Chiral Spindle-like Nanorods Reprogram Neuroinflammation by Catalyzing α-Ketoglutarate Biosynthesis

Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, and breakthroughs in effective intervention strategies are urgently needed. Here, we report that chiral spindle-like Fe₇Se₈ nanorods (NRs) promote α-ketoglutarate (AKG) biosynthesis, providing a new potential route for AD intervention through modulation of neuroimmune homeostasis. Oral administration of <i>L</i>-NRs significantly restored intestinal microbiota homeostasis in 3 × Tg AD model mice, markedly enriched <i>Lactobacillus johnsonii</i>, and enhanced biosynthesis of the metabolite AKG, which reversed cognitive impairment and neuronal degeneration in 5 × FAD mice. Moreover, AKG levels in the clinical serum and cerebrospinal fluids were found to be significantly lower in patients with AD than in healthy controls. Mechanistic studies revealed that <i>L</i>-NRs efficiently promoted AKG biosynthesis through scavenging reactive oxygen species (ROS) to restore the activities of three enzymes in the biosynthesis pathway. Crucially, these NRs are broken down by gastric juice into smaller nanoparticles and subsequently into ions in the intestines. Further studies explored that AKG crossed the blood-brain barrier via cooperatively mediated transport proteins, targeted microglial phenotypic switching, reprogrammed the neuroinflammatory microenvironment, and ultimately ameliorated cognitive deficits and neuronal pathological alterations. Our findings suggest that AKG might serve as a therapeutic drug for the precise treatment of neurodegenerative diseases.