Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA
Abstract
In vivo delivery of large RNA molecules has significant implications for novel gene therapy, biologics delivery, and vaccine applications. We have developed cationic nanolipoprotein particles (NLPs) to enhance the complexation and delivery of large self-amplifying mRNAs (replicons) in vivo. NLPs are high-density lipoprotein (HDL) mimetics, comprised of a discoidal lipid bilayer stabilized by apolipoproteins that are readily functionalized to provide a versatile delivery platform. Herein, we systematically screened NLP assembly with a wide range of lipidic and apolipoprotein constituents, using biophysical metrics to identify lead candidates for in vivo RNA delivery. NLPs formulated with cationic lipids successfully complexed with RNA replicons encoding luciferase, provided measurable protection from RNase degradation, and promoted replicon in vivo expression. The NLP complexation of the replicon and in vivo transfection efficiency were further enhanced by modulating the type and percentage of cationic lipid, the ratio of cationic NLP to replicon, and by incorporating additive molecules.
- Authors:
- Publication Date:
- Research Org.:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; Synthetic Genomics Vaccine Inc.
- OSTI Identifier:
- 1770457
- Alternate Identifier(s):
- OSTI ID: 1605526
- Report Number(s):
- LLNL-JRNL-747570
Journal ID: ISSN 1549-9634; S154996342030006X; 102154; PII: S154996342030006X
- Grant/Contract Number:
- AC52-07NA27344
- Resource Type:
- Published Article
- Journal Name:
- Nanomedicine: Nanotechnologoy, Biology, and Medicine
- Additional Journal Information:
- Journal Name: Nanomedicine: Nanotechnologoy, Biology, and Medicine Journal Volume: 24 Journal Issue: C; Journal ID: ISSN 1549-9634
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Cationic; Nanolipoprotein particle; NLP; HDL; Self-amplifying mRNA; Replicon; in vivo delivery
Citation Formats
He, Wei, Evans, Angela C., Rasley, Amy, Bourguet, Feliza, Peters, Sandra, Kamrud, Kurt I., Wang, Nathaniel, Hubby, Bolyn, Felderman, Martina, Gouvis, Heather, Coleman, Matthew A., and Fischer, Nicholas O. Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA. United States: N. p., 2020.
Web. doi:10.1016/j.nano.2020.102154.
He, Wei, Evans, Angela C., Rasley, Amy, Bourguet, Feliza, Peters, Sandra, Kamrud, Kurt I., Wang, Nathaniel, Hubby, Bolyn, Felderman, Martina, Gouvis, Heather, Coleman, Matthew A., & Fischer, Nicholas O. Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA. United States. https://doi.org/10.1016/j.nano.2020.102154
He, Wei, Evans, Angela C., Rasley, Amy, Bourguet, Feliza, Peters, Sandra, Kamrud, Kurt I., Wang, Nathaniel, Hubby, Bolyn, Felderman, Martina, Gouvis, Heather, Coleman, Matthew A., and Fischer, Nicholas O. Sat .
"Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA". United States. https://doi.org/10.1016/j.nano.2020.102154.
@article{osti_1770457,
title = {Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA},
author = {He, Wei and Evans, Angela C. and Rasley, Amy and Bourguet, Feliza and Peters, Sandra and Kamrud, Kurt I. and Wang, Nathaniel and Hubby, Bolyn and Felderman, Martina and Gouvis, Heather and Coleman, Matthew A. and Fischer, Nicholas O.},
abstractNote = {In vivo delivery of large RNA molecules has significant implications for novel gene therapy, biologics delivery, and vaccine applications. We have developed cationic nanolipoprotein particles (NLPs) to enhance the complexation and delivery of large self-amplifying mRNAs (replicons) in vivo. NLPs are high-density lipoprotein (HDL) mimetics, comprised of a discoidal lipid bilayer stabilized by apolipoproteins that are readily functionalized to provide a versatile delivery platform. Herein, we systematically screened NLP assembly with a wide range of lipidic and apolipoprotein constituents, using biophysical metrics to identify lead candidates for in vivo RNA delivery. NLPs formulated with cationic lipids successfully complexed with RNA replicons encoding luciferase, provided measurable protection from RNase degradation, and promoted replicon in vivo expression. The NLP complexation of the replicon and in vivo transfection efficiency were further enhanced by modulating the type and percentage of cationic lipid, the ratio of cationic NLP to replicon, and by incorporating additive molecules.},
doi = {10.1016/j.nano.2020.102154},
journal = {Nanomedicine: Nanotechnologoy, Biology, and Medicine},
number = C,
volume = 24,
place = {United States},
year = {Sat Feb 01 00:00:00 EST 2020},
month = {Sat Feb 01 00:00:00 EST 2020}
}
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https://doi.org/10.1016/j.nano.2020.102154
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