Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F25%3A73632082" target="_blank" >RIV/61989592:15640/25:73632082 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989100:27740/25:10258646

Výsledek na webu

<a href="https://pubs.acs.org/doi/full/10.1021/jacs.5c10908" target="_blank" >https://pubs.acs.org/doi/full/10.1021/jacs.5c10908</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/jacs.5c10908" target="_blank" >10.1021/jacs.5c10908</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption

Popis výsledku v původním jazyce

The delivery efficiency of biologics via lipid nanoparticles (LNPs) is critically dependent on the incorporation of ionizable lipids. The subtle structural changes to these lipids led to dramatic variations in cytosolic delivery efficiency. However, beyond the pK a values of tertiary amines in ionizable lipids, our understanding of the structure-activity relationships (SARs) between ionizable lipid spatial conformations and their endosomal escape efficacies remains limited. Here, we constructed a library of 18 bioreducible ionizable lipids with varying numbers of alkyl tails, ranging from two to four. We found that three-tailed ionizable lipids exhibited robust endosomal disruption and cytosolic delivery efficiency compared to those of their counterparts with similar pK a values. Molecular dynamics simulations and 31P NMR spectroscopy show that the three-tailed ionizable lipid adopts a characteristic cone-shaped structure, which upon interaction with endosomal phospholipids promotes the formation of inverted hexagonal phases and facilitates endosomal membrane disruption. These results underscore that the number of alkyl tails in ionizable lipids must be precisely tuned, as excessive tail branching may not linearly correlate with improved endosomal disruption. Our research contributes to the mechanistic comprehension of ionizable lipids, highlighting that the spatial configuration serves as a critical design parameter governing intracellular biologic transport.

Název v anglickém jazyce

Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption

Popis výsledku anglicky

The delivery efficiency of biologics via lipid nanoparticles (LNPs) is critically dependent on the incorporation of ionizable lipids. The subtle structural changes to these lipids led to dramatic variations in cytosolic delivery efficiency. However, beyond the pK a values of tertiary amines in ionizable lipids, our understanding of the structure-activity relationships (SARs) between ionizable lipid spatial conformations and their endosomal escape efficacies remains limited. Here, we constructed a library of 18 bioreducible ionizable lipids with varying numbers of alkyl tails, ranging from two to four. We found that three-tailed ionizable lipids exhibited robust endosomal disruption and cytosolic delivery efficiency compared to those of their counterparts with similar pK a values. Molecular dynamics simulations and 31P NMR spectroscopy show that the three-tailed ionizable lipid adopts a characteristic cone-shaped structure, which upon interaction with endosomal phospholipids promotes the formation of inverted hexagonal phases and facilitates endosomal membrane disruption. These results underscore that the number of alkyl tails in ionizable lipids must be precisely tuned, as excessive tail branching may not linearly correlate with improved endosomal disruption. Our research contributes to the mechanistic comprehension of ionizable lipids, highlighting that the spatial configuration serves as a critical design parameter governing intracellular biologic transport.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

ISSN

0002-7863

e-ISSN

1520-5126

Svazek periodika

147

Číslo periodika v rámci svazku

42

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

"38265–38274"

Kód UT WoS článku

001591594300001

EID výsledku v databázi Scopus

2-s2.0-105019241816