Programmed Aggregation of Lipidated Nitrobenzoselenadiazole as a Photo-Activatable Pyroptosis Inducer.

Bioactive photosensitizers in photodynamic therapy (PDT) have emerged as a promising therapeutic approach for tumor treatment. However, the aggregation of photosensitizers in aqueous solutions could hinder their efficacy, leading to reduced generation of reactive oxygen species (ROS) in biological systems and lower therapeutic effectiveness. For the first time, this work discloses a programmed aggregation system based on the nitrobenzoselenadiazole (NBSD) scaffold with varying alkyl chain lengths (C1, C3, and C8), focusing on their potential as photo-activable pyroptosis inducers. This study underscores the significance of molecular design in developing effective photosensitizers and marks a new era in controlling molecular packing and photophysical properties. Among the candidates, NBSD-NOc exhibits superior performances in several areas: (i) aggregation-enhanced PDT effect, (ii) high cellular uptake, (iii) induction of programmed cell death, (iv) implantable properties, and (v) high biocompatibility. Overall, this work highlights the critical balance between aggregation patterns and photophysical properties, presenting a promising strategy for post-surgical management using implantable photosensitizers to address the potential challenge of tumor recurrence.