Intranasal delivery of BDNF-enriched small extracellular vesicles ameliorates cognitive impairment and Alzheimer’s disease-like pathology in APP/PS1 mice

Alzheimer’s disease (AD), the leading cause of dementia, still lacks broadly effective disease-modifying therapies. Here, we engineered brain-derived neurotrophic factor (BDNF)-enriched small extracellular vesicles (BDNF-sEVs) from human induced pluripotent stem cell-derived mesenchymal stem cells (MSCs) and delivered them intranasally to APP/PS1 mice. Behavioral assessments indicated that BDNF-sEVs treatment improved cognitive performance in APP/PS1 mice and appeared to exert greater effects than unmodified sEVs. Intranasally delivered mCherry-labeled sEVs were observed in AD-vulnerable brain regions and were internalized by hippocampal neurons and activated microglia. At the pathological level, BDNF-sEVs treatment was accompanied by reduced hippocampal 6E10 immunoreactivity, improved synaptic plasticity, lower hippocampal densities of Iba1 + and Iba1 + CD68 + cells, increased neuronal density, and alleviated mitochondrial ultrastructural damage. In addition, BDNF-sEVs treatment was associated with improved aquaporin-4 distribution index and enhanced BDNF/TrkB-Akt/PLCγ1/Erk signaling. Proteomic analysis further suggested partial normalization of AD-associated protein-expression alterations, with enrichment of lipid metabolism-related pathways, including PPAR signaling, as well as neuroactive ligand–receptor interaction pathways. Repeated intranasal administration of BDNF-sEVs showed preliminary tolerability, with no overt histopathological abnormalities in major peripheral organs or nasal mucosa. Together, these findings provide preclinical evidence that intranasal delivery of BDNF-sEVs ameliorates cognitive and pathological phenotypes in the hippocampus of APP/PS1 mice, supporting further investigation of BDNF-sEVs as a candidate cell-free intervention strategy for AD.