ISIS Neutron and Muon Source Data Journal

Lipid-nanoparticle surfaces, protein corona, and endosomal escape: a structure-activity relationship

Abstract: Messenger RNA (mRNA) lipid nanoparticles (LNPs) underpin current mRNA vaccines but remain limited by inefficient endosomal escape and immune responses to the polymer polyethylene glycol (PEG). PEG enhances colloidal stability and modulates protein corona formation, however PEG and the protein corona both reduce endosomal escape, which is theorised to be due to reduced membrane interactions. We have developed alternative polymes to replace PEG in clinically relevant LNPs. The lead candidate, Alt-1, improves mRNA expression 100-fold in vitro and retains efficacy in vivo in the presence of serum and anti-PEG antibodies. We propose to use neutron reflectometry to quantify how LNP surface chemistry and protein corona composition influence interactions with model endosomal membranes. Solid-supported lipid bilayers (77% d54 DMPC, 6% 18-1 BMP, 17% cholesterol) model the endosomal membrane. Three LNP formulations (PEG-lipid, Alt-1, and polymer-free control) will be pre-incubated with human serum albumin, anti-PEG antibodies, or both. NR measurements will determine lipid exchange, bilayer disruption, and interaction kinetics. Through contrast matching, NR can uniquely resolve structural and compositional changes of the bilayer. Combined with complementary in vitro and in silico studies, these results will establish structure activity relationships linking surface chemistry, protein corona, and endosomal escape, guiding rational design of safer and more effective mRNA delivery systems.

Principal Investigator: Dr Benjamin Fiedler
Local Contact: Dr Stephen Hall
Experimenter: Dr Pratik Gurnani
Experimenter: Miss Nga Man Cheng
Experimenter: Mr Dwain Alexander Tyndale Andreu
Experimenter: Mr Gedion Girmahun

DOI: 10.5286/ISIS.E.RB2610581

ISIS Experiment Number: RB2610581

Publisher: STFC ISIS Neutron and Muon Source

Data format: RAW/Nexus
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Data Citation

The recommended format for citing this dataset in a research publication is as:
[author], [date], [title], [publisher], [doi]

For Example:
Dr Benjamin Fiedler et al; (2026): Lipid-nanoparticle surfaces, protein corona, and endosomal escape: a structure-activity relationship, STFC ISIS Neutron and Muon Source, https://doi.org/10.5286/ISIS.E.RB2610581

Data is released under the CC-BY-4.0 license.