Effective oral countermeasures against ionizing radiation-induced damage without hindering cancer radiotherapy.

High-dose ionizing radiation induces severe multi-organ injury, yet no broadly effective, orally available countermeasure has been validated. Here we describe a fully oral, multi-component formulation comprising bioavailable polyphenol derivatives (pterostilbene cocrystals and silybin-phosphatidylcholine), the NAD⁺ precursor nicotinamide riboside, and captopril, an angiotensin-converting enzyme inhibitor with established radiomitigative activity that synergizes with the polyphenols. This combination provides robust systemic radioprotection, enabling long-term survival in 90% of mice exposed to a lethal (LD50/30) dose of X-rays. Mechanistically, the formulation mitigates hematopoietic, intestinal, and neuromotor injury while enhancing DNA repair, suppressing oxidative stress, preserving NAD⁺ homeostasis, and activating autophagy. In intestinal epithelial cells, it markedly reduces radiation-induced apoptosis, inflammatory signaling, and mitochondrial dysfunction through coordinated modulation of Nrf2, NF-κB, and sirtuin-regulated stress responses. Critically, normal tissue protection does not compromise tumor control. In triple-negative breast cancer models, irradiation-induced tumor regression is preserved, whereas in glioblastoma (a typically radioresistant malignancy) tumor radiosensitivity is significantly enhanced via sustained oxidative stress, reduced PARP1 expression, and inhibition of HIF-1α and VEGF signaling. Collectively, these findings define an orally deployable, mechanistically integrated strategy that protects normal tissues while preserving or augmenting tumor radiosensitivity, supporting its translational potential as a practical and effective countermeasure against ionizing radiation exposure.