Aggregation‐Induced Triplet Symmetry‐Breaking Charge Separation Drives Electron Transfer for Autophagy Blockade‐Enhanced Type‐I Photodynamic Therapy
Xin Li, Fuping Han, Xiao Zhou, Hongyi Zhang, Tiancong Shi, Lihan Cai, Danhong Zhou, Weijie Chi, Saran Long, Wen Sun, Jianjun Du, Jiangli Fan, Xiaojun Peng
Abstract
ABSTRACT Electron transfer is considered to play a critical role in the Type‐I photodynamic therapy process, which offers superior performance under hypoxic conditions. However, developing efficient Type‐I photosensitizers remains challenging because of the competition between energy and electron transfer processes. Therefore, we designed cyanine dyes ( Cy‐R ) with tunable intersystem crossing (ISC) efficiencies, with the ISC rate reaching 9.29 × 10 6 s −1 . Unlike conventional dimers with short‐lived charge‐separated states, Cy‐R aggregates having sufficiently high ISC efficiency undergo symmetry‐breaking charge separation (SBCS) in the triplet state, generating long‐lived triplet charge‐separated species ( Cy‐R •+ − Cy‐R •− ). This mechanism significantly enhances the production of Type‐I reactive oxygen species. Furthermore, Cy‐Ac self‐aggregation facilitated passive tumor targeting and lysosomal accumulation. Upon photoactivation, Cy‐Ac induces lysosomal membrane permeabilization, disrupts autophagy, and triggers lysosome‐mediated cell death. This study provides a promising strategy for the development of hypoxia‐tolerant Type‐I photosensitizers via triplet‐state SBCS.