Anti-PEG antibodies in nanomedicine: Mechanisms, risks, and opportunities
5 affiliations
- 1Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia; School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
- 2Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
- 3School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
- 4Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.; Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria 3000, Australia. Electronic address: [email protected]
- 5Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia. Electronic address: [email protected]
Abstract
Polyethylene glycol (PEG) is widely used to improve the stability, solubility, and circulation half-life of nanoparticles, proteins, and small-molecule drugs. However, anti-PEG antibodies are increasingly recognized as a clinically relevant variable that can reshape the in vivo fate of PEGylated therapeutics, contributing to accelerated blood clearance, altered biodistribution, loss of efficacy, and, in a subset of individuals, hypersensitivity. This review integrates molecular, formulation, and host determinants of PEG immunogenicity using evidence from preclinical models and human studies. We summarize the prevalence and sources of pre-existing anti-PEG antibodies, including environmental exposure and host genetic associations, and discuss how antibody binding remodels the biomolecular corona, engages Fc- and complement-mediated pathways, and promotes phagocytic uptake that undermines PEG-mediated "stealth". We then evaluate mitigation strategies spanning polymer and lipid design, emerging PEG alternatives, and patient-centered approaches such as baseline antibody profiling and pre-treatment with free PEG in animal models. Finally, we highlight an emerging paradigm that exploits anti-PEG binding for benefit: bispecific anti-PEG antibodies and sequential pre-targeting strategies that convert PEG into a modular handle for active targeting across polymer nanoparticles, liposomes, and mRNA-lipid nanoparticles. Together, this review frames anti-PEG immunity as a central design variable in nanomedicine, linking PEG-mediated stealth, circulation time, targeting efficiency, biomolecular corona formation, and immune recognition. We propose guiding principles for deciding when PEG should be retained and optimized, replaced with alternative stealth materials, managed through patient-level screening or pre-treatment, or deliberately exploited as a modular handle for targeted delivery.
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BibTeX
@article{mihindukulasooriya2026antipeg,
title = {{Anti-PEG antibodies in nanomedicine: Mechanisms, risks, and opportunities}},
author = {Suyama Prasansali Mihindukulasooriya and Zhaoran Wang and Shiyao Li and Anamika Saini and Kirsty Wilson and Magdalena Plebanski and Stephen J. Kent and Yi Ju},
journal = {Advanced Drug Delivery Reviews},
year = {2026},
month = jun,
doi = {10.1016/j.addr.2026.115925},
url = {https://doi.org/10.1016/j.addr.2026.115925},
note = {CC BY},
}
RIS
TY - JOUR
TI - Anti-PEG antibodies in nanomedicine: Mechanisms, risks, and opportunities
AU - Suyama Prasansali Mihindukulasooriya
AU - Zhaoran Wang
AU - Shiyao Li
AU - Anamika Saini
AU - Kirsty Wilson
AU - Magdalena Plebanski
AU - Stephen J. Kent
AU - Yi Ju
PY - 2026
DA - 2026/06/26
JO - Advanced Drug Delivery Reviews
DO - 10.1016/j.addr.2026.115925
UR - https://doi.org/10.1016/j.addr.2026.115925
AB - Polyethylene glycol (PEG) is widely used to improve the stability, solubility, and circulation half-life of nanoparticles, proteins, and small-molecule drugs. However, anti-PEG antibodies are increasingly recognized as a clinically relevant variable that can reshape the in vivo fate of PEGylated therapeutics, contributing to accelerated blood clearance, altered biodistribution, loss of efficacy, and, in a subset of individuals, hypersensitivity. This review integrates molecular, formulation, and host determinants of PEG immunogenicity using evidence from preclinical models and human studies. We summarize the prevalence and sources of pre-existing anti-PEG antibodies, including environmental exposure and host genetic associations, and discuss how antibody binding remodels the biomolecular corona, engages Fc- and complement-mediated pathways, and promotes phagocytic uptake that undermines PEG-mediated "stealth". We then evaluate mitigation strategies spanning polymer and lipid design, emerging PEG alternatives, and patient-centered approaches such as baseline antibody profiling and pre-treatment with free PEG in animal models. Finally, we highlight an emerging paradigm that exploits anti-PEG binding for benefit: bispecific anti-PEG antibodies and sequential pre-targeting strategies that convert PEG into a modular handle for active targeting across polymer nanoparticles, liposomes, and mRNA-lipid nanoparticles. Together, this review frames anti-PEG immunity as a central design variable in nanomedicine, linking PEG-mediated stealth, circulation time, targeting efficiency, biomolecular corona formation, and immune recognition. We propose guiding principles for deciding when PEG should be retained and optimized, replaced with alternative stealth materials, managed through patient-level screening or pre-treatment, or deliberately exploited as a modular handle for targeted delivery.
SN - 0169-409X
SN - 1872-8294
ER -