This study presents a DNA tetrahedron-based nanosuit for efficient delivery of amifostine (AMF) and multi-organ radioprotection. The nanosuit, composed of tetrahedral framework nucleic acids (tFNAs) and AMF, was synthesized to address the short half-life issue of AMF, which limits its clinical applications. In vitro and in vivo experiments demonstrated that the nanosuit effectively protected normal cells from ionizing radiation (IR)-induced DNA damage by regulating the ATM/ATR signaling pathway, reducing oxidative stress, and enhancing cell survival. In a mouse model of accidental total body irradiation (TBI), the nanosuit significantly improved survival rates and accelerated hematopoietic recovery, while in a Lewis lung cancer model, it selectively protected normal organs without interfering with tumor control. The nanosuit's prolonged half-life and enhanced radioprotection make it a promising strategy for radiotherapy protection with significant clinical translation potential.This study presents a DNA tetrahedron-based nanosuit for efficient delivery of amifostine (AMF) and multi-organ radioprotection. The nanosuit, composed of tetrahedral framework nucleic acids (tFNAs) and AMF, was synthesized to address the short half-life issue of AMF, which limits its clinical applications. In vitro and in vivo experiments demonstrated that the nanosuit effectively protected normal cells from ionizing radiation (IR)-induced DNA damage by regulating the ATM/ATR signaling pathway, reducing oxidative stress, and enhancing cell survival. In a mouse model of accidental total body irradiation (TBI), the nanosuit significantly improved survival rates and accelerated hematopoietic recovery, while in a Lewis lung cancer model, it selectively protected normal organs without interfering with tumor control. The nanosuit's prolonged half-life and enhanced radioprotection make it a promising strategy for radiotherapy protection with significant clinical translation potential.