February 11, 2025

By: Toni Shears

College of Pharmacy researchers in the lab of Guizhi (Julian) Zhu have developed a promising new weapon in the war on cancer: small circular mRNA vaccines. These cancer antigen-encoding RNA vaccines, called circRNA, elicit a potent, long-lasting tumor immunotherapy response with less toxicity than other treatments. 

 

Early findings were reported in a paper with collaborators at Virginia Commonwealth University published in Nature Biomedical Engineering, Small circular RNAs as vaccines for cancer immunotherapy.

Cancer is now understood to be partly a failure of the immune system, where rapidly multiplying malignant cells evade and overpower the body’s natural abilities to control such cell growth. A large and growing body of cancer research and therapy aims to treat or even prevent cancer with targeted immunotherapy – vaccines engineered to stimulate and train the body to fight and destroy cancer cells. CircRNA is a targeted technology that improves on existing immunotherapy and vaccine approaches.

An Improvement on mRNA

 

“Traditional pathogen-based vaccines have numerous drawbacks that limit their benefits for treating cancer and chronic or preexisting infections. As COVID-19 demonstrated, mRNA vaccines avoid some of these drawbacks and can be very effective, but there is still much room for improvement,” says Zhu, the Ara G. Paul Associate Professor of Pharmaceutical Science.

 

Current linear mRNA vaccines still have limited biostability, which restricts shelf life and also moderates antigen translation efficiency. Their pharmacokinetics — the way they are distributed, metabolized and eliminated by the body — are suboptimal. The nanocarriers designed to deliver the mRNA can only carry a limited amount of the vaccine, and mRNA produces short immune memory. They are also complicated and time-consuming to produce. 

 

Zhu’s work focuses on engineering a novel circular mRNA structure. It turned out that a simple change from the linearity to the circularity of the RNA makes a lot of improvement, most notably significantly improved stability and the resulting long-lasting production of proteins or peptides that were programmed in these RNA molecules. Size is also key; small circRNA is made from minimal RNA elements — typically less than 300 nucleotides — to encode specific peptide antigens. Zhu’s work has shown that circRNA has high loading capacity in nanocarriers and efficiently accumulates in lymph nodes and antigen-presenting cells, both of which are important to activate antigen-specific immune responses that are critical to fight against cancer as well as pathogenic infections.

 

“We’ve tested multiple circRNA vaccines, including multivalent antigen-encoding circRNA vaccines. They generate 10 times more antigen-specific T-cells, with greater safety, relative to some of the state-of-the-art RNA vaccines,” Zhu says.  Combined with an immune checkpoint blockade (ICB), these circRNA vaccines inhibit tumor-generated processes that block the natural immune response to the tumor.

 

In July 2024, Zhu was awarded a five-year, $2.8 million National Institutes of Health grant to further investigate the effectiveness of circRNA vaccines against melanoma. The project is a collaboration with Shawn Wang, PhD, at Virginia Commonwealth University and Dr. Mike Green, then an assistant professor of radiation oncology at the U-M Rogel Cancer Center. If successful, this work will lay the groundwork for novel vaccines that can effectively treat the most serious form of skin cancer in humans.

 

In addition, together with Dr. Andrzej Dlugosz, Zhu was awarded a one-year, $250,000 grant from the Forbes Institute for Cancer Discovery at the Rogel Cancer Center in December. This grant will support a trial of circRNA in combination immunotherapy against Merkel cell carcinoma. 

 

“We are thrilled to have this funding to keep pursuing our quest to eradicate cancer. This line of research is a step toward improving outcomes for patients with melanoma and making an impact in the fight against this common, life-threatening disease,” says Zhu.

 

Broader Applications on the Horizon

Zhu’s work at the intersection of immunology, nucleic acid engineering and functional biomaterials also offers potential for the treatment of infectious and potentially genetic diseases. 

“We’re also developing a type of lipid nanoparticles as nanocarriers for the above circRNA that can be used to formulate and deliver circRNA molecule to reach its targets and stay in the body longer, for a more sustained effect,” Zhu says. 

 

“One project we’re working on is a carrier that can deliver circRNA into lungs, possibly via a nasal spray,” he adds. “One potential use is for the flu or COVID. Another is cystic fibrosis, which affects many tissues including the lungs. If you can treat the lungs, you can minimize a lot of the symptoms and improve the health and quality of life dramatically,” Zhu continues.

 

A research team at the University of Michigan and the Hospital for Sick Children in Toronto identified the gene for cystic fibrosis in 198 University of Michigan in 1989. Since then, new therapies have significantly extended the lifespan of patients born with this debilitating condition, but the disease still requires continual, extensive, often onerous treatments. 

 

For genetic diseases, circRNA is used not as a vaccine to spark an immune response, but to normalize the gene function. “One approach is to basically use a vector to express a wild type or normal type of protein,” Zhu explains. Another promising option is to use circRNA to deliver a gene editor that will correct the faulty gene(s) and change the product the gene(s) express. 

 

“We’re very excited to see how this goes in the next few years,” Zhu notes. 

 

The power of this next-gen research focusing on circRNA has the potential impact to improve the lives of millions who suffer from infectious and chronic diseases. Traversing and exploring circRNA as a means to better target and eliminate tumors, is the kind of cutting-edge research we will continue to follow as Zhu and his team make more discoveries.