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Abstract We have developed a genetically modified second-generation probiotic for the localized delivery of a known mitigator to the GI tract in order to reduce damage and regenerate tissue after exposure to ionizing radiation. Mitigating the effects of ionizing radiation exposure is critical for improving survival in the event of a radiological or nuclear (RAD-NUC) incident, where exposure could lead to hematopoietic or gastrointestinal (GI) acute radiation syndrome (ARS). While Neupogen and Neulasta have been granted label extensions by the FDA to treat casualties of a RAD-NUC incident, these drugs do not prevent GI-ARS-related mortality. There currently are no FDA-approved mitigators for GI-ARS. To address this critical need, we have engineered Limosilactobacillus reuteri to produce the therapeutic cytokine INF-β and target the mitigator to the small intestines to recover intestinal stem cells, regenerate the radiation-sensitive intestinal crypts, and dramatically improve survival from 0–10% to 70–80% after exposure to GI-ARS-inducing radiation doses. This is a new strategy for therapeutic drug delivery, using a probiotic that can be administered orally, facilitating its use in the context of a resource-limited mass casualty scenario. In addition to mitigating injury following a RAD-NUC incident, this approach is also applicable to radioprotection of the intestine during abdominal radiotherapy. Symptoms of GI toxicity affect 60–80% of the >300,000 patients that receive pelvic or abdominal radiation therapy per year. This project is based on an entirely new concept that addresses the fundamental major limitations associated with delivery of any potential radiation mitigator of GI syndrome, including (i) non-invasive administration, (ii) targeted delivery of the therapeutic, (iii) maintained bioavailability of the therapeutic at efficacious dose, (iv) trivially scalable to produce, and (v) no need for formulation. The goal of this project is to develop an FDA-approved mitigator for radiation-induced GI injury. We propose critical studies to characterize the radiation dose response, establish the pharmacodynamics of the drug, and characterize the mechanism of drug release in the intestine. These studies are in response to FDA feedback and are aligned with drug approval under the Animal Rule. Successful completion of this work will place this probiotic drug on a strong path towards eventual FDA approval.