Modified self-amplifying RNA mediates robust and prolonged gene expression in the mouse and ex vivo human brain

Nov 24, 2025bioRxiv : the preprint server for biology

Modified self-amplifying RNA produces strong and long-lasting gene activity in the mammalian brain

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Abstract

Modified saRNA encapsulated in lipid nanoparticles achieves robust and long-lasting protein expression in brain cells for over five weeks.

  • Substituting cytidine with 5-hydroxymethylcytidine reduces innate immune responses.
  • saRNA-LNPs lead to detectable protein expression in some neurons at three months post-injection.
  • The formulation containing ALC-0315 shows superior performance compared to N1mΨ mRNA.
  • saRNA-LNPs effectively transfect astrocytes and neurons at the injection site, and can label neurons retrogradely.
  • This approach represents a promising nonviral method for gene delivery in the brain.

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Full Text

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