RNA-packed hydrogel treats cancers that line organs and body cavities in mice

Cancers that grow on the surfaces of organs and the linings of body cavities are notoriously difficult to treat. A new therapeutic hydrogel that can be injected or sprayed onto large surfaces could be an effective tool in fighting such cancers (Nat. Nanotechnol. 2021, DOI: 10.1038/s41565-021-00961-w).

Unlike solid tumor masses, cancers like mesothelioma that spread on complex tissue coverings in the body are hard for surgeons to remove completely. “You always leave residual cancer behind so there is always a recurrence,” says Joel P. Schneider, an organic chemist and deputy director of the Center for Cancer Research at the National Cancer Institute. Delivering a therapy to tissue at the end of a removal surgery to combat that residual cancer “could be a game changer.”

Schneider, thoracic surgical oncologist Chuong D. Hoang, and their colleagues based their therapy on microRNA (miRNA), small bits of ribonucleic acids that regulate the formation of proteins in cells. These sequences have recently been harnessed as anticancer agents because they can be designed to suppress the creation of proteins responsible for specific cancers’ propagation. Hoang and others have identified an miRNA sequence that stifles mesothelioma, a cancer of the lining around the lungs, abdomen, or heart which is associated with asbestos exposure.

The challenge with miRNA therapy has been delivering it into cells. Its strong negative charge keeps it from getting through the dense, negatively charged protein and fat layer that surrounds cells. “So you need a Trojan horse to bring it in,” Schneider says.

And that’s exactly what research scientist Poulami Majumder, a former postdoctoral fellow in the Schneider laboratory, designed. She first made positively-charged peptides that could bind miRNA and form 50–200 nm particles. The nanoparticles’ size and slight positive charge let them quickly enter cells. Once the nanoparticles are inside, enough miRNA escapes to slow cancer propagation.

Majumder then encapsulated the miRNA nanoparticles inside a peptide-based hydrogel, which can be delivered as a spray or via a syringe. The gel is important for the therapy because it “fills all the nooks and crannies” of the tissue, Schneider says.

The team tested the hydrogel in four different tumor models in mice. The first three were mesothelioma tumors grown under the skin, in the abdominal cavity, and in the lung cavity. Just one application of the gel to the tumors, without any surgery, reduced tumor growth and improved survival rates.

In the fourth scenario, the researchers surgically removed two tumors grown under the mouse’s skin; they then injected the gel at one tumor-removal site but not the other. While the untreated tumor grew back aggressively, the miRNA hydrogel-treated tumor was barely visible after a month.

“This paper describes a clever use of the tools of peptide self-assembly…to both package and deliver a therapeutic RNA,” says Matthew Tirrell, dean of the University of Chicago’s school of molecular engineering.

The creative two-step design of packaging the miRNA into nanoparticles and putting the nanoparticles in a hydrogel is both novel and crucial for the therapy to work, says Honggang Cui, a materials scientist and engineer at Johns Hopkins University. Cui says that this work is a stellar example of chemists finding vital life-saving applications for designer molecules they have created.