This study introduces a novel chemical platform for generating enzyme-activatable near-infrared (NIR) photosensitizers, which are crucial for photodynamic therapy (PDT) in cancer treatment. The researchers optimized the Se-bridged hemicyanine scaffold to include caging groups and biocompatible moieties, creating cathepsin-triggered photosensitizers. These compounds effectively ablate human glioblastoma cells and demonstrate the potential for safe in vivo ablation of micro-tumors. The platform's key advantages include enhanced photodynamic activity, chemical modularity, and reduced off-target toxicity, making it a promising approach for targeted anti-cancer PDT agents. The study highlights the importance of enzyme-activatable NIR photosensitizers in improving the safety and efficacy of PDT treatments.This study introduces a novel chemical platform for generating enzyme-activatable near-infrared (NIR) photosensitizers, which are crucial for photodynamic therapy (PDT) in cancer treatment. The researchers optimized the Se-bridged hemicyanine scaffold to include caging groups and biocompatible moieties, creating cathepsin-triggered photosensitizers. These compounds effectively ablate human glioblastoma cells and demonstrate the potential for safe in vivo ablation of micro-tumors. The platform's key advantages include enhanced photodynamic activity, chemical modularity, and reduced off-target toxicity, making it a promising approach for targeted anti-cancer PDT agents. The study highlights the importance of enzyme-activatable NIR photosensitizers in improving the safety and efficacy of PDT treatments.