Activatable Photosensitizers: From Fundamental Principles to Advanced Designs

Abstract Photodynamic therapy (PDT) is a promising treatment that uses light to excite photosensitizers in target tissue, producing reactive oxygen species and localized cell death. It is recognized as a minimally invasive, clinically approved cancer therapy with additional preclinical applications in arthritis, atherosclerosis, and infection control. A hallmark of ideal PDT is delivering disease‐specific cytotoxicity while sparing healthy tissue. However, conventional photosensitizers often suffer from non‐specific photoactivation, causing off‐target toxicity. Activatable photosensitizers (aPS) have emerged as more precise alternatives, offering controlled activation. Unlike traditional photosensitizers, they remain inert and photoinactive during circulation and off‐target accumulation, minimizing collateral damage. These photosensitizers are designed to “turn on” in response to disease‐specific biostimuli, enhancing therapeutic selectivity and reducing off‐target effects. This review explores the principles of aPS, including quenching mechanisms stemming from activatable fluorescent probes and applied to activatable photosensitizers (RET, PeT, ICT, ACQ, AIE), as well as pathological biostimuli (pH, enzymes, redox conditions, cellular internalization), and bioresponsive constructs enabling quenching and activation. We also provide a critical assessment of unresolved challenges in aPS development, including limitations in targeting precision, selectivity under real‐world conditions, and potential solutions to persistent issues (dual‐lock, targeting moieties, biorthogonal chemistry and artificial receptors). Additionally, it provides an in‐depth discussion of essential research design considerations needed to develop translationally relevant aPS with improved therapeutic outcomes and specificity.