Activatable and multifunctional supramolecular photosensitizers via macrocycle-based host-guest interactions:...

Photodynamic therapy (PDT) has emerged as a novel therapeutic approach to treat tumors, bacterial infections and various other diseases. To further improve the safety and efficacy of PDT, diverse photosensitizers (PSs) have been designed to improve reactive oxygen species (ROS) generation, promote targeted accumulation and activation, reduce off-target toxicity and dark toxicity, and enable synergistic multimodal therapy. Among these advances, supramolecular PSs constructed via host-guest inclusion with macrocycles (e.g., cyclodextrins, calixarenes, cucurbiturils, and pillararenes) offer unique advantages, such as enhanced solubility, inhibited aggregation, controlled nano-assembly, versatile functionalization and smart functionality. Recent progress has demonstrated that host-guest interactions can be harnessed to reduce oxygen dependence, accelerate post-PDT degradation, construct activatable PSs responsive to competitive binding at lesion sites, and modularly integrate targeting, imaging, or therapeutic elements into nano-PSs in a "Lego-like" manner. This feature article reviews these emerging strategies, highlighting how macrocycle-based host-guest chemistry provides a universal platform for the rational construction of safe and efficient PSs to advance the clinical potential of PDT.