NIR photoactivated electron intersystem crossing to evoke calcium-mediated lysosome-dependent cell death and immunotherapy

Abstract

The efficacy of photodynamic therapy (PDT) highly depends on the photosensitizer (PS). How to rationally design PS with an efficient inter-system crossing (ISC) rate to enable the capacity for reactive oxygen species (ROS) production, remains a great challenge. Herein, we have successfully provided two isomers at two positions of the BODIPY core with a decoration of cyclometalated Ir(III) fragment to avoid the disadvantages of themselves as PS for PDT. With the theoretical and experimental investigations, the intact connection with BODIPY and Ir(III) fragment has been confirmed to facilitate the ISC process to produce ROS. PS could be accumulated in the lysosome, and excited with a near-infrared wavelength light (630 nm). Due to the severe ROS production upon irradiation, the lysosome membrane permeabilization (LMP) was activated. The calcium homeostasis has been subsequently disrupted with the release of the lysosomal contents, resulting in acidosis and calcium-mediated lysosome-dependent cell death (autophagy blockage and mitochondrial apoptosis). The photodynamic immunotherapy was also evoked with the disturbed calcium homeostasis, which has been demonstrated with the bilateral tumor models in vivo. This study not only provided a superior NIR photosensitizer but also presented an effective strategy to reduce the energy gap via electron intersystem crossing to boost photodynamic immunotherapy.