Intrahippocampal Supramolecular Assemblies Directed Bioorthogonal Liberation of Neurotransmitters to Suppress Seizures in Freely Moving Mice

Abstract The precise delivery of anti‐seizure medications (ASM) to epileptic loci remains the major challenge to treat epilepsy without causing adverse drug reactions. The unprovoked nature of epileptic seizures raises the additional need to release ASMs in a spatiotemporal controlled manner. Targeting the oxidative stress in epileptic lesions, here we developed the reactive oxygen species induced in situ supramolecular assemblies which synergized bioorthogonal reactions to deliver inhibitory neurotransmitter (GABA) on‐demand. Tetrazine‐bearing assembly precursors underwent oxidation and selectively self‐assembled under pathological conditions inside primary neurons and mice brains. Assemblies induced local accumulation of tetrazine in the hippocampus CA3 region, which allowed the subsequent bioorthogonal release of inhibitory neurotransmitters. For induced acute seizures, the sustained release of GABA extended the suppression effect than the direct supply of free GABA. In the model of permanent damage of CA3, bioorthogonal ligation on assemblies provided a reservoir of GABA which behaved prompt release upon 365 nm irradiation. Incorporated with the state‐of‐the‐art microelectrode arrays, we elucidated that the bioorthogonal release of GABA shifted the neuron spike waveforms to suppress seizures at the single‐neuron precision. The strategy of in situ supramolecular assemblies directed bioorthogonal prodrug activation should be promising for the effective delivery of ASMs to treat epilepsy. This article is protected by copyright. All rights reserved