Rational design of lipid nanoparticles for brain delivery of RNA therapeutics
Summary
Effective delivery of RNA therapeutics to the brain remains challenging due to the multiple barriers of the central nervous system (CNS). To probe molecular scaffolds that could help overcome these barriers, we analysed the pharmaceutical profiles of over 100 CNS-active drugs and identified hydroxyzine (HX) as a promising scaffold for designing ionizable lipids with improved brain-targeting properties. Specifically, HX1 liquid nanoparticles (LNPs) achieved robust mRNA delivery to the brain through multiple trafficking pathways across CNS barriers.
Effective delivery of RNA therapeutics to the brain remains challenging due to the multiple barriers of the central nervous system (CNS). To probe molecular scaffolds that could help overcome these barriers, we analysed the pharmaceutical profiles of over 100 CNS-active drugs and identified hydroxyzine (HX) as a promising scaffold for designing ionizable lipids with improved brain-targeting properties. Specifically, HX1 liquid nanoparticles (LNPs) achieved robust mRNA delivery to the brain through multiple trafficking pathways across CNS barriers. HX1 LNPs also enabled efficient gene editing in mouse brains via co-delivery of CRISPR mRNA and guide RNA and effectively delivered luciferase mRNA to the brain of a non-human primate. Moreover, HX1 LNPs carrying Il10 mRNA mitigated radiation-induced brain injury in mice, highlighting their potential for preventive treatment in the presence of intact CNS barriers. These findings establish HX1 LNPs as a promising translational platform for delivering therapeutic mRNAs and genome-editing components to the brain.
Abstract from PubMed (PMID 42977805). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.
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