Immune memory and the future of RNA delivery

To improve and expand RNA therapies, scientists are tinkering with the chemistry of the lipid nanoparticles used to protect and deliver RNA in the body. Much of the current research focuses on developing alternatives for one of the compounds in the delivery vehicles.

These efforts are rooted in the assumption that polyethylene glycol (PEG)-lipids can cause undesirable immune responses. The prevailing approach asks: what can we use instead of PEG to avoid triggering immunity?

In Nature Materials, Kathryn Whitehead and Namit Chaudhary propose reframing the challenge: rather than simply replacing PEG, how can we design lipid nanoparticle delivery vehicles that work around the immune system's memory?

When the body comes into contact with a germ or particle for the first time, it stores information about the foreign substance, or antigen, and how to fight it. If that antigen enters the body again, the immune system recognizes it and can rapidly produce antibodies to fight it.

That immune memory can be a problem for repeat dosing of RNA therapies. After the first injection of lipid nanoparticles, the immune system is primed to clear them. As a result, the efficacy of the RNA therapy decreases over time.

Many people associate RNA therapies with the global deployment of the COVID-19 vaccines. Beyond these approved products and clinical successes is the potential to treat other diseases where immune responses are not desirable. Protein replacement therapies could be used to treat cystic fibrosis and multiple sclerosis, for example, by instructing the patient's cells to make the missing protein. One dose of those instructions, however, will only last so long.

For these patients, and others requiring repeat dosing, scientists are working to develop immunologically silent delivery systems.

Whitehead, a professor of chemical engineering and biomedical engineering, and Chaudhary ('22), who worked in her lab as a Ph.D. student, are reframing how to think about the solution. Their earlier work links the immune response caused by lipid nanoparticles to their lipid chemistry. Framed this way, PEG isn't the problem underneath the body's immune response.

Because many people are exposed to PEG in cosmetics, shampoo, and other common consumer goods, they may already have anti-PEG antibodies in their blood. When the immune system begins to mount a response against the contents of a lipid nanoparticle, it can quickly make antibodies for PEG because it recognizes it on the surface of the lipid nanoparticle and remembers it from other exposure.

Designing around immune memory will require a more fundamental understanding of how the immune system responds to lipid nanoparticles. "We can use that information to de-risk existing formulations, rather than develop new formulations," says Whitehead. "The goal is RNA delivery systems that anticipate and circumvent immune memory."

For media inquiries, please contact Lauren Smith at lsmith2@andrew.cmu.edu.