Polyelectrolyte nanocomplexes responsive to pathological neuronal discharge realize precise drug delivery for treating acute epilepsy via neurotransmitter homeostasis modulation

Abstract

Abnormal neuronal discharge due to disordered neurotransmitter homeostasis and harsh inflammation in epileptic focus is prone to cause recurrent seizures. However, current difficulties in drug delivery across blood-brain barrier (BBB) and regulation of complex pathological microenvironment hinder complete control of epilepsy with clinical therapies. Herein, a novel microenvironment-responsive drug-loaded polyelectrolyte nanocomplex (HCT-Fu@VB₆) formed by electrostatic self-assembly between tryptophan-modified hydroxypropyl chitosan (HCT) and fucoidan (Fu) with efficient vitamin B₆ (VB₆) loading, is developed for potent epilepsy treating, innovatively aiming to modulate neurotransmitters balance and attenuate the neuroinflammatory responses. Specifically, HCT confers the nanoparticles with specific binding affinity towards L-type amino acid transporter 1 expressed on brain endothelial cells, thereby significantly contributing to enhanced trans-BBB drug delivery efficiency. The fucoidan-containing polyelectrolyte nanocomplexes serve to provide intrinsic antioxidant property. Notably, the prepared polyelectrolyte nanocomplexes are dissociated in response to the mimic pathological neuronal discharges due to disturbed electrostatic equilibrium, facilitating accelerated VB₆ release for enhanced oxidative stress mitigation and effective neurotransmitter homeostasis modulation, acting as a competitive antagonist of ATP-gated purinergic P2RX7. The developed HCT-Fu@VB₆ nanoparticles demonstrate significant therapeutic efficacy as an electrically responsive trans-BBB drug delivery system, remarkably reducing seizure in epileptic rats while maintaining an excellent safety profile.