Oral delivery of liquid mRNA therapeutics by an engineered capsule for treatment of preclinical intestinal disease

Oral delivery of messenger RNA (mRNA) therapeutics could offer noninvasive and self-administered treatments and vaccinations. However, the development of oral mRNA therapeutics remains challenging because of the degradative conditions of the gastrointestinal (GI) tract. Here, we engineered a capsule-based device, named RNACap, designed for oral delivery of liquid mRNA nanoparticle (NP) therapeutics to the intestines. RNACap protects mRNA from the acidic stomach environment while allowing rapid release into the intestines in response to intestinal neutral pH, pressure release due to the dissolution of capsule cap, and natural intestinal contractions (peristalsis). This process enables NP-mediated delivery of mRNA into intestinal cells for in vivo transfection. We optimized an NP formulation for rapid intestinal mRNA delivery. In rat and porcine models, we confirmed that the RNACap remains intact in the stomach but releases its contents within the intestines. The release of mRNA NPs led to the expression of multiple mRNAs. The therapeutic effect of the RNACap was demonstrated by acute and delayed treatment in two rat colitis models. Orally administered RNACaps loaded with mRNA encoding interleukin-10 (<i>IL-10</i> mRNA NP) reduced proinflammatory cytokine concentrations in both blood and tissues, ultimately alleviating colitis. Furthermore, using a large-animal model of swine, we showed that RNACaps remained intact in the stomach, disassembled in the intestine, and resulted in robust mRNA expression just 8.5 hours after administration. RNACap represents a promising platform for the oral delivery of liquid mRNA therapeutics to the GI tract for treating challenging intestinal diseases and potentially other conditions.