CRISPR Nanomachinery‐Sensitized Nanocatalytic Tumor Ferroptosis in Triple‐Negative Breast Cancer

ABSTRACT The luminal androgen receptor (LAR) subtype of triple‐negative breast cancer (TNBC) represents a formidable therapeutic challenge, necessitating sophisticated strategies that exploit unique tumor vulnerabilities. In the present work, we introduce a biomimetic nanotherapeutic that integrates single‐atom iron nanocatalysts (FeSA) co‐loaded with a CRISPR‐Cas9 plasmid targeting Glutathione Peroxidase 4 ( Gpx4 ), 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‐TNBC model, the nanotherapeutic achieved ∼98% tumor regression and markedly extended survival. Comprehensive mechanistic analyses confirmed efficient on‐target Gpx4 disruption, which synergistically amplified the FeSA‐catalyzed 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.