Optimizing Photosensitizers with Type I and Type II ROS Generation Through Modulating Triplet Lifetime and Intersystem Crossing Efficiency

Abstract Organic photosensitizers (PSs) can generate reactive oxygen species (ROS) via electron transfer (type I) and energy transfer (type II) pathways during photodynamic therapy (PDT). However, although numerous organic PSs have been constructed, the methods to optimize both type I and type II ROS generation are still not well explored. In this work, molecular engineering is applied to design three new organic PSs with varying triplet lifetimes and intersystem crossing (ISC) efficiency to achieve highly efficient type I&II ROS generation. The results reveal that after coated into nanoparticles (NPs) with DSPE‐PEG2000‐Biotin, the PS of mBDP‐PyH with the longest triplet lifetime and moderate ISC efficiency possesses good type II ROS and moderate type I ROS generation. With other properties being similar, the PS of mBDP‐2Py exhibits a shorter triplet lifetime, accompanied by concurrently reduced ROS generation for both types inside NPs. In contrast, the most potent PS of mBDP‐PyBr exhibits the shortest triplet lifetime but highly efficient ISC, with its NPs showing superior type I&II ROS generation. Moreover, both in vitro and in vivo experiments indicate that mBDP‐PyBr NPs display outstanding light toxicity under normoxic and hypoxic conditions. Overall, this study provides valuable guidance in designing effective organic PSs for PDT.