Iridium and rhenium complexes in photodynamic and sonodynamic therapy: mechanistic insights and therapeutic potential

Cancer maintains to be a major worldwide health epidemic, and despite breakthroughs in targeted agents, immunotherapy, chemotherapy, and surgery, considerable limitations persist. These comprise therapeutic resistance, dose-limiting toxicities, late diagnosis, and microenvironmental barriers, including hypoxia and poor perfusion. The spatiotemporally regulated, locally activated cytotoxicity that photodynamic therapy (PDT) and sonodynamic therapy (SDT) provide has made them appealing substitutes. They may also be used in conjunction with immunotherapy and imaging. SDT uses ultrasound to allow for deeper penetration and partial oxygen independence, whereas PDT uses light to activate photosensitisers. Both approaches produce radical intermediates and reactive oxygen species (ROS), which harm vital biomolecules and activate several pathways leading to programmed cell death, hence decreasing the probability of resistance. However, SDT necessitates the optimisation of acoustic parameters and verified clinical protocols, while PDT is limited by oxygen reliance and poor light penetration. Transition metal complexes, especially those of iridium (III) and rhenium (I), offer special benefits for PDT and SDT because of their intrinsic luminescence, effective triplet-state creation, high spin-orbit coupling, and variable photophysical characteristics. Their translational potential is being advanced by rational design tactics such as theranostic pairing, red/NIR and two-photon activation, nanocarrier integration, and Type I biasing for hypoxia tolerance. With continuous attempts to standardise dosimetry and sensitiser design, SDT is still in the early phases of evaluation, whereas PDT is clinically established. This study highlights Ir and Re complexes as adaptable next-generation sensitisers that could broaden the therapeutic reach of externally activated cancer medicines by synthesising molecular insights, representative chemical classes, and translational obstacles.