The　brain-gut　axis　plays　an　important　role　in　regulating　cognitive　ability　in　obesity-related　Alzheimer＇s　disease　(AD).　In　this　study,　we　aimed　to　investigate　the　correlation　between　the　barrier　penetration　ability　of　the　DMY　nanodelivery　system　in　vivo　and　the　regulation　of　the　gut-brain　axis　to　alleviate　cognitive　impairment.　Brain-targeted　peptide　(TGN:　TGNYKALHPHNG)　and　DMY　loaded　chitosan　(CS)/sodium　tripolyphosphate　(TPP)　nanoparticles　(TGN-DMY-CS/TPP-NPs)　and　ovalbumin　(OVA)/sodium　carboxymethylcellulose　(CMC)　nanoparticles　(TGN-DMY-OVA/CMC-NPs)　were　prepared.　TGN-DMY-CS/TPP-NPs　demonstrated　superior　mucus　penetration　and　BBB　targeting　ability　compared　to　TGN-DMY-OVA/CMC-NPs,　while　the　latter　showed　notable　intestinal　accumulation.　TGN-DMY-CS/TPP-NPs　treatment　significantly　increased　the　relative　abundance　of　Alistipes　and　Rikenellaceae_RC9_gut_group,　and　TGN-DMY-OVA/CMC-NPs　treatment　obviously　enhanced　the　relative　abundance　of　Lactobacillus.　Furthermore,　both　nanoparticles　alleviated　lipid　metabolism　disorder,　oxidative　stress,　and　inflammation　in　the　liver,　reduced　oxidative　stress　and　neuroinflammation　in　the　brain,　inhibited　neuronal　apoptosis,　and　enhanced　mitochondrial　biogenesis　and　synaptic　plasticity　in　obesity-related　AD　mice.　Despite　different　mucus　penetration　and　biodistribution,　their　similar　efficacy　in　improving　obesity-related　AD　is　attributed　to　the　gut-brain　bidirectional　connection.　©　2025　Elsevier　B.V.