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

Chirality-induced biochemical response has emerged as a prominent research focus. This research demonstrates the chiral self-sorting assembly of atomically precise Au₁₆ supramolecular rings via aurophilic interactions. Enantiomers (MR,RM'R,R)-Au₁₆Cl₈ and (PS,SP'S,S)-Au₁₆Cl₈ are fabricated through homochiral self-sorting assembly and are unaffected by anion types. But the chiral self-sorting assembly of (MR,RM'A,A)-Au₁₆(PF₆)₈ and (PS,SP'A,A)-Au₁₆(PF₆)₈ in a heterochiral system is influenced by anion types. Crucially, (MR,RM'R,R)-Au₁₆Cl₈ displayed superior in vitro antitumor efficacy with IC₅₀ = 0.812 ± 0.002 µM against 4T1 cells compared to (PS,SP'S,S)-Au₁₆Cl₈ enantiomer. This enantioselectivity stems from asymmetric glutathione (GSH)-catalyzed decomposition of chiral supramolecular Au₁₆ rings in the tumor microenvironment (apparent kinetic constants: kM = 14.97 × 10⁻⁵ min⁻¹ × M⁻¹ vs. kP = 8.56 × 10⁻⁵ min⁻¹ × M⁻¹ at 8 mM GSH), releasing the thioredoxin reductase (TrxR) inhibitor dppm₂Au₂Cl₂. The chiral Au₁₆ 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. (MR,RM'R,R)-Au₁₆Cl₈ (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 Au₁₆ assemblies as promising platforms for enantioselective cancer therapy with high efficacy and low toxicity.