The　onset　of　Alzheimer’s　disease　(AD)　is　significantly　influenced　by　oxidative　stress.　Trace　element　selenium　(Se)　can　be　incorporated　into　selenoproteins　to　participate　in　redox　regulation.　In　our　previous　study,　it　was　found　that　brain-targeting　chlorogenic　acid-modified　selenium　nanoparticles　(SeNPs)　could　effectively　relieve　oxidative　stress　in　AD.　However,　the　main　mechanism　of　polyphenol-decorated　SeNPs　on　antioxidant　enzymes　such　as　glutathione　peroxidase　is　still　unknown.　Dihydromyricetin　(DMY)　is　one　polyphenol　that　has　neuroprotective　effects　through　antioxidant　activities.　In　this　study,　chitosan　(CS)　was　introduced　as　a　stabilizer　for　the　synthesis　of　a　brain-targeted　peptide　(Tg:　TGNYKALHPHNG)　and　DMY-modified　SeNPs　(Tg-CS/DMY@SeNPs).　Tg-CS/DMY@SeNPs　could　improve　the　solubility　of　DMY　and　exhibited　better　free　radical　scavenging　ability　than　DMY.　Meanwhile,　Tg-CS/DMY@SeNPs　significantly　enhanced　the　activity　of　antioxidant　enzymes,　which　effectively　inhibited　ROS　accumulation　in　Aβ　aggregate-induced　PC12　cells.　More　importantly,　Tg-CS/DMY@SeNPs　could　activate　the　Nrf2/Keap-1　signaling　pathway　to　regulate　the　activity　of　antioxidant　enzymes,　especially　selenophenase　glutathione　peroxidase　in　the　brain　and　liver　of　APP/PS1　mice.　In　that　case,　Tg-CS/DMY@SeNPs　also　prevented　oxidative　damage-induced　apoptosis　by　inhibiting　the　Caspase-3　signaling　pathway　in　the　brain　and　liver　of　APP/PS1　mice.　Finally,　Tg-CS/DMY@SeNPs　remarkably　improved　cognitive　disorders　in　the　APP/PS1　mice.　These　results　indicated　that　Tg-CS/DMY@SeNPs　exhibited　promising　therapeutic　effects　in　the　antioxidant　therapy　of　AD.　©　2024　American　Chemical　Society.