Coordination acid-engineered Prussian Blue affects glycometabolic reprogramming in microglia for epileptic treatment

Seizures induce significant immune and metabolic stress in microglia, but the interaction between these processes remains unclear. This study, utilizing single-nucleus RNA sequencing data from temporal lobe epilepsy (TLE) patients, reveals that reactive oxygen species (ROS) stabilize hypoxia-inducible factor 1-alpha (HIF-1α), thereby inducing glycometabolic reprogramming in microglia and driving the development of a pro-inflammatory phenotype. To address this, a coordination acid-engineered Prussian Blue (PB@ZIF) nanosystem is developed, where Zn²⁺ sites in the zeolitic imidazolate framework (ZIF) lower the local pKa, thereby enhancing the reaction efficiency of PB with free radicals. In vivo experiments using a TLE model demonstrate that PB@ZIF is effectively internalized by microglia and significantly alleviates spontaneous recurrent seizures and seizure-related behaviors. PB@ZIF mitigates microglial inflammatory activation and reduces neuronal injury. Notably, PB@ZIF-induced ROS reduction enhances the enzymatic activity of prolyl hydroxylase domain enzymes, effectively inhibiting HIF-1α-driven glycometabolic reprogramming in microglia. This study identifies a molecular mechanism underlying the immune-metabolic interactions in epilepsy and proposes a promising therapeutic strategy regulating microglial metabolism to improve epilepsy management.