Mitochondrial dysfunction, primarily induced by oxidative stress, triggers excessive reactive oxygen species (ROS) production. This cascade results in ATP depletion, the opening of mitochondrial permeability transition pores, and a consequent cytokine surge. These pathological events ultimately lead to the loss of dopaminergic neurons and α-synuclein accumulation, both of which are key factors in the pathogenesis and progression of Parkinson’s disease (PD). However, achieving a synergistic strategy that combines potent exogenous ROS scavenging with activation of endogenous antioxidant defenses has remained challenging. Here, we introduce glutathione (GSH)–modified selenium nanoparticles (G-Se NPs) that specifically eliminate bursts of neuronal mitochondrial ROS (mtROS) while simultaneously upregulating selenoprotein P (SelP) to strengthen intrinsic antioxidant capacity. On the one hand, G-Se NPs directly remove excess ROS through multi-enzymatic activity; on the other hand, they accumulate in the liver to promoting SelP synthesis. Notably, SelP can cross the blood-brain barrier, making it the principal transporter for delivering selenium to the brain, thereby initiating endogenous antioxidant pathways and conferring robust overall antioxidant effects. Consequently, G-Se NPs protect mitochondria, reverse neuroinflammation, and inhibit neuronal apoptosis. Across cell, nematode, and mouse PD models, G-Se NPs produced restoring dopaminergic neuron counts by 87.5% and extending lifespan in nematodes by 22 days, with an ultralow dose (1.5 mg/kg) sufficient to reverse behavioral disorders, noting that G-Se NPs are safe and well tolerated at therapeutic doses. This exogenous–endogenous synergy—combining nanoparticle-mediated ROS clearance with SelP-driven antioxidant amplification—signals a paradigm shift in PD nanotherapy, advancing from symptomatic relief toward modification of disease progression and supporting their promise as a safe, translatable PD nanotherapy.
Lei et al. (Sat,) studied this question.