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  • Review Article
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Polyethylene glycol immunogenicity in nanomedicine

Nature Reviews Bioengineering volume 3, pages 742–760 (2025)Cite this article

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Abstract

Polyethylene glycol (PEG) endows nanomedicines with stealth properties, reducing interactions with immune cells, prolonging blood circulation and stabilizing lipid-based formulations. However, anti-PEG antibodies, either pre-existing or induced by PEGylated medicines and vaccines, might adversely affect the safety and efficacy of nanomedicines by altering nanocarrier biodistribution, inducing unwanted inflammatory responses, destabilizing lipid formulations and causing hypersensitivity reactions. Therefore, the effect of PEG immunogenicity on nanomedicines should be critically assessed, and alternative approaches explored. In this Review, we first discuss PEG immunogenicity and the sources, detection and effects of anti-PEG antibodies. We then highlight strategies to address PEG immunogenicity, including the adjustment of dosing, routes and timing of nanomedicine administration, competition with high-molecular-mass PEG, engineering strategies to improve stealth effects of PEG and the design of complement inhibitors to reduce opsonization. In addition, we examine approaches for the design of PEG-free stealth nanomedicines, such as the use of alternative polymers, protein nanocages and biomimetic particles cloaked with cell membranes, serum components or bioactive molecules to prevent immune system recognition. Finally, we explore the application of anti-PEG antibodies in the creation of artificial cell receptors, reloadable hydrogels and bispecific antibodies for targeted delivery of PEGylated therapeutics.

Key points

  • Polyethylene glycol (PEG) is commonly incorporated in preclinical and clinical nanomedicines.

  • Immune responses to PEG depend on the immunogenicity of the nanomedicine cargo.

  • Anti-PEG antibodies have been detected in the circulation of individuals, albeit at low concentrations in the majority of people.

  • A small population of individuals have high levels of anti-PEG antibodies and might thus be at risk of loss of treatment efficacy of nanomedicines and development of hypersensitivity reactions.

  • Strategies to reduce PEG immunogenicity have mainly been tested in animal models thus far and remain to be clinically validated.

  • Standardization of assays and experimental testing of PEG and its alternatives will accelerate the identification of clinically useful solutions to PEG immunogenicity.

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Fig. 1: Anti-polyethylene glycol antibodies.
Fig. 2: Measurement of anti-PEG antibody responses in humans.
Fig. 3: Points of intervention and engineering strategies to address PEG immunogenicity in nanomedicines.
Fig. 4: Polyethylene glycol alternatives.

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Acknowledgements

This work is dedicated to the memory of T.-L. Cheng, our colleague, collaborator and friend who made many contributions to developing PEG monoclonal antibodies, anti-PEG antibody assays, PEG receptors and bispecific PEG engagers.

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Author notes

  1. These authors contributed equally: Yunching Chen, Yu-Cheng Su.

Authors and Affiliations

  1. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan

    Yunching Chen  (陳韻晶)

  2. Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan

    Yunching Chen  (陳韻晶)

  3. Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

    Yu-Cheng Su  (蘇昱誠)

  4. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Steve R. Roffler

  5. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Steve R. Roffler

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  1. Yunching Chen  (陳韻晶)
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  2. Yu-Cheng Su  (蘇昱誠)
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  3. Steve R. Roffler
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Correspondence to Steve R. Roffler.

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Chen, Y., Su, YC. & Roffler, S.R. Polyethylene glycol immunogenicity in nanomedicine. Nat Rev Bioeng 3, 742–760 (2025). https://doi.org/10.1038/s44222-025-00321-6

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