Recent advances in developing bioorthogonally activatable photosensitizers for photodynamic therapy

Photodynamic therapy (PDT) is a promising and powerful cancer therapeutic modality, which can generate cytotoxic reactive oxygen species (ROS) from light-irradiated photosensitizers (PSs) to eradicate tumors. To overcome the drawbacks of currently used PSs, researchers have leveraged the advantages of bioorthogonal reactions to design diverse bioorthogonally activatable photosensitizers with excellent tumor selectivity, high ROS generation controllability, and low adverse effect for effective antitumor photodynamic therapy. In this review, we comprehensively summarize and highlight the recent advances in the development of bioorthogonally activatable photosensitizers, including the structure types, designing strategies, activation patterns, photophysical properties, ROS generation efficiency, in vitro and in vivo activities, biological applications, and limitations. We also provide directions and perspectives to address the therapeutic challenges of bioorthogonally activatable photosensitizers for promoting clinical applications. We believe that the principles summarized here will offer useful references for further development of next-generation advanced intelligent photosensitizers and related strategies to realize precise and efficient tumor treatment in the future.