Neuroinflammation　plays　a　critical　role　in　Alzheimer＇s　disease　(AD).　However,　it　is　still　unknown　if　neuroinflammation　can　be　effectively　treated　using　selenium　nanoparticles　(SeNPs)　with　different　surface　modifications.　In　this　study,　SeNPs　were　coated　with　dihydromyricetin　(DMY),　a　natural　polyphenol,　to　obtain　DMY@SeNPs.　Given　that　DMY@SeNPs　are　unstable　under　physiological　conditions,　they　were　decorated　step-by-step　with　chitosan　(CS/DMY@SeNPs)　and　with　the　blood　brain　barrier　(BBB)　targeting　peptide　Tg　(TGNYKALHPHNG)　to　yield　Tg-CS/　DMY@SeNPs,　which　significantly　reduced　the　aggregation　of　A　beta　and　improved　the　anti-inflammatory　effects　of　SeNPs　in　vitro.　The　mechanisms　of　CS/DMY@SeNPs　and　Tg-CS/DMY@SeNPs　on　regulating　neuroinflammation　are　different.　Only　Tg-CS/DMY@SeNPs　can　cross　the　BBB;　therefore,　Tg-CS/DMY@SeNPs　more　successfully　inhibited　A　beta　aggregation　and　reduced　inflammatory　cytokine　secretion　via　the　NF-kappa　B　pathway　in　the　brain　of　APP/PS1　mice　compared　to　CS/DMY@SeNPs.　Furthermore,　both　types　of　nanoparticles,　however,　were　able　to　repair　the　gut　barrier　and　regulate　the　population　of　inflammatory-related　gut　microbiota　such　as　Bifidobacterium,　Dubosiella,　and　Desulfovibrio.　Of　note,　the　relative　abundance　of　Gordonibacter　was　only　enhanced　by　Tg-CS/DMY@SeNPs,　thereby　downregulating　the　protein　expression　of　the　NLRP3　inflammasome　and　the　concentrations　of　serum　inflammatory　factors.　This　demonstrates　that　Tg-CS/DMY@SeNPs　ameliorate　neuroinflammation　through　the　gut　microbiota-NLRP3　inflammasome-brain　axis.　Overall,　our　data　suggest　that　Tg-CS/DMY@SeNPs　are　an　ideal　drug　candidate　for　AD　treatment.