Pharmacological treatment of epilepsy presents several challenges, particularly the ineffectiveness of antiseizure medicines (ASMs) in modifying disease. In fact, the removal of reactive oxygen species (ROS) and preconditioning with tolerable dose of nitric oxide (NO) can activate neuroprotective mechanisms during latency and enhance tolerance to oxidative stress during seizures. To address this, a ROS-responsive cascade Nano-formulation (RRCN) is developed, which will transform ROS into NO. Remarkably, RRCN significantly reduces seizure severity, prolongs seizure latency, and extends inter-seizure intervals, though it does not increase the latency of generalized seizures. Microglia, the primary immune cells of the brain, play a crucial role in the initiation and progression of epilepsy. In the kainic acid (KA) epilepsy model, microglial processes elongate, branching increases, and interactions between microglia and neurons are strengthened in the CA1 and CA3 regions of the hippocampus compared to the Vehicle group. RRCN reverses these dynamic changes in microglia and their interactions with neurons, which are mediated by the NO/HIF/ErBb2 pathway. Thus, RRCN can inhibit seizures generalization by preconditioning the dynamic changes of microglia.