α‐Lipoic Acid‐Based Nanozyme for Treating Acute Epilepsy

Abstract Anti‐epilepsy drugs (AEDs), a common therapeutic approach for clinically treating epilepsy, suffer from low permeability toward the blood‐brain barrier (BBB), side effect risks, and a failure to regulate the pathological microenvironment. These issues hinder the complete control of epilepsy and lead to a vicious cycle of inflammation‐epileptogenesis. Herein, an α‐lipoic acid (LA)‐based nanozyme that loads phenytoin (PHT) and complexes calcium ions (LA@PHT‐Ca²⁺) is developed. This nanozyme combines the functions of delivering AEDs across the BBB and regulating undesirable microenvironments to treat epilepsy. Amphipathic LA self‐assembles into stable nanoparticles in water with BBB crossing ability endowed by the transporting of LA through sodium‐dependent multivitamin transporter. LA's enzyme‐like and redox functions provide LA@PHT‐Ca²⁺ with excellent scavenging effects on several free radicals via cascade reactions, thereby protecting neurons from oxidative stress. Moreover, Ca²⁺ disrupts neuronal respiration, resulting in reduced production of bioenergetic adenosine triphosphate and an improved hypoxic microenvironment. This leads to decreased expression of P‐glycoprotein, a drug‐efflux gating protein. This novel lipoic acid‐based nanozyme, with intrinsic BBB crossing capability, prolonged intracellular drug retention time, and the ability to block the inflammation‐epileptogenesis cycle, presents a satisfactory therapeutic effect in epileptic rats, resulting in attenuated symptoms and an improved microenvironment.