Polyethylene glycol immunogenicity in nanomedicine

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. Polyethylene glycol (PEG) is used in many nanomedicines but might cause the production of anti-PEG antibodies. This Review critically assesses mechanisms and effects of PEG immunogenicity and explores strategies to address PEG immunogenicity in the context of nanomedicine.