Selenium-engineered self-assembling protein nanoparticles rescue synaptic integrity and cognition via ferroptosis inhibition in Alzheimer’s mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective disease-modifying therapies remain elusive. Here, we apply a semantic logic framework of Gene Ontology-based protein function prediction to identify ferroptosis-inhibitory proteins with potential neuroprotective activity. Guided by these predictions, we engineer selenium-modified apolipoprotein A1 supramolecular nanoparticles (Se-NDs) that intrinsically display glutathione peroxidase 4 (GPX4)-like catalytic activity and exhibit high brain penetrance. Se-ND suppresses lipid peroxidation, restores redox balance, and blocks ferroptotic neuronal death, thereby promoting mitochondrial repair and synaptic integrity and reversing structural and functional deficits underlying cognitive decline. Moreover, Se-ND synergizes with anti-inflammatory interventions and other AD-associated pathways. Our findings identify ferroptosis inhibition as a critical disease-modifying mechanism and establish Se-ND as a promising therapeutic avenue for Alzheimer's disease.