Phototherapeutic Efficacy and Cell Death Pathways of Atomically Precise Chiral Au25 Nanoclusters in Tumor Therapy
Chirality profoundly influences tumor therapy by regulating key physiological processes, yet the link between chirality and therapeutic properties of atomically precise metal nanoclusters (NCs) remains poorly understood. Atomically precise Au25 NCs protected by chiral cysteine ligands (L-Au25(cys)18, D-Au25(cys)18, and Rac-Au25(cys)18) were constructed and systematically investigated to elucidate the association between chirality and tumor therapeutic performance. Although no significant difference in enzyme-like activity was observed among the three NCs, Rac-Au25(cys)18 exhibited enhanced reactive oxygen species generation under 808 nm laser irradiation, achieving superior phototherapeutic effects in both in vitro and in vivo tumor models. The chiral Au25 NCs induced distinct cell death pathways: L-Au25(cys)18 primarily triggered ferroptosis, D-Au25(cys)18 induced both ferroptosis and apoptosis, and all three NCs activated disulfidptosis. In vivo, tumor inhibition rates for L-Au25, D-Au25, and Rac-Au25 groups were 46.7%, 42.5%, and 68.3%, respectively, with no significant body weight fluctuations and minimal hepatorenal toxicity. Hematological and histopathological analyses confirmed favorable systemic biocompatibility. This work clarifies the correlation between chiral structures and tumor therapeutic performance of gold NCs, providing experimental insights and theoretical support for the design of novel chiral nanomaterials and optimization of precise tumor phototherapeutic strategies.