This Pill Is Packed With mRNA

Covid vaccines turned mRNA treatments from a long-simmering research topic to dinner table conversations. We remember the shot all too well.

The technology has since begun tackling cancer, liver problems, heart failure, and genetic diseases, with some efforts already in clinical trials.

But these have a universal problem: Needles. Rather than swallowing a pill—like Tylenol—people have to visit health professionals who deliver the treatment with a shot. Regular doses will likely be needed for mRNA treatments that battle chronic diseases. While repeated jabs are tolerable for some, they’re hardly appealing, especially for people afraid of needles.

A new study from Harvard’s Brigham and Women’s Hospital and others said goodbye to the jab. The team engineered a capsule that protects the mRNA payload as it travels through the highly acidic environment of the stomach. In the study, the capsule released the treatment into the digestive tract of animal models of colitis, a chronic inflammation of the colon.

Dubbed RNACap, the capsule is a bit like a multi-stage rocket. The two-compartment design protects the payload and releases it based on natural fluctuations in acidity levels and pressure in the gut. In rats and pigs, RNACap successfully delivered a therapeutic immune molecule that, in just a few hours, eased gut inflammation without notable side effects.

RNACap promises to advance “the development of noninvasive and self-administered oral mRNA therapeutics,” wrote the team.

What Is mRNA Again?

There are many ways to influence how our bodies work. Gene editing changes DNA—the body’s genetic blueprint—by altering disease-causing genes. Small molecules or peptides target the function of proteins. These kinds of drugs range from everyday products like Tylenol to immunotherapies that combat cancer.  

Treatments focused on mRNA are another alternative. Molecules of mRNA carry the genetic instructions cells use to make proteins. In Covid vaccines, mRNA instructs cells to make the virus’s spike protein. This trains the immune system to recognize and fight off the virus. In other cases like cystic fibrosis—a genetic disease that gradually drowns the lung in mucus—mRNA delivers a functional version of a missing protein whose lack causes the disease.

Compared to DNA editors and protein-targeting molecules, mRNA is the best of both worlds. It can change protein levels without altering DNA sequences. This lowers the risk of unexpected mutations in the genome, and the effects of mRNA treatments only stick around for a limited time, making it easier to dial in dosage and limit side effects.

But mRNA molecules are delicate. Most treatments use tiny capsules of fat—known as lipid nanoparticles—to protect mRNA from the body’s enzymes. Turning them into a swallowable pill is harder. Stomach acids and enzymes in the stomach and intestines readily break down foreign mRNA, and a barrier in the gut only allows select nutrients and molecules to pass.

A Swallowable Bypass

The new study designed RNACap to usher mRNA past these obstacles. The team encapsulated mRNA encoding an inflammation-easing molecule called IL-10 inside nanoparticles. These were specially engineered to bypass the intestinal barrier and deliver the payload directly to cells. The fatty blobs were then suspended in a liquid and loaded into the capsule.

This approach makes mRNA readily absorbable in the gut, wrote the team.

The team began development with a common FDA-approved capsule made of gelatin and split it into two sections, with a detachable cap and a carrier for the mRNA liquid. The inside of the capsule is coated in a stretchy membrane to hold the liquid and prevent it from dissolving the outer shell. Another membrane seals the top of the carrier from the cap, which keeps the contents inside the capsule through pressure. In the intestines, the cap rapidly dissolves and releases its pressure on the membrane, allowing it to peel off and free the mRNA contents. The entire capsule is coated in chemicals that can sense acidity and protect it from stomach acid.

The final product is a bit like an extended-release liquid Tylenol gelcap.

After it’s been swallowed, the pill passes through the stomach and the chemical coating and cap gradually dissolve. As the acidity declines, the pill’s sealing membrane releases the mRNA. The gut has an internal rhythm to move things along. The now softer capsule takes advantage of these squeezes to more effectively pump out the mRNA nanoparticles.

A Quiet Place

Inflammation in the bowels, also known as colitis, can lead to uncomfortable and inopportune bathroom visits. There’s often a lag time between symptoms, diagnosis, and treatment.

The team gave rodent models of colitis three RNACap doses spread out across a week or so. Compared to untreated animals, the critters lost less weight and had fewer inflammatory molecules in their colon and blood. Although mRNA treatments can spur unexpected immune responses that damage other organs, the team found no toxic effects in this case.

A subsequent test in pigs, which are more like humans, also found RNACaps released their cargo and increased IL-10 protein levels in the gut and blood after roughly seven hours. The dosage was on the low end of mRNA treatments in clinical trials, suggesting that it’s likely safe.

RNACap isn’t the first gut-stable RNA treatment. A recent study used ginger-derived nanoparticles to deliver a different mRNA molecule to the guts of mice with colitis and healed damaged tissues faster. Capsules using microneedles to inject mRNA into the stomach also tamed inflammation, but the formulation could damage more delicate intestinal tissues.

The team hopes RNACap leads to an affordable, widespread mRNA delivery alternative for colitis, vaccines, and other diseases. They’re working to make the system more shelf-stable, so it could be easier to distribute to remote and resource-limited regions.