TY - JOUR
T1 - Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA
AU - He, Wei
AU - Evans, Angela C.
AU - Rasley, Amy
AU - Bourguet, Feliza
AU - Peters, Sandra
AU - Kamrud, Kurt I.
AU - Wang, Nathaniel
AU - Hubby, Bolyn
AU - Felderman, Martina
AU - Gouvis, Heather
AU - Coleman, Matthew A.
AU - Fischer, Nicholas O.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - Cationic
KW - HDL
KW - in vivo delivery
KW - Nanolipoprotein particle
KW - NLP
KW - Replicon
KW - Self-amplifying mRNA
UR - http://www.scopus.com/inward/record.url?scp=85078967402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078967402&partnerID=8YFLogxK
U2 - 10.1016/j.nano.2020.102154
DO - 10.1016/j.nano.2020.102154
M3 - Article
C2 - 31982617
AN - SCOPUS:85078967402
VL - 24
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
SN - 1549-9634
M1 - 102154
ER -