Insights into type I photoreactivity of cyclometalated iridium( <scp>iii</scp> ) and ruthenium( <scp>ii</scp> ) photosensitizers

Photodynamic therapy (PDT) is a light-activated treatment that relies on the generation of cytotoxic reactive oxygen species (ROS). While most clinically approved photosensitizers (PSs) operate through a type II mechanism-based on energy transfer to molecular oxygen-their efficacy is often compromised in hypoxic tumor microenvironments. In this context, type I PSs capable of initiating electron or hydrogen atom transfer reactions have gained increasing attention due to their reduced dependency on oxygen levels. In this Feature Article, we review recent advances in cyclometalated iridium- and ruthenium-based PSs exhibiting type I photoreactivity, highlighting representative examples from both our own work and the literature. Although rational design strategies are still emerging, selected examples demonstrate how subtle modifications in complex architecture, ligand environment, or metal center identity can influence the balance between type I and type II pathways. In particular, we outline conceptual design motifs-such as cyclometalation with thiophenyl-based ligands, conjugation with fluorophores such as coumarin or BODIPY, and multinuclear architectures-that have been explored to enhance electron-transfer reactivity under hypoxic conditions. Beyond photophysical considerations, we discuss common challenges in the experimental identification of type I mechanisms and emphasize the importance of biologically relevant models, such as 3D cell cultures, for evaluating PS performance. Ultimately, we offer a perspective on how molecular design can be tailored to meet the demands of next-generation PDT agents, aiming to improve therapeutic outcomes in low-oxygen tumor microenvironments, which are characteristic of highly aggressive and treatment-resistant tumors.