Small Gold Nanoparticles Alleviate Huntington's Disease via Modulating p38α Mitogen-Activated Protein Kinase and Pyruvate Dehydrogenase Kinase 1

Huntington's disease (HD) is a severe neurodegenerative disorder that causes motor impairment and ultimately death. Yet, safe and effective disease-modifying treatments of HD are scarce, and delivery to the HD brain is challenging. Here, we present a small, ∼11 nm polyethylene glycol-coated gold nanoparticle (NP) for brain delivery and treating HD in R6/2 mice. Upon intravenous injection, this NP crosses brain barriers, preferentially accumulates in the brain of R6/2 mice than healthy littermates without pronounced liver or kidney sequestration, diffuses to the cortex and striatum, and enters neurons and microglia. Devoid of known chemical or biological drugs, this NP improves motor deficit as effectively as tetrabenazine (standard therapy for symptomatic relief) and prolongs survival, without long-term brain retention or systemic toxicity. This NP activates the Oxidative Phosphorylation pathway, blocks p38α mitogen-activated protein kinase phosphorylation and pyruvate dehydrogenase kinase 1 activity, and inhibits Pyroptosis. Our data offer molecular insights into gold nanomedicines against neurodegenerative diseases.

Huntington’s disease; gold nanoparticles; nanomedicine; neurodegenerative disease; oxidative phosphorylation; p38α; pyruvate dehydrogenase kinase 1.