Metabolic GLUT1 Priming with Disulfide-Stabilized Micelles Enables Noninvasive mRNA Delivery across the Blood–Brain Barrier

The blood-brain barrier (BBB) remains the single most obstructive bottleneck to mRNA therapeutics for central nervous system (CNS) disorders. Here we introduce a metabolically primed, redox-locked nanoplatform that converts the brain's glucose addiction into a gate-cracking key. A disulfide-stabilized, glucose-decorated block-cationic copolymer self-assembles with mRNA into 36 nm micelles (ζ potential approximately +4.5 mV) that withstand serum nucleases and polyanionic assault yet disassemble on cytosolic glutathione. Fasting-induced GLUT1 upregulation (4.2-fold) is exploited as a transiently overexpressed "receptor"; a subsequent glycemic spike drives receptor-mediated transcytosis, yielding 160-fold higher cerebral mRNA accumulation versus untargeted controls. Single-cell intravital imaging confirms parenchymal penetration within 120 min and pan-brain GFP expression. The strategy affords spatiotemporally sharp CNS transfection without BBB disruption or systemic toxicity, offering a generalizable, nonviral avenue for genomic medicine of neurological diseases.