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In the present work, we introduce a biomimetic nanotherapeutic that integrates single\u2010atom iron nanocatalysts (FeSA) co\u2010loaded with a CRISPR\u2010Cas9 plasmid targeting\n                    <jats:italic>Glutathione Peroxidase 4<\/jats:italic>\n                    (\n                    <jats:italic>Gpx4<\/jats:italic>\n                    ), the key regulator of ferroptosis, and is camouflaged with a homologous cancer cell membrane to ensure precise tumor tropism and excellent biocompatibility. In an orthotopic LAR\u2010TNBC model, the nanotherapeutic achieved \u223c98% tumor regression and markedly extended survival. Comprehensive mechanistic analyses confirmed efficient on\u2010target\n                    <jats:italic>Gpx4<\/jats:italic>\n                    disruption, which synergistically amplified the FeSA\u2010catalyzed ferroptotic cascade. Unbiased transcriptomic profiling further revealed extensive reprogramming of the tumor molecular landscape, resulting in significant cancer cell ferroptosis by DNA damage response and p53 signaling pathway activation. This work establishes a highly synergistic and targeted approach, presenting a potent therapeutic modality for aggressive and chemoresistant malignancies.\n                  <\/jats:p>","DOI":"10.1002\/adma.75199","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:19:27Z","timestamp":1791353967000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR Nanomachinery\u2010Sensitized Nanocatalytic Tumor Ferroptosis in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","author":[{"given":"Yuemei","family":"Wang","sequence":"first","affiliation":[{"name":"Putuo People's Hospital Shanghai Frontiers Science Center of Nanocatalytic Medicine The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Tongji University  Shanghai P. R. China"},{"name":"Shanghai Tenth People's Hospital  Shanghai P. R. 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