Abstract <p>Acute radiation sickness (ARS) is a systemic disease caused by exposure to high doses of ionizing radiation within a short period. The development of effective high-dose radiation protectants remains a critical yet unresolved challenge in this field. The fabrication of metal-phenolic networks (MPNs) is emerging as a promising strategy for the prevention and treatment of ARS. In light of this, we have adopted a novel nano-self-assembly strategy based on metal–organic coordination synthesis to develop the EGCG-Fe-Cur nanosystem, which not only exhibits robust in vitro antioxidant activity and reactive oxygen species (ROS) responsiveness but also enhances bioavailability and water solubility, thereby minimizing adverse effects. In vitro cell studies have shown that EGCG-Fe-Cur alleviates G₂/M phase cell cycle arrest in AHH-1 cells after γ-ray irradiation, reduces DNA damage, and lowers levels of ROS and lipid peroxidation. Animal experimental results indicate that EGCG-Fe-Cur significantly increases the survival rate of irradiated mice, efficiently restores their hematopoietic system function, and, within a specific concentration range, provides better protective effects than the traditional radioprotectant WR2721. Mechanistic exploration reveals that this nanoparticle maintains normal mitochondrial morphology and function, effectively inhibits ferroptosis and apoptosis processes by activating the PPARγ/NRF2 signaling pathway, thereby offering comprehensive and multi-level radiation protection for the organism.</p> Graphical abstract <p></p>