Editorial Feature

PEGylated Nanomaterials may Elicit Undesired Immune Responses

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In recent years, nanomaterials have been used in a variety of biomedical applications including drug delivery, biosensors, imaging, and tissue engineering. To survive in the body and complete their chosen function, nanomaterials employed in biomedical applications must demonstrate stability within the body, and compatibility with biological systems.

Nanomaterials employed in biomedical applications are often designed with specific surface properties. However, in biological systems, nanomaterials often become covered in biomolecular compounds including molecules such as proteins and lipids, forming a layer known as a ‘corona’. The corona can interfere with the properties of the nanomaterials and affect how cells ‘see’ the nanomaterial, thereby influencing the physiological response of the body.

To prevent the formation of biological corona and therefore achieve more controllable responses to nanomaterials, it is common practice to coat nanomaterials such as nanoparticles, micelles, liposomes, and polymers for biomedical applications with a non-fouling layer. Such layers typically consist of poly(ethylene glycol) (PEG), polyoxazoline, poly(vinyl alcohol) or polyglycerol. Coating the nanomaterials to produce ‘passivated’ surfaces is intended to make the nanomaterials ‘invisible’ and results in reduced internalization by macrophages, therefore preventing immunological responses and increasing the circulation half-life of the nanomaterials within the body.

New research reports that an international group of researchers attempting to produce surface-passivated 2D nano-graphene oxide (nGO) have found that PEGylated (i.e. coated with PEG) nGO (nGO-PEG) elicit undesired macrophage responses, indicating that PEGylation may not render nanomaterials ‘invisible’ as previously thought.

The team exposed macrophages to nGO-PEG and observed the reaction of the cells using confocal laser microscopy. In common with previous investigations, the team found that coating the nGO with PEG reduced internalization by the macrophages compared with pristine nGO.

However, contrary to expectations, the macrophages exposed to nGO-PEG displayed significantly higher cytokine production compared with the macrophages exposed to pristine nGO. Cytokines are proteins that allow communication between cells; their secretion indicates that the macrophages were ‘activated’ and suggests the potential for further immunological responses. Furthermore, the presence of nGO-PEG resulted in increased macrophage migration, confirming their ‘activation’.

The activation of the macrophages in the presence of nGO-PEG was investigated computationally and was attributed to absorption of the nGO-PEG on the macrophage membranes triggering signaling pathways and resulting in cytokine secretion.

In comparison with other nanomaterials, the 2D structure of nGO increases the available surface area of nGO-PEG for membrane binding, which may explain the increased immunological response. Although the nGO-PEG bound to the macrophage membranes, they did not damage the cells. The cells exposed to nGO-PEG remained highly viable and were able to produce more cytokines than the cells exposed to pristine nGO, which was internalized and resulted in substantial nuclear damage.

Surface passivation using PEG is widely thought to improve nanoparticle stability and biocompatibility, and prevent immunological responses. While the nGO-PEG nanomaterials were stable and biocompatible, their presence activated macrophages and caused a significant release of cytokines. In vivo investigations are required to determine the scale of the inflammatory or immunological responses caused by nGO-PEG. As the immune response was attributed to the high surface area of nGO-PEG, the same effect may be observed of all 2D nanomaterials, thereby limiting their biomedical applications.

An unintended, positive outcome of this research is that as the 2D nGO-PEG activated the macrophages without internalization or damaging the macrophages, they may be suitable for applications that require immune system stimulation. Targeted cytokine secretion induced by nGO-PEG may, therefore, represent a potential future immunotherapy.


Luo N., Weber J.K., Wang S., Luan B., Yue H., Xi X., Du J., Yang Z., Wei W., Zhou R., Ma G., Nature Communications, 2017, 8, 14537.


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