Nanoparticles target immune response using red blood cells

Polystyrene nanoparticles deliver drug payload directly to the spleen and bypass lengthy clinical trial requirements.

Vaccines are making headlines at the moment, for obvious reasons,  but making a vaccine isn’t the end of the story. Antigen-containing vaccines have to get to where they are needed in the body, they need adjutants and they need clinical trials. Enter smart nanoparticles:

Longevity.Technology: The new platform from a Wyss/SEAS team uses an existing delivery network – the circulatory system – and an existing group of ready shuttles – red blood cells – to provide a way to bypass lengthy clinical trials and generate a targeted immune response.

This research would be exciting in non-pandemic times, but in the age of COVID-19 it could prove vital. Looking further ahead, the platform has the potential to assist in preventing cancer, as well as increasing the viable treatment window.

As an age-related disease (the incidence of most cancers increases with age), cancer is a considerable threat to Longevity; we hope this platform might change that.

Erythrocytes, commonly called red blood cells, perform a vital function, transporting oxygen round the body. However, they are also one of the body’s lines of defence, fighting off infection by capturing pathogens on the cell surface, deactivating them and then delivering them to immune cells in the spleen and liver.

A team from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) wanted to exploit this ability and deliver antigens to antigen-presenting cells (APCs) in the spleen; the resulting generated immune response could be used to slow cancer growth or as an adjuvant (improving the immune response of a vaccine) for vaccines.

The new technology platform, called Erythrocyte-Driven Immune Targeting (EDIT), was designed with spleen-targeting in mind.


“… this study unlocks the door to an exciting array of future developments in the field of using human cells for disease treatment and prevention.”


“The spleen is one of the best organs in the body to target when generating an immune response, because it is one of the few organs where red and white blood cells naturally interact,” said senior author Samir Mitragotri, PhD, a Wyss Core Faculty member.

“Red blood cells’ innate ability to transfer attached pathogens to immune cells has only recently been discovered, and this study unlocks the door to an exciting array of future developments in the field of using human cells for disease treatment and prevention [1].”

Using red blood cells as nanotech drug delivery vehicles is already in use as a therapy, but existing treatments target the lungs, as the vast network of tiny capillaries there that the body uses for gas exchange usually results in any cargo being sheared off the cells’ surfaces as they squeeze through the vessels.

When the Wyss and SEAS team wanted to deliver their antigens to the spleen, they needed to devise a way to ensure the antigens would stick to the red blood cells sufficiently to resist being sheared off and reach the spleen intact.

Nanoparticles coated in an antigen stick to red blood cells strongly enough to resist being sheared off in the lungs, allowing them to reach the spleen and be passed off to immune cells, initiating an antigen-specific immune response. Credit: Wyss Institute at Harvard University

The researchers coated polystyrene nanoparticles with ovalbumin, an antigenic protein known to cause a mild immune response; they were then incubated with mouse red blood cells. Using ratio of 300 nanoparticles per blood cell resulted retention of about 80% of the nanoparticles when the cells were exposed to the double danger of shear stress (as would be found in lung capillaries) and a moderate expression of a lipid molecule called phosphatidyl serine (PS) on the cells’ membranes.

Anvay Ukidve, co-first author of the paper, explained: “A high level of PS on red blood cells is essentially an ‘eat me’ signal that causes them to be digested by the spleen when they are stressed or damaged, which we wanted to avoid. We hoped that a lower amount of PS would instead temporarily signal ‘check me out’ to the spleen’s APCs, which would then take up the red blood cells’ antigen-coated nanoparticles without the cells themselves getting destroyed [2].”

Once the red blood cells had been coated with nanoparticles, they were injected into mice; the cells were then tracked to see in which parts of the body they accumulated. 20 minutes after injection, more than 99% of the nanoparticles had moved out of the blood, with more nanoparticles present in mouses’ spleens than their lungs [3].

This higher nanoparticle accumulation in the spleen lasted for 24 hours; in addition, the number of EDIT red blood cells in the circulatory system was unchanged. This demonstrated that the red blood cells had successfully delivered their payload to the spleen unscathed.

After a series of weekly injections, the murine spleens were sampled. Treated mice had 8-fold more T cells displaying the delivered antigen than control mice. Mice treated with EDIT also produced more antibodies.

To explore the therapy potential, the team repeated the experiment on lymphoma cells which were injected into mice following three weeks of EDIT treatment; the treated mice had three-fold slower tumour growth compared with the control group, meaning a longer treatment window during which the tumour could be tackled.

“EDIT essentially is an adjuvant-free vaccine platform. Part of the reason why vaccine development today takes so long is that foreign adjuvants delivered along with an antigen have to go through a full clinical safety trial for each new vaccine,” said Zongmin Zhao, PhD, co-first author of the paper.

“Red blood cells have been safely transfused into patients for centuries, and their ability to enhance immune responses could make them a safe alternative to foreign adjuvants, increasing the efficacy of vaccines and speed of vaccine creation [4].”

The Wyss/SEAS time are continuing to develop their work, optimising the clinical setting for the technology and testing it with other antigens.