The　effect　of　digestion　on　nanocarriers　will　affect　the　release　and　pharmacological　effects　of　bioactive　compounds　in　delivery　systems.　The　digestion　of　cellulose　is　limited　to　gut　microbiota,　which　offers　a　new　research　strategy　for　targeted　delivery　of　bioactive　compounds.　Herein,　positively　charged　cellulose-like　chitosan/polyvinylpyrrolidone　nanofiber　was　prepared　to　improve　the　residence　time,　colon　target　and　gut　microbiota　regulation　activity　of　quercetin　decorated　selenium　nanoparticles　(QUE@SeNPs/CS/PVPNFs).　Selenium　nanoparticles　block　the　degradation　of　quercetin　and　QUE@SeNPs/CS/PVPNFs　only　decompose　when　caused　by　chitosanase　secretion　from　gut　microbiota.　In　vivo　imaging　showed　that　the　residence　time　of　QUE@SeNPs/CS/PVPNFs　was　longer　than　that　of　QUE@SeNPs.　Thus,　it　significantly　decreased　the　lipid　concentrations　in　liver,　which　further　inhibited　insulin　resistance　in　mice.　Moreover,　QUE@SeNPs/CS/PVPNFs　treatment　improves　gut　barrier　integrity,　increased　the　relative　abundance　of　anti-obesity　and　anti-inflammation　related　bacterial　including　Akkermansia,　Lactobacillus　and　Bacteroides.　Consequently,　the　inflammatory　factor　(IL-β　and　TNF-α)　levels　in　gut,　liver　and　brain　were　also　decreased.　Nissl　and　PSD-95　staining　indicated　that　QUE@SeNPs/CS/PVPNFs　ameliorated　synapse　dysfunction　in　the　brain.　Therefore,　QUE@SeNPs/CS/PVPNFs　has　a　greater　effect　than　QUE@SeNPs　in　improving　cognitive　ability　in　Morris　water　maze.　Overall,　QUE@SeNPs/CS/PVPNFs　with　prolonged　residence　time　attenuates　cognitive　disorder　via　gut-liver-brain　axis　in　AD.　©　2024　Elsevier　B.V.