Self-assembling ferritin nanoplatform enables amyloid-β-targeted immunotherapy and cognitive rescue in APP/PS1 mice

Alzheimer’s disease (AD) is a progressively neurodegenerative disorder. The accumulation and pathological aggregation of amyloid-β (Aβ) peptides are key events in the occurrence and progression of AD, positioning Aβ-targeted immunotherapy as a precision therapeutic approach. We present a click chemistry-assisted modular nanoparticle vaccine, Fe-Spy-3CAβ, constructed via SpyCatcher-SpyTag-mediated site-specific conjugation of Aβ1-6 epitopes onto engineered ferritin nanocages. This self-assembling nanoparticle vaccine elicited enhanced immunogenicity in APPswe/PSEN1dE9 transgenic mice, generating high-titer antibodies that specifically recognize neurotoxic Aβ42 oligomers. The vaccine promotes robust clearance of Aβ plaques in the cortical and hippocampal regions while rescuing spatial memory deficits. Notably, sex-specific differences are observed in pathological clearance and behavioral improvements, with male mice exhibiting better cognitive performance and reduced neuroinflammation compared to female counterparts, highlighting sex-specific differences in AD progression. Further immunization of rhesus monkeys confirmed the potent immunogenicity and favorable safety of Ferritin-based Aβ vaccine. Critically, serum antibodies from vaccinated monkeys specifically bound Aβ plaques in AD model mouse brain tissues.   Our modular nanoassembly platform overcomes key limitations of conventional AD vaccines regarding immune activation efficiency and safety profiles, while offering a versatile approach for developing immunotherapies for neurodegenerative diseases.