Abstract
Messenger RNA lipid-nanoparticle-based therapies represent an emerging class of medicines for a variety of applications. However, anti-poly(ethylene glycol) (anti-PEG) antibodies generated by widely used PEGylated medicines and lipid nanoparticles hinder therapeutic efficacy upon repeated dosing. Here we report the chemical design, synthesis and optimization of high-density brush-shaped polymer lipids that reduce anti-PEG antibody binding to improve protein production consistency in repeated dosing. Brush-shaped polymer lipid parameters, including side chain length, degree of polymerization, anchor alkyl length and surface regimes on lipid nanoparticles modulate anti-PEG antibody binding affinity and control their blood circulation pharmacokinetics. Compared to widely used 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, lipid nanoparticles containing brush-shaped polymer lipids generate superior therapeutic outcomes in protein replacement therapy and genome editing models, reformulating structure–activity guidelines for the design of PEG lipid substitutes. Overall, these findings contribute to the general effort in the development of lipid nanoparticles with low immunogenicity to overcome current roadblocks to nucleic acid medicines.
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All the data are available from the corresponding author upon request. Source data are provided with this paper.
Change history
04 June 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41563-025-02270-2
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Acknowledgements
The research was supported by the Welch Foundation (I-2123-20220031); the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB; R01 5R01EB025192-06) and National Cancer Institute (NCI; R01 CA269787-01); and the Cystic Fibrosis Foundation (CFF; SIEGWA18XX0 and SIEGWA21XX0). J.G.M. was supported in part by NIH UL1TR003163, NIH 1P30DK127984-01A1 and NIH 1P01HL160487-01. C.L. was supported by NIH; R01GM143723. We acknowledge support from H. Zhu and his lab for assistance with the FAH knock-out mouse study, and from the University of Texas Southwestern Small Animal Imaging Resource (NCI P30CA142543), Whole Brain Microscopy Facility (SCR_017949), Metabolic Phenotyping Core, Tissue Management Shared Resource (P30CA142543) and Histo Pathology Core. LNPs and mice in Figs 1a,b, 3b,i, 4a,e, 5a and 6a,f created with BioRender.com.
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Y.X. and D.J.S. conceived and designed the experiments and wrote the manuscript. Y.X., X.L., Y.S., Y.-C.S., A.V., Z.C., A.G., J.G.M., S.C., L.Z., E.G., X.W., L.F., Y.Y., M.I.D. and C.L. performed experiments. All authors discussed the results and commented on the manuscript. D.J.S. directed the research.
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The University of Texas Southwestern has filed patent applications on the technologies described in this manuscript with some co-authors listed as inventors. D.J.S. discloses financial interests in ReCode Therapeutics, Signify Bio, Jumble Therapeutics and Tome Biosciences.
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Nature Materials thanks Camilla Foged, Liangfang Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Xiao, Y., Lian, X., Sun, Y. et al. High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics. Nat. Mater. (2025). https://doi.org/10.1038/s41563-024-02116-3
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DOI: https://doi.org/10.1038/s41563-024-02116-3
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