Engineered copper-doped gold nanoclusters supported ROS prolongation for enhanced photodynamic therapy

Photodynamic therapy (PDT) is a minimally invasive anti-tumor treatment modality that relies on the cytotoxicity of reactive oxygen species (ROS) produced by light-activated photosensitizers. However, traditional photosensitizers only produce ROS upon photoexcitation, resulting in limited treatment duration of ROS, which largely restricts the therapeutic efficacy of PDT. To address such limitation, here we engineered a copper doped gold nanoclusters with holo-transferrin (Tf) as ligand (Tf@ACNCs), realizing the generation of superoxide anions (O 2 − ) under irradiation and the sustained production of hydroxyl radicals ( OH) without any limitations on photoexcitation periods. Specifically, benefiting from copper doping, Tf@ACNCs exhibit a lower highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap, which is favorable for easier photoexcitation, and a lower Gibbs free energy barrier, which is conducive to stronger peroxidase (POD)-like catalysis compared to undoped gold nanoclusters (Tf@AuNCs). Therefore, Tf@ACNCs can significantly prolong the ROS generation for up to 6 h following irradiation through its multi-source ROS generation capability. Moreover, the prolongation of ROS effectively promoted ferroptosis and apoptosis, achieving a 41.38 % improvement in the anti-tumor efficacy of Tf@ACNCs compared with Tf@AuNCs. Overall, this ROS prolongation strategy affords a novel reference for enhancing PDT.