Mechanism-guided design of specific-activated photosensitizers for precision photodynamic therapy

The clinical application of conventional photodynamic therapy (PDT) is often limited by the nonspecific phototoxicity of "always-on" photosensitizers. Activatable photosensitizers (aPSs) have emerged as a promising solution to this challenge. These smart agents are designed to remain inactive under normal physiological conditions and become activated only by disease-specific stimuli, thereby significantly improving treatment specificity and safety. This review summarizes the key design strategies for developing effective aPSs. We focus on the general principles of utilizing various quenching mechanisms, such as energy or electron transfer processes and aggregation behavior control, to suppress photosensitizer activity until a specific trigger is encountered. Representative examples are discussed to illustrate how these designs respond to biomarkers like enzymes, glutathione, or acidic pH to activate therapeutic functions. By minimizing off-target effects and enhancing spatial control, these mechanism-guided approaches pave the way for more precise and clinically viable PDT protocols, aligning with the core objectives of precision medicine.