Dual-action selenium nanodrugs confer synergistic protection against Parkinson’s Disease via mitochondrial-targeted antioxidant therapy and selenoprotein p-mediated selenium mobilization

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.