ArticleProceedings of the National Academy of Sciences of the United States of America2023
pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
What it found
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Who cites it
59 citing papers in PubMed, 116 citations in OpenAlex.
- Structural evolution of ionizable lipids for nucleic acid delivery.Nature reviews. Chemistry · 2026Review
- A multiscale modeling framework for transport of PEGy-lated lipid nanoparticle through the extracellular matrix.bioRxiv : the preprint server for biology · 2026Article
- Navigating Lipid Nanostructure Design Space Through Continuous Microfluidic Automation.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Low reactogenicity and high tumour antigen expression from mRNA-LNPs with membrane-destabilizing zwitterionic lipids.Nature biomedical engineering · 2026Article
- Single-ligand dual-targeting lipid nanoparticles for therapeutic mRNA delivery to glioblastoma across the blood-brain barrier.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Construction of a translational whole-body physiologically based pharmacokinetic model to investigate the biodistribution of lipid nanoparticle-based mRNA therapeutics for intracellular protein targets.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- Post-loading ribonucleic acid into lipid nanoparticle carriers.bioRxiv : the preprint server for biology · 2026Article
- From Morphology to Mechanism: Cryo-Electron Microscopy Insights into Lipid Nanoparticles for RNA Delivery.ACS nano · 2026Review
- Lipoic Acid Derivative/PEI Composite Nanoparticles Enable Efficient mRNA Delivery via Thiol-Mediated Cellular Uptake.Macromolecular bioscience · 2026Article
- Storage Buffer Composition Impacts Internal Structure, Freeze-Thaw Stability, and Transfection Efficiency of mRNA-Lipid Nanoparticles.ACS nano · 2026Article
- A Time-Resolved In Situ SAXS Method for Real-Time Monitoring of Lipid Nanoparticles Assembly.Membranes · 2026Article
- Designed Liquid Crystalline Nanoassemblies From Clinically Validated Polyunsaturated Lipids for Combined Antioxidant, Anti-Apoptotic, and Neurotrophic Treatments.Advanced healthcare materials · 2026Article
- Stimuli-responsive nanocarriers for targeted mRNA therapeutics: a paradigm shift in mRNA delivery for biomedical applications.Drug delivery and translational research · 2026Review
- Decoding Undesirable Inflammatory Responses of Nucleic Acid-Delivering Lipid Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mechanistic Insight Into Ionizable Cationic Lipid-Mediated Endosomal Escape via Transient Lipid Complexes.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- mRNA Lipid Nanoparticles for Cell Engineering in Vivo and in Vitro: Current Applications and Future Directions.MedComm · 2026Review
- Industrial Perspective on the Manufacturing of Lipid Nanoparticles for Nucleic Acid Delivery.Pharmaceutics · 2026Review
- Breathing lung-on-chip: a versatile tool for assessing respiratory toxicity across multiple therapeutic modalities.Archives of toxicology · 2026Article
- Artificial intelligence-guided design of LNPs for in vivo targeted mRNA delivery via analysis of the spatial conformation of ionizable lipids.Nature biomedical engineering · 2026Article
- Decoding pH-Driven Phase Transition of Lipid Nanoparticles.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 3 countries.
Funding
Abstract
Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism of pH-dependent response that is believed to cause endosomal release of LNPs is not well understood. Here, we show that eGFP (enhanced green fluorescent protein) protein expression in the mouse liver mediated by the ionizable lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), and DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery of mRNA per cell in all cell fractions isolated. We hypothesize that the three CIL-LNPs react differently to pH changes and hence study the structure of CIL/chol bulk phases in water. Using synchrotron X-ray scattering a sequence of ordered CIL/chol mesophases with lowering pH values are observed. These phases show isotropic inverse micellar, cubic Fd3m inverse micellar, inverse hexagonal [Formula: see text] and bicontinuous cubic Pn3m symmetry. If polyadenylic acid, as mRNA surrogate, is added to CIL/chol, excess lipid coexists with a condensed nucleic acid lipid [Formula: see text] phase. The next-neighbor distance in the excess phase shows a discontinuity at the Fd3m inverse micellar to inverse hexagonal [Formula: see text] transition occurring at pH 6 with distinctly larger spacing and hydration for DD vs. MC3 and KC2. In mRNA LNPs, DD showed larger internal spacing, as well as retarded onset and reduced level of DD-LNP-mediated eGFP expression in vitro compared to MC3 and KC2. Our data suggest that the pH-driven Fd3m-[Formula: see text] transition in bulk phases is a hallmark of CIL-specific differences in mRNA LNP efficacy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.