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Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption
Yu Zhao1,2, Zhiyuan Qu1, Markéta Paloncýová3
1Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States.
Journal of the American Chemical Society
|October 10, 2025
Summary
Three-tailed ionizable lipids enhance biologic delivery by improving endosomal escape. Their cone shape promotes membrane disruption, crucial for cytosolic delivery via lipid nanoparticles (LNPs).
Area of Science:
- Biochemistry
- Materials Science
- Drug Delivery
Background:
- Lipid nanoparticles (LNPs) are key for delivering biologics.
- Ionizable lipids are crucial for LNP efficiency, but structure-activity relationships (SARs) are not fully understood.
- Endosomal escape is a critical step for cytosolic delivery.
Purpose of the Study:
- To investigate the SARs of ionizable lipids concerning their spatial conformations and endosomal escape.
- To determine how the number of alkyl tails affects ionizable lipid performance in LNP delivery.
- To elucidate the mechanism by which ionizable lipids facilitate endosomal disruption.
Main Methods:
- Construction of a library of 18 bioreducible ionizable lipids with varying alkyl tails (two to four).
- Evaluation of endosomal disruption and cytosolic delivery efficiency.
- Molecular dynamics simulations and 31P NMR spectroscopy to study lipid behavior.
Main Results:
- Three-tailed ionizable lipids showed superior endosomal disruption and cytosolic delivery compared to two- or four-tailed lipids with similar pKa values.
- Molecular dynamics and NMR revealed a cone shape for three-tailed lipids, promoting inverted hexagonal phase formation and membrane disruption.
- Tail branching does not linearly correlate with improved endosomal disruption.
Conclusions:
- The spatial configuration, specifically the number of alkyl tails, is a critical design parameter for ionizable lipids.
- Three-tailed ionizable lipids offer enhanced endosomal escape and cytosolic delivery of biologics.
- Understanding lipid spatial conformation is vital for optimizing LNP-based drug delivery systems.
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