A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

Srinivas Ramishetti; Inbal Hazan-Halevy; Ramesh Palakuri; Sushmita Chatterjee; Somu Naidu Gonna; Niels Dammes; Inbar Freilich; Luba Kolik Shmuel; Dganit Danino; Dan Peer

doi:10.1002/adma.201906128

A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

Srinivas Ramishetti, Inbal Hazan-Halevy, Ramesh Palakuri, Sushmita Chatterjee, Somu Naidu Gonna, Niels Dammes, Inbar Freilich, Luba Kolik Shmuel, Dganit Danino, Dan Peer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

Abstract

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.

Original language	English
Article number	1906128
Journal	Advanced Materials
Volume	32
Issue number	12
DOIs	https://doi.org/10.1002/adma.201906128
State	Published - 1 Mar 2020
Externally published	Yes

Keywords

T-lymphocytes
gene silencing
lipid nanoparticles
synthetic small interfering RNA
targeted delivery

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title = "A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes",

abstract = "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.",

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author = "Srinivas Ramishetti and Inbal Hazan-Halevy and Ramesh Palakuri and Sushmita Chatterjee and {Naidu Gonna}, Somu and Niels Dammes and Inbar Freilich and {Kolik Shmuel}, Luba and Dganit Danino and Dan Peer",

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AU - Ramishetti, Srinivas

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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

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.

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A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

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Keywords

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