Cited by 312RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvancements in Transdermal Drug Delivery

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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.·2019·Small

DOI 10.1002/smll.201805097

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Abstract

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, 306O 10 and 306O i10 , 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 306O 10 tail is straight and the 306O i10 tail has a one‐carbon branch. Remarkably, this small difference in structure conferred a tenfold improvement in 306O i10 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 O i10 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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Authors: Hajj, K. A., Ball, R. L., Deluty, S. B., Singh, S. R., Strelkova, D., Knapp, C. M., & Whitehead, K. A.
Affiliations: Carnegie Mellon University (US)
Corresponding author: Whitehead, Kathryn A.
ORCID: Singh, Shridhar R.
Whitehead, Kathryn A.
Venue: Small
Publisher: Wiley
Published: 2019-01-13
Volume: 15
Issue: 6
Pages: e1805097-e1805097
ISSN: 1613-6810 (ISSN-L)
1613-6829
DOI: 10.1002/smll.201805097
OpenAlex: W2908627286
Cited by: 312
References: 32
Citations by year: 2026: 37 · 2025: 62 · 2024: 61 · 2023: 47 · 2022: 45 · 2021: 30 · 2020: 22 · 2019: 8
FWCI: 8.68
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#am (am, 365 d)
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Small (publishedVersion)
PubMed (publishedVersion)
Funders: Defense Advanced Research Projects Agency (D16AP00143)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
Keywords: mRNA delivery, surface ionization, endosomal pH, mRNA therapeutics, structure-function relationship, luciferase expression
MeSH terms: Animals, Female, Hydrogen-Ion Concentration, Ions, Lipids, Mice, Inbred C57BL, Endosomes, RNA, Messenger, Tissue Distribution, Gene Transfer Techniques, Nanoparticles

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Branched‐Tail Lipid Nanoparticles Potently Deliver mRNA In Vivo due to Enhanced Ionization at Endosomal pH

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