Hierarchically Chiral Silver Nanoclusters Mediated Enantioselective Glutathione Depletion and Intracellular Self-Assembly for Enhanced Anticancer Therapy.

Chiral nanomedicine design benefits from understanding enantioselective interactions between hierarchically chiral nanoclusters and tumor biomarkers. In this study, we synthesized a pair of silver nanoclusters with bilevel chirality, designated as D-Ag6SP6 and L-Ag6SP6, which were further functionalized with polyethylene glycol (PEG) to enhance their biocompatibility, yielding D-Ag6SP6@PEG and L-Ag6SP6@PEG nanoparticles. Notably, these chiral nanoclusters show enantioselective interactions with glutathione (GSH), as evidenced by their distinct binding constants (Ka). Specifically, the Ka values for L-Ag6SP6 are 2.47 × 107 M-1, while those for D-Ag6SP6 reach 1.33 × 108 M-1, indicating that the D-enantiomer exhibits significantly stronger GSH-binding affinity. Both D-Ag6SP6@PEG and L-Ag6SP6@PEG deplete intracellular GSH in tumor cells through a ligand-exchange mechanism, subsequently forming homochiral coordination supramolecular polymers (CSPs) composed of Ag(I)-GSH complexes. Following adequate aging, these CSPs aggregate into microscale fibers that induce mitochondrial mechanical damage, leading to a significant increase in intracellular reactive oxygen species (ROS) levels, which ultimately induces apoptosis and ferroptosis of tumor cells. Consistently, D-Ag6SP6@PEG demonstrates superior tumor-killing efficacy in both in vitro and in vivo studies compared with L-Ag6SP6@PEG, attributed to its higher GSH-binding affinity. This work underscores the significance of chiral design in nanomedicines and provides valuable insights for the development of advanced chiral nanotherapeutics.