizer designs. Herein, it is provided a useful guideline for constructing A−D−A photosensitizers with superior phototheranostics performance. Various cyanoacetate group‐modified end groups containing ester side chains of different length are designed to construct a series of A−D−A photosensitizers (F8CA1 ∼ F8CA4) to study the structure‐property relationships. It is surprising to find that the photophysical properties of A−D−A photosensitizers can be precisely regulated by these tiny structural changes. The results reveal that the increase in the steric hindrance of ester side chains has positive impacts on their photothermal conversion capabilities, but adverse impacts on the fluorescence emission and photodynamic activities. Notably, these tiny structural changes lead to their different aggregation behavior. The molecule mechanisms are detailedly explained by theoretical calculations. Finally, F8CA2 nanoparticles with more balanced photophysical properties perform well in fluorescence imaging‐guided photothermal and type I&II photodynamic synergistic cancer therapy, even under hypoxic conditions. Therefore, this work provides a novel practicable construction strategy for desired A−D−A photosensitizers.