Green Onion-Derived Exosome-like Nanoparticles Prevent Ferroptotic Cell Death Triggered by Glutamate: Implication for GPX4 Expression

Abstract

In recent years, alongside research on mammalian-derived exosomes, there has been increasing interest in the physiological activities of plant-derived exosome-like nanoparticles (PDEN). The biocompatibility, minimal side effects, and diverse bioactive ingredients contained in PDEN make them valuable as potential therapeutic agents for an extensive range of diseases. In this study, we cost-effectively isolated exosome-like nanoparticles from green onion (Allium fistulosum) using polyethylene glycol and examined their biological activity in HT-22 cells exposed to glutamate. The isolated green onion-derived exosome-like nanoparticle (GDEN) had an average diameter of 167.4 nm and a zeta potential of −16.06 mV. GDEN effectively inhibited glutamate-induced Ca2+ influx and lipid peroxidation, thereby preventing ferroptotic cell death in HT-22 mouse hippocampal cells. Additionally, GDEN reduced the intracellular iron accumulation by modulating the expression of proteins associated with iron metabolism, including transferrin receptor 1, ferroportin 1, divalent metal transporter 1, and ferritin. Notably, GDEN upregulated the expression of glutathione peroxidase 4, a potent antioxidant protein involved in ferroptosis, along with an increase in glutathione synthesis. These findings indicate that GDENs have the potential to serve as bioactives from natural sources against glutamate-induced neuronal cell death, like ferroptosis. This study advances the investigation into the potential medical applications of GDEN and may provide a new approach for the utilization of these bioactive components against neuronal disorders.