Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Designing around immune memory to counter PEG immunogenicity

Nature Materials volume 24, pages 1666–1669 (2025)Cite this article

Subjects

The emergence of lipid nanoparticles as nucleic acid delivery vehicles has revolutionized medicine, with polyethylene glycol (PEG)-lipids playing a crucial role in particle formation and in vivo fate. However, PEG has been linked to immune responses that can provoke side effects and may prevent repeat dosing, and so PEG alternatives are now being developed. Here we argue that, rather than concentrating on PEG replacement, the field should prioritize designing around pre-existing immune memory.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanism of T-independent anti-PEG response.
Fig. 2: Strategies to mitigate PEG-driven immune responses and enable next-generation LNP design.

References

  1. Riddler, S. A. et al. Ann. Intern. Med. 178, 963–974 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Willis, J. R. et al. Science 389, eadr8382 (2025).

    Article  CAS  PubMed  Google Scholar 

  3. Li, S. et al. Nat. Commun. 13, 5561 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen, B.-M., Cheng, T.-L. & Roffler, S. R. ACS Nano 15, 14022–14048 (2021).

    Article  CAS  PubMed  Google Scholar 

  5. Koeberl, D. et al. Nature 628, 872–877 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Abe, S. et al. J. Control. Release 383, 113821 (2025).

    Article  CAS  PubMed  Google Scholar 

  7. Sanchez, A. J. D. S. et al. Adv. Healthc. Mater. 13, 2304033 (2024).

    Article  CAS  Google Scholar 

  8. Xiao, Y. et al. Nat. Mater. https://doi.org/10.1038/s41563-024-02116-3 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Nogueira, S. S. et al. ACS Appl. Nano Mater. 3, 10634–10645 (2020).

    Article  CAS  Google Scholar 

  10. Kang, D. D. et al. Bioact. Mater. 37, 86–93 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Luozhong, S. et al. Nat. Mater. https://doi.org/10.1038/s41563-025-02240-8 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Besin, G. et al. ImmunoHorizons 3, 282–293 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Chaudhary, N. et al. Nat. Biomed. Eng. 8, 1483–1498 (2024).

    Article  CAS  PubMed  Google Scholar 

  14. Zelkoski, A. E. et al. npj Vaccines 10, 73 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Omo-Lamai, S. et al. Nat. Nanotechnol. 20, 1285–1297 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA

    Namit Chaudhary

  2. Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA

    Kathryn A. Whitehead

  3. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA

    Kathryn A. Whitehead

Authors
  1. Namit Chaudhary
    View author publications

    Search author on:PubMed Google Scholar

  2. Kathryn A. Whitehead
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Kathryn A. Whitehead.

Ethics declarations

Competing interests

N.C. is an inventor on several patent applications on lipid nanoparticles. K.A.W. is an inventor on numerous patents on lipid nanoparticles and is a co-founder and advisor of numerous gene therapy companies.

Peer review

Peer review information

Nature Materials thanks Marina Dobrovolskaia, Hyukjin Lee and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chaudhary, N., Whitehead, K.A. Designing around immune memory to counter PEG immunogenicity. Nat. Mater. 24, 1666–1669 (2025). https://doi.org/10.1038/s41563-025-02383-8

Download citation

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41563-025-02383-8

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research