Stabilizing therapeutic RNA for delivery by mouth requires overcoming harsh gastrointestinal conditions and preserving biological activity until the RNA reaches target cells. The gut exposes nucleic acids to low pH, abundant ribonucleases, a thick mucus barrier, and tight epithelial junctions, all of which cause rapid degradation or prevent uptake. These challenges motivate combined chemical and formulation strategies to protect RNA, limit immune sensing, and enable transcytosis across the intestinal epithelium.
Chemical and sequence strategies
Modifying the RNA backbone and bases reduces susceptibility to nucleases and innate immune recognition. Katalin Karikó at the University of Pennsylvania and Drew Weissman at the University of Pennsylvania showed that incorporation of modified nucleosides can blunt pattern-recognition receptor responses and improve stability, a principle underpinning modern mRNA therapeutics. Nucleoside modification and optimized untranslated regions also increase translational persistence. Such changes do not completely eliminate degradation risk in the gut, but they substantially raise the baseline stability that formulation can build on.Formulation, coatings, and delivery vehicles
Encapsulation inside protective carriers is central to oral approaches. Pieter Cullis at the University of British Columbia and Daniel Anderson at Massachusetts Institute of Technology have advanced lipid nanoparticle and lipid-like systems that shield RNA from enzymes and aid cellular entry; similar protective roles are played by polymeric nanoparticles pioneered by Robert Langer at Massachusetts Institute of Technology. Enteric or pH-responsive coatings can prevent release in the stomach and enable payload release in the small intestine. Mucoadhesive or mucus-penetrating materials are used to either prolong residence time at the epithelium or to traverse the mucus layer, while targeted ligands or exploitation of M-cell transcytosis in Peyer’s patches can enhance uptake into immune or epithelial cells. Alternative carriers like exosomes or bacterial outer membrane vesicles offer biologically derived camouflage that may reduce inflammation and facilitate cellular uptake.Combining enteric protection, nanoparticle encapsulation, and chemical RNA stabilization can reduce cold-chain dependence and simplify dosing, which has important cultural and territorial implications: oral formulations are often more acceptable in communities with needle hesitancy and easier to distribute in low-resource settings. However, consequences include the need for rigorous safety evaluation of gut interactions, possible effects on the microbiome, and ensuring controlled systemic exposure to avoid off-target effects. Regulatory pathways will require demonstration of reproducible manufacturing and long-term safety for both the RNA modifications and the delivery materials. Progress is promising, but most approaches remain in preclinical or early clinical stages, requiring integration of chemistry, formulation science, and clinical validation.