TY - JOUR
T1 - A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes
AU - Ramishetti, Srinivas
AU - Hazan-Halevy, Inbal
AU - Palakuri, Ramesh
AU - Chatterjee, Sushmita
AU - Naidu Gonna, Somu
AU - Dammes, Niels
AU - Freilich, Inbar
AU - Kolik Shmuel, Luba
AU - Danino, Dganit
AU - Peer, Dan
N1 - Funding Information:
S.R., I.H., and R.P. contributed equally to this work. This work was supported in part from the Momentum fund at Tel Aviv University and the Lewis Trust for blood cancer awarded to D.P.
Publisher Copyright:
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Lipid nanoparticles (LNPs) are the most advanced nonviral platforms for small interfering RNA (siRNA) delivery that are clinically approved. These LNPs, based on ionizable lipids, are found in the liver and are now gaining much attention in the field of RNA therapeutics. The previous generation of ionizable lipids varies in linker moieties, which greatly influences in vivo gene silencing efficiency. Here novel ionizable amino lipids based on the linker moieties such as hydrazine, hydroxylamine, and ethanolamine are designed and synthesized. These lipids are formulated into LNPs and screened for their efficiency to deliver siRNAs into leukocytes, which are among the hardest to transfect cell types. Two potent lipids based on their in vitro gene silencing efficiencies are also identified. These lipids are further evaluated for their biodistribution profile, efficient gene silencing, liver toxicity, and potential immune activation in mice. A robust gene silencing is also found in primary lymphocytes when one of these lipids is formulated into LNPs with a pan leukocyte selective targeting agent (β7 integrin). Taken together, these lipids have the potential to open new avenues in delivering RNAs into leukocytes.
AB - Lipid nanoparticles (LNPs) are the most advanced nonviral platforms for small interfering RNA (siRNA) delivery that are clinically approved. These LNPs, based on ionizable lipids, are found in the liver and are now gaining much attention in the field of RNA therapeutics. The previous generation of ionizable lipids varies in linker moieties, which greatly influences in vivo gene silencing efficiency. Here novel ionizable amino lipids based on the linker moieties such as hydrazine, hydroxylamine, and ethanolamine are designed and synthesized. These lipids are formulated into LNPs and screened for their efficiency to deliver siRNAs into leukocytes, which are among the hardest to transfect cell types. Two potent lipids based on their in vitro gene silencing efficiencies are also identified. These lipids are further evaluated for their biodistribution profile, efficient gene silencing, liver toxicity, and potential immune activation in mice. A robust gene silencing is also found in primary lymphocytes when one of these lipids is formulated into LNPs with a pan leukocyte selective targeting agent (β7 integrin). Taken together, these lipids have the potential to open new avenues in delivering RNAs into leukocytes.
KW - T-lymphocytes
KW - gene silencing
KW - lipid nanoparticles
KW - synthetic small interfering RNA
KW - targeted delivery
KW - Humans
KW - Transfection/methods
KW - Lipids/chemistry
KW - Leukocytes/cytology
KW - Fluorescent Dyes/chemistry
KW - RNA Interference
KW - Integrin beta Chains/chemistry
KW - RNA, Small Interfering/chemistry
KW - Nanoparticles/chemistry
KW - Cell Line, Tumor
KW - Microscopy, Fluorescence
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U2 - 10.1002/adma.201906128
DO - 10.1002/adma.201906128
M3 - Article
C2 - 31999380
AN - SCOPUS:85078860233
SN - 0935-9648
VL - 32
SP - e1906128
JO - Advanced Materials
JF - Advanced Materials
IS - 12
M1 - 1906128
ER -