Approximately 60 percent of all individuals diagnosed with cancer in the United States undergo radiation therapy as part of their treatment regimen. Nonetheless, this radiation can result in severe adverse effects that often prove to be overly challenging for patients to endure.

Inspired by a minuscule organism that can survive extensive doses of radiation, scientists at MIT, Brigham and Women’s Hospital, and the University of Iowa have created a novel strategy that may safeguard patients against this type of harm. Their method utilizes a protein from tardigrades, commonly referred to as “water bears,” which typically measure less than a millimeter in size.

Upon the researchers injecting messenger RNA coding for this protein into mice, they observed that it produced sufficient protein to shield the DNA of cells from radiation-related injury. If adapted for human use, this method could benefit a significant number of cancer patients, according to the researchers.

“Radiation can be extremely beneficial for a variety of tumors, but we also acknowledge that the side effects can be restrictive. There’s an unfulfilled requirement in assisting patients to minimize the risk of harming adjacent tissues,” states Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital.

Traverso and James Byrne, an assistant professor of radiation oncology at the University of Iowa, are the leading authors of the research, which is published today in Nature Biomedical Engineering. The principal authors of the paper include Ameya Kirtane, an instructor in medicine at Harvard Medical School and a visiting scientist at MIT’s Koch Institute for Integrative Cancer Research, and Jianling Bi, a research scientist at the University of Iowa.

Remarkable endurance

Radiation is frequently utilized to address cancers affecting the head and neck, where it can harm the mouth or throat, causing significant pain when consuming food or beverages. It is also commonly employed for gastrointestinal cancers, which may result in rectal bleeding. Numerous patients ultimately postpone treatments or discontinue them entirely.

“This impacts a vast number of patients and can manifest in various ways, from mouth sores that limit a person’s ability to eat due to severe pain, to necessitating hospitalization because individuals are suffering greatly from the pain, weight loss, or bleeding. It can be quite dangerous, and it’s something that we genuinely aimed to tackle,” Byrne remarks.

Presently, there are very few methods available to avert radiation-induced harm among cancer patients. A limited selection of medications can be administered to mitigate damage, and for those with prostate cancer, a hydrogel can serve as a physical barrier between the prostate and the rectum during radiation therapy.

For several years, Traverso and Byrne have been seeking innovative solutions to prevent radiation injury. In this new investigation, they drew inspiration from the remarkable survival capabilities of tardigrades. Found globally, predominantly in aquatic habitats, these organisms are renowned for their durability under extreme conditions. Scientists have even sent them into space, where they demonstrated resilience to severe dehydration and cosmic radiation.

A critical element of tardigrades’ defense mechanism is a unique damage-suppressing protein known as Dsup, which adheres to DNA and assists in safeguarding it from radiation-induced harm. This protein significantly contributes to tardigrades’ capability to tolerate radiation doses 2,000 to 3,000 times greater than what a human can endure.

In contemplating potential strategies to shield cancer patients from radiation, the researchers pondered whether they could administer messenger RNA coding for Dsup to patient tissues before radiation exposure. This mRNA would stimulate cells to temporarily produce the protein, thus protecting DNA during treatment. After several hours, the mRNA and protein would dissipate.

For this approach to succeed, the researchers required a method to deliver mRNA that would generate substantial quantities of protein in the targeted tissues. They evaluated libraries of delivery particles with both polymer and lipid components, which had previously been used independently for efficient mRNA delivery. From these evaluations, they identified one polymer-lipid particle that was particularly effective for targeting the colon and another optimized for delivering mRNA to oral tissues.

“We hypothesized that by merging these two systems—polymers and lipids—we could achieve optimal RNA delivery. And that’s effectively what we observed,” Kirtane explains. “One of the advantages of our method is that we utilize messenger RNA, which only temporarily expresses the protein, so it’s regarded as much safer compared to something like DNA, which could integrate into the cells’ genome.”

Shielding against radiation

After demonstrating that these particles could successfully convey mRNA to cells cultivated in the laboratory, the researchers examined whether this strategy could effectively shield tissues from radiation in a mouse model.

They injected the particles into either the cheek or the rectum hours before administering a radiation dose akin to what cancer patients would experience. In these mice, the researchers observed a 50 percent reduction in the frequency of double-stranded DNA breaks caused by radiation.

“This study exhibits significant potential and presents a truly innovative concept leveraging natural protective mechanisms against DNA damage to safeguard healthy cells during radiation therapies for cancer,” remarks Ben Ho Park, director of the Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center, who did not participate in the study.

The researchers also confirmed that the protective effect of the Dsup protein did not extend beyond the injection site, a crucial factor since they do not wish to shield the tumor itself from radiation effects. To enhance the feasibility of this treatment for possible human application, the researchers now aim to engineer a version of the Dsup protein that would avoid triggering an immune response, as the original tardigrade protein likely would.

If adapted for humans, this protein could potentially offer protection against DNA damage induced by chemotherapy medications, the researchers suggest. Another potential application could involve preventing radiation damage for astronauts in space.

Additional authors of the paper include Netra Rajesh, Chaoyang Tang, Miguel Jimenez, Emily Witt, Megan McGovern, Arielle Cafi, Samual Hatfield, Lauren Rosenstock, Sarah Becker, Nicole Machado, Veena Venkatachalam, Dylan Freitas, Xisha Huang, Alvin Chan, Aaron Lopes, Hyunjoon Kim, Nayoon Kim, Joy Collins, Michelle Howard, Srija Manchkanti, and Theodore Hong.

Funding for the research was provided by the Prostate Cancer Foundation Young Investigator Award, the U.S. Department of Defense Prostate Cancer Program Early Investigator Award, a Hope Funds for Cancer Research Fellowship, the American Cancer Society, the National Cancer Institute, MIT’s Department of Mechanical Engineering, and the U.S. Advanced Research Projects Agency for Health.