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Metabolic GLUT1 Priming with Disulfide-Stabilized Micelles Enables Noninvasive mRNA Delivery across the Blood-Brain
Yanhua Li1,2, Xia Cheng3, Yue Wang4,5,6
1Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116011, China.
None:
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.
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