Nucleic acids are enabling a new generation of therapeutics and vaccines to treat and prevent a range of diseases. While these therapies have typically been limited to parenteral dosing, patients and clinicians prefer oral dosage forms. Furthermore, oral delivery enables local transfection of cells in the gastrointestinal tract not easily targeted via parenteral administration. To address these challenges, we synthesized and screened a library of branched hybrid poly(β-amino ester) mRNA nanoparticles for transfection efficiency; then we combined the highest performing formulations with ingestible milli-injector capsules capable of delivering formulations directly into gastric tissue. We validated the performance of formulations and devices in rodents and pigs, demonstrating protein translation in the delta, gastric, and parietal cells of the gastric mucosa, in addition to systemic uptake. We anticipate oral delivery of mRNA could facilitate rapid deployment of episodic interventions, such as vaccines, and support long-term therapies.