Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption
The result's identifiers
Result code in 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>
Alternative codes found
RIV/61989100:27740/25:10258646
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10403 - Physical chemistry
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
ISSN
0002-7863
e-ISSN
1520-5126
Volume of the periodical
147
Issue of the periodical within the volume
42
Country of publishing house
US - UNITED STATES
Number of pages
10
Pages from-to
"38265–38274"
UT code for WoS article
001591594300001
EID of the result in the Scopus database
2-s2.0-105019241816