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Customizable Lipid Nanoparticle Materials for the Delivery of siRNAs and mRNAs
Author(s) -
Fenton Owen S.,
Kauffman Kevin J.,
McClellan Rebecca L.,
Kaczmarek James C.,
Zeng Manhao D.,
Andresen Jason L.,
Rhym Luke H.,
Heartlein Michael W.,
DeRosa Frank,
Anderson Daniel G.
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201809056
Subject(s) - gene silencing , small interfering rna , messenger rna , rna interference , linker , in vivo , rna , chemistry , in vitro , luciferase , microbiology and biotechnology , gene expression , nanotechnology , computational biology , biology , gene , transfection , biochemistry , materials science , computer science , operating system
Abstract RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid materials influences LNP potency with siRNAs and mRNAs. Eight lipid materials are synthesized, and 16 total formulations are screened for activity in vitro; the lead material is evaluated with mRNA for in vivo use and demonstrates luciferase protein expression in the spleen. In undertaking this approach, not only do we develop synthetic routes to delivery materials, but we also reveal structural criteria that could be useful for developing next‐generation delivery materials for RNA therapeutics.