Solvent Polarization‐Induced Aggregation Modulation in Zwitterionic‐Resonance‐Structure Squaraine Derivative to Enhance Photosensitization for Effective Tumor Inhibition

Abstract Photosensitization, involving the energy or electron transfer to generate reactive oxygen species (ROS), has been extensively employed for photodynamic therapy (PDT) in clinics. Recent studies have highlighted the critical influence of molecular aggregation on photosensitization, however, the complex intermolecular interactions within aggregates remain a challenge to control. Herein, solvent‐induced polarization is exploited to modulate the aggregation behavior of a zwitterionic squaraine derivative, SQ‐CHO, resulting in two distinct aggregate structures of SQ‐CHO‐C 2 H 2 Cl 4 and SQ‐CHO‐TFA. Electrostatic potential mapping confirmed the polarization effect of the solvents on SQ‐CHO, while single‐crystal X‐ray diffraction revealed that SQ‐CHO‐TFA adopts a less twisted conformation with pronounced face‐to‐face π–π stacking compared to SQ‐CHO‐C 2 H 2 Cl 4 , thereby resulting in reduced exciton binding energy, favorable energy levels, and enhanced intersystem crossing for boosting multiple ROS generation. Leveraging this effect, a strategy is developed to construct efficient photosensitizers by introducing TFA‐mediated polarization. Nanoparticles formed from SQ‐CHO with the aggregate structure resembled to SQ‐CHO‐TFA exhibited potent generation of O 2 •− , • OH, and 1 O 2 , achieving excellent PDT efficacy. This work provides significant insights into aggregation manipulation via polarization microenvironment and demonstrates a straightforward strategy to design high‐performance photosensitizers.