Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Zongyi Li; Jessica Carter; Luis Santos; Carl  Webster; Christopher F van der Walle; Peixun Li; Sarah E. Rogers; Jian Ren Lu

doi:10.1021/acsnano.2c06213

Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Zongyi Li, Jessica Carter, Luis Santos, Carl Webster, Christopher F van der Walle, Peixun Li, Sarah E. Rogers, Jian Ren Lu

Biological Physics Group

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

Abstract

The rational design of lipid nanoparticles (LNPs) for enhanced gene delivery remains challenging because of incomplete knowledge of their formulation–structure relationship that impacts their intracellular behavior and consequent function. Small-angle neutron scattering has been used in this work to investigate the structure of LNPs encapsulating plasmid DNA upon their acidification (from pH 7.4 to 4.0), as would be encountered during endocytosis. The results revealed the acidification-induced structure evolution (AISE) of the LNPs on different dimension scales, involving protonation of the ionizable lipid, volume expansion and redistribution of aqueous and lipid components. A similarity analysis using an LNP’s structural feature space showed a strong positive correlation between function (measured by intracellular luciferase expression) and the extent of AISE, which was further enhanced by the fraction of …

Original language	English
Pages (from-to)	979-990
Number of pages	12
Journal	ACS Nano
Volume	17
Issue number	2
DOIs	https://doi.org/10.1021/acsnano.2c06213
Publication status	Published - 6 Jan 2023

Keywords

lipid nanoparticles
nonviral gene delivery
small-angle neutron scattering
cellular expression
acidification-induced structure evolution (AISE)

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10.1021/acsnano.2c06213

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title = "Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections",

abstract = "The rational design of lipid nanoparticles (LNPs) for enhanced gene delivery remains challenging because of incomplete knowledge of their formulation–structure relationship that impacts their intracellular behavior and consequent function. Small-angle neutron scattering has been used in this work to investigate the structure of LNPs encapsulating plasmid DNA upon their acidification (from pH 7.4 to 4.0), as would be encountered during endocytosis. The results revealed the acidification-induced structure evolution (AISE) of the LNPs on different dimension scales, involving protonation of the ionizable lipid, volume expansion and redistribution of aqueous and lipid components. A similarity analysis using an LNP{\textquoteright}s structural feature space showed a strong positive correlation between function (measured by intracellular luciferase expression) and the extent of AISE, which was further enhanced by the fraction of …",

keywords = "lipid nanoparticles, nonviral gene delivery, small-angle neutron scattering, cellular expression, acidification-induced structure evolution (AISE)",

author = "Zongyi Li and Jessica Carter and Luis Santos and Carl Webster and {van der Walle}, {Christopher F} and Peixun Li and Rogers, {Sarah E.} and Lu, {Jian Ren}",

year = "2023",

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journal = "ACS Nano",

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T1 - Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

AU - Li, Zongyi

AU - Carter, Jessica

AU - Santos, Luis

AU - Webster, Carl

AU - van der Walle, Christopher F

AU - Li, Peixun

AU - Rogers, Sarah E.

AU - Lu, Jian Ren

PY - 2023/1/6

Y1 - 2023/1/6

N2 - The rational design of lipid nanoparticles (LNPs) for enhanced gene delivery remains challenging because of incomplete knowledge of their formulation–structure relationship that impacts their intracellular behavior and consequent function. Small-angle neutron scattering has been used in this work to investigate the structure of LNPs encapsulating plasmid DNA upon their acidification (from pH 7.4 to 4.0), as would be encountered during endocytosis. The results revealed the acidification-induced structure evolution (AISE) of the LNPs on different dimension scales, involving protonation of the ionizable lipid, volume expansion and redistribution of aqueous and lipid components. A similarity analysis using an LNP’s structural feature space showed a strong positive correlation between function (measured by intracellular luciferase expression) and the extent of AISE, which was further enhanced by the fraction of …

AB - The rational design of lipid nanoparticles (LNPs) for enhanced gene delivery remains challenging because of incomplete knowledge of their formulation–structure relationship that impacts their intracellular behavior and consequent function. Small-angle neutron scattering has been used in this work to investigate the structure of LNPs encapsulating plasmid DNA upon their acidification (from pH 7.4 to 4.0), as would be encountered during endocytosis. The results revealed the acidification-induced structure evolution (AISE) of the LNPs on different dimension scales, involving protonation of the ionizable lipid, volume expansion and redistribution of aqueous and lipid components. A similarity analysis using an LNP’s structural feature space showed a strong positive correlation between function (measured by intracellular luciferase expression) and the extent of AISE, which was further enhanced by the fraction of …

KW - lipid nanoparticles

KW - nonviral gene delivery

KW - small-angle neutron scattering

KW - cellular expression

KW - acidification-induced structure evolution (AISE)

U2 - 10.1021/acsnano.2c06213

DO - 10.1021/acsnano.2c06213

M3 - Article

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JO - ACS Nano

JF - ACS Nano

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ER -

Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Abstract

Keywords

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