Latest developments in photosensitizers: improving stability, specificity and responsiveness

Photodynamic therapy (PDT) has emerged as a promising anticancer strategy utilizing photosensitizers (PSs) to generate cytotoxic reactive oxygen species (ROS) upon light irradiation. This review highlights recent advancements in optimizing PSs through structural modifications, nanocarrier systems, and stimulus-responsive designs, aiming to enhance their stability, specificity, and responsiveness. Key strategies include chemical modifications (e.g. D-A type structures, shortening the polymethine chain or incorporation of rigid cyclic segments, etc.), nanocarrier encapsulation (e.g. extracellular vesicles and liposomes), host-guest interactions, and specific targeting mechanisms (e.g. organelle-specific localization, antibody conjugation). Additionally, the responsiveness to tumor microenvironment (TME) factors, such as glutathione levels, viscosity, pH, and ROS, has been leveraged to improve the precision and minimize off-target toxicity. Despite significant progress, challenges persist in balancing photostability, biocompatibility, and clinical translatability, highlighting the need for continued innovation in PS design.