Theoretical insights into the rational design of small organic phototheranostic agents for promoting image-guided cancer surgery

To realize the precise regulation of phototheranostics for AIE luminogens (AIEgens), unraveling the molecular configuration, molecular packing and phototheranostic property relationships is of vital importance. Through a multiscale modeling protocol that combines molecular dynamics simulations, implicit polarizable continuum models and thermal vibration correlation function formalism coupled quantum mechanics/molecular mechanics models, the inherent mechanism of two structurally similar donor-(π)-acceptor-type AIEgens (TI and TSSI) with significantly different performances in phototheranostics were firstly explored. It is found that TSSI with additional thiophene rings as a bridge largely improves the phototheranostic properties, which includes a redshifted emission, a high photothermal conversion efficiency (PCE) and a good intersystem crossing (ISC) efficiency. Based on that, we propose a molecular design strategy and design a series of AIEgens via structural modification of the acceptor moiety or extending the π-bridge of TSSI. It is found that, TSSSSI is predicted to be a potential candidate for NIR-II fluorescence imaging guided photodynamic and photothermal therapy applications owing to its excellent fluorescence efficiency, efficient ISC process, and emission spectrum in the NIR-II region. Lastly, the fluorescence quantum efficiency enhancement of TSSI upon aggregation was caused by suppressing the rotational vibrations in the low-frequency region. Our theoretical protocol is general and applicable to other AIEgens, thus laying a solid foundation for the rational design of advanced AIEgens for applications in phototheranostics.