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

Background
EGFR-mutant NSCLC brain metastasis with acquired TKI resistance remains a hard niche. Resistant cells show redox perturbation: elevated ROS, weakened antioxidant capacity, upregulated NOX4/NOX2, and a suppressed xCT-GSH-GPX4 axis, creating a latent ferroptosis vulnerability. Existing ferroptosis inducers are limited by poor blood-brain barrier crossing, low brain accumulation, and uncontrolled release. The key direction is brain-targeted delivery to intracranial resistant foci.

Innovation
This work turns resistance-associated redox adaptation into a targetable weakness. MIL-S@M uses a PMPC shell mimicking acetylcholine to hitchhike choline transporter and α7 nicotinic acetylcholine receptor-mediated transcytosis across the blood-brain barrier, plus disulfide crosslinks for GSH-responsive release. Iron overload drives Fenton reactions, sorafenib blocks xCT, and GSH depletion with GPX4 inactivation amplifies lipid peroxidation. In mouse brain metastasis models, MIL-S@M alone and with osimertinib suppressed intracranial growth and prolonged survival, with no obvious systemic or neural toxicity. Brain targeting is the core.

Materials
MIL-100(Fe) MOF core loaded with sorafenib forms MIL-S, wrapped by a crosslinked PMPC shell to give MIL-S@M. TEM shows a core-shell structure; DLS is about 134.5 nm; zeta is near neutral; serum stability lasts 7 days. XPS/FTIR/XRD/BET confirm payload loading and shell coating; loading is about 13.55%, encapsulation about 54.22%. Rapid release occurs under high GSH, with low leakage without GSH. The PMPC shell prolongs circulation and actively targets brain endothelium, boosting brain and tumor-site accumulation.

Note: This is only a frontier update for sharing and does not constitute any related advice.

#BrainTargeting #Ferroptosis #TKIResistance #LungCancerBrainMetastasis #MOF #NanoDelivery #GSHResponsive #PMPC #RedoxVulnerability

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