This study introduces a novel chemical platform for generating enzyme-activatable near-infrared (NIR) photosensitizers (PS) based on Se-bridged hemicyanines. The platform enables the design of modular, biocompatible, and enzyme-activatable PS for targeted photodynamic therapy (PDT) in cancer treatment. The Se-bridged hemicyanine scaffold was optimized to include caging groups and biocompatible moieties, allowing for the development of cathepsin-triggered PS that effectively ablate human glioblastoma cells. The PS were shown to be effective for the safe ablation of microtumors in vivo, offering new possibilities for the chemical design of targeted PDT agents. The PS were designed to be activated by specific enzymes, such as cathepsin B, which is overexpressed in many cancer cells. This activation mechanism ensures that the PS are only released in the tumor microenvironment, minimizing off-target toxicity. The study demonstrated that the Se-bridged hemicyanine PS, when activated by cathepsin B, exhibited high singlet oxygen generation and phototoxicity in cancer cells, with minimal dark toxicity. The PS were synthesized using a scalable approach that allows for the incorporation of various functional groups, including water-soluble moieties and enzymatic caging groups. The study also showed that the PS could be used to safely ablate microtumors in vivo, as demonstrated in a zebrafish model. The PS were found to be non-toxic to the zebrafish and did not cause any abnormalities in morphology or behavior. The study highlights the potential of Se-bridged hemicyanine PS as a promising platform for the development of enzyme-activatable NIR PS for targeted PDT. The PS were shown to have excellent biocompatibility, high phototoxicity, and the ability to be selectively activated by enzymes in the tumor microenvironment. The results suggest that these PS could be used for the treatment of various cancers, including glioblastoma, with minimal side effects. The study also emphasizes the importance of chemical modularity in the design of PS for PDT, as it allows for the fine-tuning of properties such as solubility, reactivity, and toxicity.This study introduces a novel chemical platform for generating enzyme-activatable near-infrared (NIR) photosensitizers (PS) based on Se-bridged hemicyanines. The platform enables the design of modular, biocompatible, and enzyme-activatable PS for targeted photodynamic therapy (PDT) in cancer treatment. The Se-bridged hemicyanine scaffold was optimized to include caging groups and biocompatible moieties, allowing for the development of cathepsin-triggered PS that effectively ablate human glioblastoma cells. The PS were shown to be effective for the safe ablation of microtumors in vivo, offering new possibilities for the chemical design of targeted PDT agents. The PS were designed to be activated by specific enzymes, such as cathepsin B, which is overexpressed in many cancer cells. This activation mechanism ensures that the PS are only released in the tumor microenvironment, minimizing off-target toxicity. The study demonstrated that the Se-bridged hemicyanine PS, when activated by cathepsin B, exhibited high singlet oxygen generation and phototoxicity in cancer cells, with minimal dark toxicity. The PS were synthesized using a scalable approach that allows for the incorporation of various functional groups, including water-soluble moieties and enzymatic caging groups. The study also showed that the PS could be used to safely ablate microtumors in vivo, as demonstrated in a zebrafish model. The PS were found to be non-toxic to the zebrafish and did not cause any abnormalities in morphology or behavior. The study highlights the potential of Se-bridged hemicyanine PS as a promising platform for the development of enzyme-activatable NIR PS for targeted PDT. The PS were shown to have excellent biocompatibility, high phototoxicity, and the ability to be selectively activated by enzymes in the tumor microenvironment. The results suggest that these PS could be used for the treatment of various cancers, including glioblastoma, with minimal side effects. The study also emphasizes the importance of chemical modularity in the design of PS for PDT, as it allows for the fine-tuning of properties such as solubility, reactivity, and toxicity.