A Facile Supramolecular Strategy to Switch Photodynamic Pathway and Augment ROS Production of Sensitizers for Enhanced Tumor Therapy

The photosensitizers (PSs) capable of generating radical reactive oxygen species (ROS) via the type-I electron transfer pathway under photoirradiation offer a promising solution to the challenge of unsatisfactory photodynamic therapy (PDT) in hypoxic environments. Classical PSs (type-II), however, primarily transfer excited energy to ground state O2 rather than undergoing photoinduced electron transfer, posing a tough challenge in promoting the type-I pathway through existing strategies. Herein, we demonstrate a novel and straightforward approach using bioinspired supramolecular assembly to convert classical type-II PSs into type-I supramolecular PSs with augmented ROS production. The phosphate-templated assembly facilitated the formation of nanoscale aggregates with orderly and efficient packing of PSs, effectively suppressing the energy transfer pathway by promoting photoinduced charge- separation between PSs (resulting in PS+· and PS−·), thereby enhancing the generation of superoxide radicals (O2−·) through electron transfer from PS−· to O2 (Scheme 1). Additionally, this shift of photosensitization pathway also enhances overall ROS production, overcoming the typical inhibition usually associated with PS aggregation and indicating the highly efficient ROS generation via the type-I pathway. Consequently, the type-I supramolecular PSs demonstrated excellent ROS generation capability in the treatment of hypoxic tumors, thus achieving outstanding therapeutic outcomes. This study not only addresses a critical challenge in PDT under hypoxic conditions but also opens a new avenue for modifying the sensitization behavior of clinically approved type-II PSs to achieve superior therapeutic outcomes.