Efficacy Augmentation of Ferroptosis-Inducing Nanomedicine for Tyrosine Kinase Inhibitor-Resistant Lung Cancer Brain Metastasis

Abstract Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) poses a major clinical challenge for EGFR-mutant non-small-cell lung cancer patients with brain metastasis. A key unresolved question is whether the adaptive mechanisms driving TKI resistance also confer new therapeutic vulnerabilities. Here, we reveal that TKI-resistant lung cancer brain metastatic cells develop a redox perturbation state, characterized by elevated oxidative stress and diminished antioxidant capacity, which confers a latent sensitivity to ferroptosis induction. To exploit this vulnerability, we developed MIL-S@M, a brain-targeted nanoplatform capable of efficient blood-brain barrier penetration and glutathione-responsive drug release. MIL-S@M potently induces ferroptosis through the synergistic effects of iron overload, glutathione depletion, and glutathione peroxidase 4 inactivation. In mouse models of osimertinib-resistant brain metastasis, MIL-S@M significantly suppressed tumor growth and extended survival, both as a monotherapy and in combination with osimertinib, without inducing systemic or neurotoxic effects. This work unveils a targetable adaptation in TKI-resistant brain metastasis and presents a translatable nanotherapeutic strategy.