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Tailoring HDL mimetics for in vivo delivery of mRNA
Author(s) -
He Wei,
Rasley Amy,
Gilmore Sean F.,
Peters Sandra,
Coleman Matthew A.,
Fischer Nicholas O.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04308
Subject(s) - in vivo , rna , nucleic acid , messenger rna , rnase p , replicon , chemistry , rnase h , oligonucleotide , microbiology and biotechnology , biophysics , biochemistry , biology , dna , gene , genetics , plasmid
In vivo delivery of nucleic acid‐based therapeutics utilizing messenger RNA (mRNA) has significant implications for gene therapy, counteragent delivery, and vaccine applications. The mRNA therapeutics harness the body’s own cells to produce and deliver therapeutic protein molecules. However, large RNA molecules are prone to RNase degradation and exhibit marked difficulty in in vivo delivery compared with smaller RNA molecules. We have successfully engineered reconstituted high‐density lipoproteins (termed nanolipoprotein particles, NLPs) to deliver self‐amplifying mRNA (aka. Replicon) constructs in vivo . NLPs are nanometer‐scale, discoidal particles. They are safe, non‐immunogenic, and amenable to multiple routes of delivery. Also, the size and surface chemistry of NLPs allow for facile optimization of the delivery of compounds with wide range of physicochemical properties. To tailor NLPs for in vivo delivery of large nucleic acids molecules, a panel of NLPs formulated with a wide range of cationic lipids and assembly constituents were screened. Cationic lipids confer NLPs positive charge which successfully complexed with RNA Replicons encoding luciferase, provided protection from RNase degradation, and enhanced mRNA in vivo expression efficiency. These results represent the experimental foundation of utilizing the NLP technology to advance for RNA delivery. Future efforts focus on elucidating the correlation of NLP composition, NLP‐Replicon structure, and in vivo efficacy that will eventually allow for the rational design of a highly potent in vivo delivery platform that can be used as a universal mRNA delivery technology. Support or Funding Information This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE‐AC52‐07NA27344, through LDRD award 20‐ERD‐004. This work was also supported by U19 AI144184 from the National Institute of Allergy and Infectious Diseases