ACS nanoJun 9, 2026

Hydroxyl-ended polyethylene glycol avoids detection by existing human anti-polyethylene glycol antibodies

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 10, 2026

Abstract

In a study of 1970 human blood samples, pre-existing anti-PEG antibodies were widely detected and linked to adverse effects of PEGylated nanomedicines.

Pre-existing anti-PEG IgM antibodies bind more effectively to methoxy-terminated polyethylene glycol (MeO-PEG) than to hydroxy-terminated polyethylene glycol (OH-PEG).
Methoxy-terminated PEG is the only configuration currently used in marketed PEGylated nanomedicines.
Replacing MeO-PEG with OH-PEG in lipid nanoparticles reduced complement activation caused by pre-existing anti-PEG IgM.
Lipid nanoparticles modified with OH-PEG exhibited improved stability and reduced mRNA leakage in human serum.
OH-PEG demonstrated reduced immunogenicity compared to MeO-PEG, which is important for repeated treatment applications.
Current preclinical models may not accurately reflect the biological effects of pre-existing anti-PEG antibodies seen in clinical settings.

Simplified

Polyethylene glycol (PEG) has been extensively utilized in food, cosmetics, and pharmaceutical fields, especially in the realm of nanomedicines, where it serves as a pivotal excipient to prolong the nanoparticles' circulation half-life. Contrary to its historical perception as being nonimmunogenic, pre-existing anti-PEG antibodies have been widely detected in human even in individuals without prior exposure to PEGylated therapeutics and are associated with clinically relevant adverse effects of PEGylated nanomedicines including infusion reactions and hypersensitive reactions. Herein, we elucidated the prevalence and distribution characteristics of pre-existing anti-PEG antibodies in 1970 human blood samples and investigated its binding with PEG. The binding between pre-existing anti-PEG IgM and PEG was modulated by PEG terminal chemistry, with methoxy groups enhancing overall antibody-PEG interactions. Notably, methoxy is the only terminal configuration used in currently marketed PEGylated nanomedicines. In contrast, hydroxy PEG (OH-PEG) significantly evaded binding with pre-existing anti-PEG IgM among most clinical samples from three independent hospitals. Noteworthily, replacing methoxy PEG (MeO-PEG) with OH-PEG significantly attenuated complement activation of lipid nanoparticle (LNP) caused by pre-existing anti-PEG IgM, thereby markedly enhancing stability and reducing mRNA leakage in human serum. Additionally, LNP modified with OH-PEG exhibited reduced immunogenicity, which is crucial for repeated administrations. Collectively, this study elucidated the crucial role of OH-PEG in evading human pre-existing anti-PEG antibodies and discovered that the current preclinical studies inadequately simulated the biological effects of clinical pre-existing anti-PEG antibodies on such formulations through interspecies study, which had a profound impact on clinical translation of PEGylated nanomedicines.

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Hydroxyl-ended polyethylene glycol avoids detection by existing human anti-polyethylene glycol antibodies

Abstract

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