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Branched-Tail Lipid Nanoparticles Potently Deliver mRNA In Vivo due to Enhanced Ionization at Endosomal pH.
Hajj, Khalid A; Ball, Rebecca L; Deluty, Sarah B; Singh, Shridhar R; Strelkova, Daria; Knapp, Christopher M; Whitehead, Kathryn A.
Afiliação
  • Hajj KA; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
  • Ball RL; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
  • Deluty SB; Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
  • Singh SR; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
  • Strelkova D; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
  • Knapp CM; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
  • Whitehead KA; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
Small ; 15(6): e1805097, 2019 02.
Article em En | MEDLINE | ID: mdl-30637934
The potential of mRNA therapeutics will be realized only once safe and effective delivery systems are established. Unfortunately, delivery vehicle development is stymied by an inadequate understanding of how the molecular properties of a vehicle confer efficacy. Here, a small library of lipidoid materials is used to elucidate structure-function relationships and identify a previously unappreciated parameter-lipid nanoparticle surface ionization-that correlates with mRNA delivery efficacy. The two most potent materials of the library, 306O10 and 306Oi10 , induce substantial luciferase expression in mice following a single 0.75 mg kg-1 mRNA dose. These lipidoids, which have ten-carbon tails and identical molecular weights, vary only in that the 306O10 tail is straight and the 306Oi10 tail has a one-carbon branch. Remarkably, this small difference in structure conferred a tenfold improvement in 306Oi10 efficacy. The enhanced potency of this branched-tail lipidoid is attributed to its strong surface ionization at the late endosomal pH of 5.0. A secondary lipidoid library confirms that Oi10 materials ionize more strongly and deliver mRNA more potently than lipidoids containing linear tails. Together, these data highlight the exquisite control that lipid chemistry exerts on the mRNA delivery process and show that branched-tail lipids facilitate protein expression in animals.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Endossomos / RNA Mensageiro / Técnicas de Transferência de Genes / Nanopartículas / Lipídeos Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Endossomos / RNA Mensageiro / Técnicas de Transferência de Genes / Nanopartículas / Lipídeos Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article