A cationization strategy to simultaneously enhance reactive oxygen species generation and mitochondria targeting ability for enhanced photodynamic therapy

Mitochondria-targeted photodynamic therapy (PDT) circumvents the short lifetime and action radius limitation of reactive oxygen species (ROS) and greatly improves the anticancer PDT efficacy. However, current approaches require different molecular engineering strategies to separately improve ROS production and introduce mitochondria targeting ability, which involve tedious synthetic procedures. Herein, we report a facile one-step cationization strategy that simultaneously improves the ROS generation efficiency and introduces mitochondria targeting ability for enhanced PDT. This strategy is demonstrated with AIE-active photosensitizers ITPAPy and ITPAPyI, where cationization transforms the pyridine ring in ITPAPy into a positively charged pyridinium salt in ITPAPyI. Cationization promotes intramolecular charge separation and enhances intersystem crossing without compromising the AIE properties, and ITPAPyI generates higher levels of ROS over its neutral counterpart ITPAPy. Moreover, the cationic ITPAPyI profoundly enriched at the mitochondrial membrane of cancer cells, while the neutral ITPAPy mainly accumulated in lysosomes. Since mitochondria are the main target of ROS, ITPAPyI causes massive oxidative damage to mitochondria and promotes apoptosis, showing a more effective PDT effect. This cationic molecular engineering strategy establishes an attractive paradigm for designing photosensitizers with concurrent ROS enhancement and mitochondria-targeting capabilities, paving the way for highly efficient PDT applications.