A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems.
Aldehydes
/ chemistry
Chromatography, Liquid
Drug Delivery Systems
Humans
Ions
/ chemistry
Lipids
/ chemistry
Liposomes
/ chemistry
Nanoparticles
/ chemistry
Nucleosides
/ chemistry
Oxidation-Reduction
Protein Biosynthesis
RNA Stability
RNA, Messenger
/ chemistry
Vaccine Potency
mRNA Vaccines
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 11 2021
22 11 2021
Historique:
received:
22
06
2021
accepted:
28
09
2021
entrez:
23
11
2021
pubmed:
24
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Lipid nanoparticle (LNP)-formulated mRNA vaccines were rapidly developed and deployed in response to the SARS-CoV-2 pandemic. Due to the labile nature of mRNA, identifying impurities that could affect product stability and efficacy is crucial to the long-term use of nucleic-acid based medicines. Herein, reversed-phase ion pair high performance liquid chromatography (RP-IP HPLC) was used to identify a class of impurity formed through lipid:mRNA reactions; such reactions are typically undetectable by traditional mRNA purity analytical techniques. The identified modifications render the mRNA untranslatable, leading to loss of protein expression. Specifically, electrophilic impurities derived from the ionizable cationic lipid component are shown to be responsible. Mechanisms implicated in the formation of reactive species include oxidation and subsequent hydrolysis of the tertiary amine. It thus remains critical to ensure robust analytical methods and stringent manufacturing control to ensure mRNA stability and high activity in LNP delivery systems.
Identifiants
pubmed: 34811367
doi: 10.1038/s41467-021-26926-0
pii: 10.1038/s41467-021-26926-0
pmc: PMC8608879
doi:
Substances chimiques
Aldehydes
0
Ions
0
Lipid Nanoparticles
0
Lipids
0
Liposomes
0
Nucleosides
0
RNA, Messenger
0
mRNA Vaccines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6777Informations de copyright
© 2021. The Author(s).
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