Chiral Self‐Sorting Assembly of Au ₁₆ Rings for Cancer Therapy via Enantioselectivity‐Induced Ferroptosis and Apoptosis

ABSTRACT Chirality‐induced biochemical response has emerged as a prominent research focus. This research demonstrates the chiral self‐sorting assembly of atomically precise Au 16 supramolecular rings via aurophilic interactions. Enantiomers ( M R,R M’ R,R )‐Au 16 Cl 8 and ( P S,S P’ S,S )‐Au 16 Cl 8 are fabricated through homochiral self‐sorting assembly and are unaffected by anion types. But the chiral self‐sorting assembly of ( M R,R M’ A,A )‐Au 16 (PF 6 ) 8 and ( P S,S P’ A,A )‐Au 16 (PF 6 ) 8 in a heterochiral system is influenced by anion types. Crucially, ( M R,R M’ R,R )‐Au 16 Cl 8 displayed superior in vitro antitumor efficacy with IC 50 = 0.812 ± 0.002 µM against 4T1 cells compared to ( P S,S P’ S,S )‐Au 16 Cl 8 enantiomer. This enantioselectivity stems from asymmetric glutathione (GSH)‐catalyzed decomposition of chiral supramolecular Au 16 rings in the tumor microenvironment (apparent kinetic constants: k M = 14.97 × 10 −5 min −1 × M −1 vs. k P = 8.56 × 10 −5 min −1 × M −1 at 8 mM GSH), releasing the thioredoxin reductase (TrxR) inhibitor dppm 2 Au 2 Cl 2 . The chiral Au 16 rings induce dual cell death via TrxR‐inhibition‐mediated apoptosis and GPX4‐suppression‐driven ferroptosis, validated by ROS (reactive oxygen species) accumulation, lipid peroxidation and caspase‐3 activation. ( M R,R M’ R,R )‐Au 16 Cl 8 (20 mg/kg) achieved 55.4% tumor growth inhibition in 4T1‐bearing mice with no detectable organ toxicity, outperforming auranofin in biosafety. This work establishes chiral self‐sorting Au 16 assemblies as promising platforms for enantioselective cancer therapy with high efficacy and low toxicity.