High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics

Yufen Xiao; Xizhen Lian; Yehui Sun; Yun Chieh Sung; Amogh Vaidya; Zexiang Chen; Ankit Gupta; Sumanta Chatterjee; Lining Zheng; Erick Guerrero; Xu Wang; Lukas Farbiak; Yangyang Yang; Marc I. Diamond; Cecilia Leal; Jeffrey G. McDonald; Daniel J. Siegwart

doi:10.1038/s41563-024-02116-3

High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics

Yufen Xiao, Xizhen Lian, Yehui Sun, Yun Chieh Sung, Amogh Vaidya, Zexiang Chen, Ankit Gupta, Sumanta Chatterjee, Lining Zheng, Erick Guerrero, Xu Wang, Lukas Farbiak, Yangyang Yang, Marc I. Diamond, Cecilia Leal, Jeffrey G. McDonald, Daniel J. Siegwart

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	2454
Journal	Nature Materials
Early online date	Feb 28 2025
DOIs	https://doi.org/10.1038/s41563-024-02116-3
State	E-pub ahead of print - Feb 28 2025

ASJC Scopus subject areas

General Chemistry
General Materials Science
Condensed Matter Physics
Mechanics of Materials
Mechanical Engineering

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10.1038/s41563-024-02116-3

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Xiao, Y., Lian, X., Sun, Y., Sung, Y. C., Vaidya, A., Chen, Z., Gupta, A., Chatterjee, S., Zheng, L., Guerrero, E., Wang, X., Farbiak, L., Yang, Y., Diamond, M. I., Leal, C., McDonald, J. G., & Siegwart, D. J. (2025). High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics. Nature Materials, Article 2454. Advance online publication. https://doi.org/10.1038/s41563-024-02116-3

Xiao, Y, Lian, X, Sun, Y, Sung, YC, Vaidya, A, Chen, Z, Gupta, A, Chatterjee, S, Zheng, L, Guerrero, E, Wang, X, Farbiak, L, Yang, Y, Diamond, MI, Leal, C, McDonald, JG & Siegwart, DJ 2025, 'High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics', Nature Materials. https://doi.org/10.1038/s41563-024-02116-3

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title = "High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics",

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.",

author = "Yufen Xiao and Xizhen Lian and Yehui Sun and Sung, {Yun Chieh} and Amogh Vaidya and Zexiang Chen and Ankit Gupta and Sumanta Chatterjee and Lining Zheng and Erick Guerrero and Xu Wang and Lukas Farbiak and Yangyang Yang and Diamond, {Marc I.} and Cecilia Leal and McDonald, {Jeffrey G.} and Siegwart, {Daniel J.}",

note = "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 , , , and created with BioRender.com .",

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doi = "10.1038/s41563-024-02116-3",

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T1 - High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics

AU - Xiao, Yufen

AU - Lian, Xizhen

AU - Sun, Yehui

AU - Sung, Yun Chieh

AU - Vaidya, Amogh

AU - Chen, Zexiang

AU - Gupta, Ankit

AU - Chatterjee, Sumanta

AU - Zheng, Lining

AU - Guerrero, Erick

AU - Wang, Xu

AU - Farbiak, Lukas

AU - Yang, Yangyang

AU - Diamond, Marc I.

AU - Leal, Cecilia

AU - McDonald, Jeffrey G.

AU - Siegwart, Daniel J.

N1 - 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 , , , and created with BioRender.com .

PY - 2025/2/28

Y1 - 2025/2/28

N2 - 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.

AB - 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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U2 - 10.1038/s41563-024-02116-3

DO - 10.1038/s41563-024-02116-3

M3 - Article

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SN - 1476-1122

JO - Nature Materials

JF - Nature Materials

M1 - 2454

ER -

High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics

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