Smart Cyclometalated Iridium Photosensitizers: Stimuli-Responsive and Theranostic Systems for Precision Phototherapy

Abstract Cyclometalated Iridium(III) complexes have emerged as one of the most versatile classes of photosensitizers for photodynamic therapy (PDT), owing to their tunable photophysics, high phosphorescence quantum yields, and intrinsic capacity for real-time optical imaging. However, the clinical translation of conventional PDT remains limited by nonspecific activation, poor selectivity, and off-target phototoxicity. The dynamic and heterogeneous tumour microenvironment (TME)- defined by anomalous pH, elevated Glutathione (GSH) levels, malfunctioned redox homeostasis, enzyme overexpression, and irregular vascularisation, which thus offers an opportunity to engineer next-generation photosensitizers that respond selectively to these cancer-specific stimuli. This review aims to explore recent advances in stimuli-responsive and theranostic cyclometalated iridium(III) systems designed to achieve anticancer activity in a spatiotemporal manner. We discuss the molecular design principles and mechanistic bases of TME-, redox-, enzyme-, and light-triggered activation, along with emerging multi-stimuli architectures that enhance the robustness in complexes. The review further focuses on the way Ir(III) Complexes unite therapy and diagnostics. Due to their inherent luminescence, redox characteristics, and excited-state behaviour, these complexes enable simultaneous imaging, ROS production, microenvironment sensing, and real-time monitoring of treatment responses. By correlating structural features with activation pathways and biological outcomes, the review seeks to provide a mechanistic framework for designing smart Ir(III)-based PDT agents with improved selectivity, reduced systemic toxicity, and enhanced therapeutic precision.