Phototherapeutic Efficacy and Cell Death Pathways of Atomically Precise Chiral Au25 Nanoclusters in Tumor Therapy

• • Rac-Au25(cys)18 achieved a tumor inhibition rate of 68.3% in vivo under 808 nm laser irradiation (10 min), significantly outperforming L-Au25 (46.7%) and D-Au25 (42.5%), establishing racemic nanoclusters as superior phototherapeutic agents for clinical translation. • • All three chiral Au25 NCs exhibited comparable intrinsic enzyme-like activities, yet Rac-Au25 displayed enhanced ROS generation under NIR irradiation, indicating that chirality modulates photosensitization rather than catalytic activity, a critical distinction for designing targeted therapies. • • L-Au25 preferentially induced ferroptosis, D-Au25 co-induced ferroptosis and apoptosis, and all three activated disulfidptosis, revealing chirality-dependent cell death pathway engagement that can be exploited to overcome apoptosis resistance in tumors. • • No significant body weight fluctuations, minimal hepatorenal toxicity (ALT, CR, UR, T-CHO comparable to PBS), and no morphological damage to major organs were observed, confirming favorable systemic biocompatibility and a wide therapeutic window for Au25 NCs.