Biodegradable nanoparticles have been engineered to help the immune system find and destroy diseased immune cells in an early mouse study.
Researchers said the work advances efforts to engineer immune cells inside a patient’s own body to tackle cancers and autoimmune diseases such as lupus.
Engineered immune cells have already been used to treat a range of blood cancers through CAR-T cell therapy, in which T cells, a type of white blood cell, are taken from a patient’s blood and altered in a lab to recognise and kill cancer cells.
However, researchers said removing blood cells and engineering them outside the body is costly and inefficient.
Jordan Green, professor of biomedical engineering at the Johns Hopkins University School of Medicine, said: “These experiments were successful using just one dose of the nanoparticles, and an advantage of using an off-the-shelf therapy is the potential for scalable manufacture and broad accessibility, whereas current forms of CAR-T therapies are very expensive and time-consuming.”
In the new study, funded by the National Institutes of Health and published on 11 March, the researchers said their nanoparticles were designed to travel to and stimulate disease-fighting T cells.
Those T cells then seek out and destroy B cells, immune cells that can drive diseases such as lupus and blood cancers including leukaemia and lymphoma.
The researchers described the nanoparticle as being made of polymers, which are chains of molecules called ester units that biodegrade in water.
Its surface is decorated with two main components, antiCD3 and antiCD28 antibody molecules, which help the nanoparticles find and stimulate T cells.
The nanoparticles also carry mRNA, a genetic material that gives T cells instructions to express receptors on their surface that detect cancer and lupus-causing B cells.
The team said the Johns Hopkins nanoparticles use three components, compared with five in lipid-based nanoparticles developed by other researchers.
In the current study, 24 hours after the nanoparticles were injected into healthy mice, 95 per cent of the target B cells were depleted in circulating blood and about 50 per cent of B cells were destroyed in the spleen in all the mice.
After a week, B cells in the blood returned to about 50 per cent of their original quantity.
Green said it had taken five years to reach this point, working with immunology expert Jonathan Schneck to develop the nanoparticles used in the study.
The researchers combined Schneck’s work on artificial immune cells that stimulate other immune cells with Green’s research on polymer-based nanoparticles.
Green said designing nanoparticles that can reach T cells throughout the blood and organs is more difficult than delivering them directly to a localised site such as the eye.
When nanoparticles reach T cells, the cells tend to resist taking them up, and even if they do become internalised, the cells often break them down and expel them.
Green said: “This makes sense, because if T cells easily internalise things like viruses, viral programming would take over the immune system, like what happens in HIV.
He said the nanoparticles work in stages, like rockets travelling to outer space.
In this case, the nanoparticles were designed to seek out T cells, stimulate them to activate and multiply, pass through the cell wall into the T cells, and then degrade to deliver an mRNA cargo.
The scientists created a blend of two molecules, antiCD3 and antiCD28, to help the nanoparticles find and latch on to T cells.
They found the degradable nanoparticles worked as well as commercially made magnetic beads designed to latch on to T cells for laboratory research, but were also able to enter the T cells to re-engineer them from the inside out.
In a previous study, Green and colleagues found that about 10 per cent of the Johns Hopkins-developed nanoparticles successfully escape the cell’s degradation compartments to deliver their genetic cargo, compared with one to two per cent of other nanoparticles that are immediately degraded and ejected from the cell.
In the current study, the scientists saw that the nanoparticles degrade and release their mRNA contents within a few hours in mice.
Green, Schneck and colleagues at Johns Hopkins have recently been named as collaborators by biotechnology company ImmunoVec on a more than US$40m grant from the Advanced Research Projects Agency for Health, a US federal agency, to develop these cell engineering tools.
The researchers said they aim to continue refining the nanoparticles, tailoring them more closely to diseased B cells and making it possible to adjust the amount of T-cell stimulation.
