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Researchers at Harvard Medical School and Brigham and Women's Hospital designed an ingestible capsule that delivers liquid mRNA to the intestines, producing gene expression and reducing inflammation in rats.

Injection remains the standard for mRNA-based drugs, including vaccines. Injections, usually administered by a health professional, limit home use in chronic conditions requiring repeat doses and slow distribution during outbreaks. Patients prefer oral formulations over needles generally, and an oral intake seems especially reasonable when targeting gastrointestinal (GI) tissues.

Barriers such as stomach acid and intestinal mucus interfere with mRNA getting to where it needs to go when delivered orally. Nanoparticles have been shown to offer some protection but still degrade by the time they reach the upper GI tract.

In the study, "Oral delivery of liquid mRNA therapeutics by an engineered capsule for treatment of preclinical intestinal disease," in Science Translational Medicine, researchers engineered RNACap to deliver liquid mRNA nanoparticle therapeutics to intestinal epithelial cells for in vivo transfection in Sprague-Dawley rats and Yorkshire swine.

RNACap uses pH-sensitive coatings and pressure-triggered release membranes to remain intact in the stomach. Contents are released in the intestine in response to neutral pH and peristalsis.

Nanoparticles were formulated using G0-C14, PLGA, and PEG-lipid components for mucus penetration and endosomal escape. A 5% DMPE-PEG formulation showed optimal transfection in vitro.

In rats, RNACap delivered interleukin-10 (IL-10) mRNA, resulting in elevated IL-10 protein levels in serum and colon tissue. IL-10鈥搈RNA RNACap significantly reduced proinflammatory cytokines and improved outcomes in acute and delayed dextran sodium sulfate鈥搃nduced colitis models.

Toxicity was not detected by blood chemistry, cytokine panels, or histological examination. Serum cytokine levels remained low following RNACap dosing, with only modest increases in IL-1Ra, IL-5, and IL-6.

In the swine model, intestinal administration of RNACap led to measurable mRNA expression within 8.5 hours.

The authors conclude that RNACap represents a promising platform for the oral delivery of mRNA therapeutics for intestinal disease and potentially other conditions.

Compatibility with liquid formulations avoids the need for lyophilization, a cost and time-consuming process of removing water to produce dry formulations that can reduce mRNA efficacy and complicate global distribution.

Expression in swine intestines supports the feasibility of human translation, with some further optimization for shelf life and future clinical validation.

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