The　pathology　of　Alzheimer＇s　disease　(AD)　is　highly　correlated　with　obesity-induced　insulin　resistance.　Resveratrol　(Res)　is　a　natural　phenol　that　demonstrates　a　neuroprotective　effect,　but　the　bioactivity　of　Res　is　low　in　vivo.　Here,　chitosan　(CS)　was　cross-linked　with　sodium　tripolyphosphate　(TPP)　to　encapsulate　low　water　solubility　Res.　Next,　a　brain-targeted　peptide　(TG:　TGNYKALHPHNG)　was　modified　on　the　surface　of　Res-loaded　CS/TPP　nanoparticles　(TG-Res-CS/TPP-NPs)　to　specifically　deliver　Res　to　the　brain.　Morris　water　maze　results　indicated　that　cognitive　impairments　were　ameliorated　by　TG-Res-CS/TPP-NPs　in　obesity-related　AD　mice.　Obesity-related　insulin　resistance　promotes　Tau　phosphorylation　and　Aβ　aggregation　in　the　brain.　Administration　of　TG-Res-CS/TPP-NPs　alleviated　lipid　deposition-induced　insulin　resistance　and　decreased　the　level　of　phosphorylated　Tau　and　Aβ　aggregation　via　the　JNK/AKT/GSK3β　pathway.　Additionally,　TG-Res-CS/TPP-NPs　transported　across　blood-brain　barrier　which　in　turn　increased　glucose　transporter　expression　levels,　antioxidant　enzyme　activity　and　inhibited　microglial　cell　activation.　Thus,　TG-Res-CS/TPP-NPs　were　more　effective　than　Res-CS/TPP-NPs　at　regulating　glucose　homeostasis,　oxidative　stress　and　neuroinflammation　in　the　brain.　Moreover,　inflammatory,　lipid　metabolism　and　oxidative　stress-related　gut　microbiota　including　Helicobacter,　Colidextribacter,　Anaerotruncus,　Parasutterella,　Allobaculum,　Alloprevotella,　Alistipes,　Bifidobacterium　and　Candidatus_Saccharimonas　were　also　regulated　by　TG-Res-CS/TPP-NPs.　This　work　indicates　the　potential　use　of　TG-Res-CS/TPP-NPs　for　the　delivery　of　Res.　©　2023　Elsevier　Ltd