Molecular engineering of aggregation-induced emission enhanced photosensitizers to boost the theranostic performance in photodynamic therapy

Aggregation-induced emission (AIE)-based theranostic agents with efficient reactive oxygen species (ROS) generation efficiency and long-term imaging capability are highly in demand but still challenging. Photosensitizers (PSs) with AIE characteristics have emerged as promising theranostic agents in cancer therapy. However, their high oxygen dependency, low molar extinction coefficients, and non-cellular organelle targeting ability significantly limit their theranostic effectiveness, especially in hypoxic tumor environments. In this study, tetraphenylethylene-vinyl pyridinium (TPEPy) bearing three AIE-active photosensitizers (AIE-PSs), namely TPEPyTMB-1, TPEPyTMB-2, and TPEPyTMB-3, were synthesized to enhance aggregation-induced intersystem crossing (AI-ISC), molar absorption coefficients, and reactive oxygen species (ROS) generation efficiency. Among the synthesized AIE-PSs, TPEPyTMB-3, which features a highly twisted structure and a large molar absorption coefficient, exhibited superior ROS generation efficiency and was selected as an ideal candidate for image-guided photodynamic therapy (PDT). Furthermore, TPEPyTMB-3 nanoparticles (TPEPyTMB-3 NPs) were prepared via a simple nanoprecipitation procedure, demonstrating efficient photodynamic therapy (PDT) efficacy under both normoxic and hypoxic conditions, as well as outstanding long-term in vivo imaging capability. In vivo results revealed that TPEPyTMB-3 NPs can effectively inhibit the growth of subcutaneous tumors, under white light irradiation with minimized systemic toxicity. This work highlights the potential of AIE-PSs for the development of highly efficient cancer theranostic agents.