A polymeric nanocarrier platform was developed to enable efficient, non-invasive delivery of mRNA to the brain following systemic administration, overcoming long-standing barriers imposed by blood instability and the blood–brain barrier. Through precise molecular engineering, the system integrates three critical functions: circulatory stability, brain translocation, and intracellular trafficking into a single design. The nanocarriers stabilize mRNA via combined electrostatic and hydrophobic interactions, while pH-responsive features drive endosomal escape and enhance cytoplasmic availability for translation. Targeted surface functionalization further promotes selective brain accumulation. This coordinated optimization results in an approximately tenfold increase in protein expression in the brain while minimizing off-target effects in peripheral tissues. By establishing a unifying design principle for extrahepatic mRNA delivery, this work expands the therapeutic reach of mRNA beyond the liver and positions systemic brain-targeted delivery as a viable strategy for treating central nervous system disorders.
Papers
Journal: Molecular Pharmaceutics
Title: Ionizable polymeric micelles targeting transferrin receptor 1 enhance systemic mRNA delivery to the brain
Authors: Jumpei Norimatsu, Hayato Mizuno, Yuki Mochida, Shigeto Fukushima, Satoshi Uchida, Horacio Cabral, Yasutaka Anraku
Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans
