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In this study, we synthesized a pair of silver nanoclusters with bilevel chirality, designated as\n                    <jats:italic>D<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    and\n                    <jats:italic>L<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    , which were further functionalized with polyethylene glycol (PEG) to enhance their biocompatibility, yielding\n                    <jats:italic>D<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    @PEG and\n                    <jats:italic>L<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    @PEG nanoparticles. Notably, these chiral nanoclusters show enantioselective interactions with glutathione (GSH), as evidenced by their distinct binding constants (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    ). Specifically, the\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    values for\n                    <jats:italic>L<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    are 2.47 \u00d7 10\n                    <jats:sup>7<\/jats:sup>\n                    M\n                    <jats:sup>\u22121<\/jats:sup>\n                    , while those for\n                    <jats:italic>D<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    reach 1.33 \u00d7 10\n                    <jats:sup>8<\/jats:sup>\n                    M\n                    <jats:sup>\u22121<\/jats:sup>\n                    , indicating that the\n                    <jats:italic>D<\/jats:italic>\n                    \u2010enantiomer exhibits significantly stronger GSH\u2010binding affinity. Both\n                    <jats:italic>D<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    @PEG and\n                    <jats:italic>L<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    @PEG deplete intracellular GSH in tumor cells through a ligand\u2010exchange mechanism, subsequently forming homochiral coordination supramolecular polymers (CSPs) composed of Ag(I)\u2010GSH 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,\n                    <jats:italic>D<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    @PEG demonstrates superior tumor\u2010killing efficacy in both in vitro and in vivo studies compared with\n                    <jats:italic>L<\/jats:italic>\n                    \u2010Ag\n                    <jats:sub>6<\/jats:sub>\n                    SP\n                    <jats:sub>6<\/jats:sub>\n                    @PEG, attributed to its higher GSH\u2010binding affinity. This work underscores the significance of chiral design in nanomedicines and provides valuable insights for the development of advanced chiral nanotherapeutics.\n                  <\/jats:p>","DOI":"10.1002\/anie.8981456","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:25:03Z","timestamp":1779456303000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hierarchically Chiral Silver Nanoclusters Mediated Enantioselective Glutathione Depletion and Intracellular Self\u2010Assembly for Enhanced Anticancer Therapy"],"prefix":"10.1002","volume":"65","author":[{"given":"Xuejuan","family":"Wang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Chemical Assessment and Sustainability School of Chemical Science and Engineering Advanced Research Institute Tongji University  Shanghai P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Catalysis Dalian National Laboratory For Clean Energy Dalian Institute of Chemical Physics Chinese Academy of Sciences  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaolong","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Chemical Assessment and Sustainability School of Chemical Science and Engineering Advanced Research Institute Tongji University  Shanghai P. R. 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