Engineered 3D cultured human nasal mucosa mesenchymal stem cell derived sEVs for targeted brain‐derived neurotrophic factor delivery to enhance neurogenesis and attenuate brain damage

Abstract Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons. However, conventional therapies primarily manage symptoms rather than promote neural restoration. Mesenchymal stem cell‐derived small extracellular vesicles (sEVs) represent promising therapeutic strategies, but their clinical utility is limited by poor brain‐targeting efficiency and low loading capacity. To address these limitations, we developed a nanomedicine platform (BDNF@RVG‐sEVs) using a membrane fusion strategy. We fused high‐potency human nasal mucosa mesenchymal stem cell derived sEVs, harvested from a 3D dynamic culture system, with RVG‐modified liposomes pre‐loaded with brain‐derived neurotrophic factor. This platform leverages the bioactivity of 3D‐cultured sEVs while bypassing the macromolecular loading constraints inherent to traditional sEVs. Our results demonstrate that, compared to native sEVs, intranasal administration of BDNF@RVG‐sEVs significantly enhances brain accumulation and cargo stability. This targeted delivery led to improved behavioral performance, maintained dopaminergic neuron integrity, and promoted endogenous neurogenesis in mice with manganese‐induced PD‐like damage. Mechanistically, transcriptomic and metabolomic analyses revealed that these therapeutic effects may be related to the activation of neurotrophic pathways and the restoration of systemic metabolic homeostasis. Overall, this nanomedicine provides a potential strategy for the targeted treatment of neurodegenerative conditions.