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On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device

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Title: On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device
Authors: Okuda, Kento Browse this author
Sato, Yusuke Browse this author →KAKEN DB
Iwakawa, Kazuki Browse this author
Sasaki, Kosuke Browse this author
Okabe, Nana Browse this author
Maeki, Masatoshi Browse this author
Tokeshi, Manabu Browse this author →KAKEN DB
Harashima, Hideyoshi Browse this author →KAKEN DB
Keywords: Size-regulation
DLVO theory
Hofmeister series
RNA delivery
Lipid nanoparticles
Microfluidic device
Issue Date: Aug-2022
Publisher: Elsevier
Journal Title: Journal of controlled release
Volume: 348
Start Page: 648
End Page: 659
Publisher DOI: 10.1016/j.jconrel.2022.06.017
Abstract: The use of lipid nanoparticles (LNPs) for nucleic acid delivery is now becoming a promising strategy with a number of clinical trials as vaccines or as novel therapies against a variety of genetic and infectious diseases. The use of microfluidics for the synthesis of the LNPs has attracted interest because of its considerable advantages over other conventional synthetic methods including scalability, reproducibility, and speed. However, despite the potential usefulness of large particles for nucleic acid delivery to dendritic cells (DCs) as a vaccine, the particle size of the LNPs prepared using microfluidics is typically limited to approximately from 30 to 100 nm. In this study, focusing on Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, the effect of some synthetic parameters, including total flow rate, flow rate ratio, buffer pH, lipid concentration, molar ratio of PEG-lipid as well as salt concentration, on particle size was systematically examined by means of the design of experiment approaches. The findings indicated that the simple addition of salt (e.g. NaCl) to a buffer containing nucleic acids contributed greatly to the synthesis of large LNPs over 200 nm and this effect was concentration-dependent with respect to the salt. The effect of salt on particle size was consistent with a Hofmeister series. The systemic injection of larger mRNA-loaded LNPs resulted in a higher transgene expression in mouse splenic DCs, a higher activation of various splenic immune cells, and had a superior effect as a therapeutic cancer vaccine in a syngeneic mouse model compared to the smaller-sized counterpart with constant lipid composition prepared with lower NaCl concentration. Collectively, size-regulation by the simple addition of salt is a promising strategy for developing potent LNPs.
Rights: ©2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 佐藤 悠介

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