These complementary biological and physicochemical actions synergistically enhance tumor cell killing and markedly improve radiosensitivity <i>in vitro</i> and <i>in vivo</i>.<h4>Conclusions</h4>This study establishes a synergistic nanotherapeutic strategy to concurrently disrupt the HIF-1α/ATR axis and augment radiodynamic ROS production. The gene discussed is HIF1A; the disease is neoplasm.