Plain-language summary
Alzheimer's disease involves mitochondrial dysfunction, oxidative stress, and disturbed lipid metabolism, but brain-targeted treatments are limited by poor delivery along the nose-to-brain route and low precision at the subcellular level. In this study, researchers loaded icariin, a plant-derived compound, into mesenchymal stem cell-derived extracellular vesicles and engineered the vesicle surface with two modifications: an L-DOPA lipid to improve performance in the nasal environment and association with neurons, and a triphenylphosphonium lipid to steer cargo toward mitochondria after uptake. The engineered vesicles kept their typical size and morphology, remained stable under storage and simulated nasal conditions, and showed greater neuronal uptake than unmodified vesicles in a human nasal epithelial model without disturbing the epithelial barrier. In amyloid-beta-injured neurons, the formulation reduced mitochondrial oxidative stress, improved membrane potential and ATP production, and limited mitochondrial pore opening. After intranasal dosing in mice, brain-associated fluorescence was stronger and longer-lasting, and treated APP/PS1 Alzheimer's model mice performed better in cognitive tests with fewer mitochondrial and histological abnormalities. Proteomic and metabolomic analyses further linked the effects to sphingolipid pathway changes.
Key findings
- Researchers engineered mesenchymal stem cell-derived extracellular vesicles with L-DOPA and mitochondria-targeting lipids to deliver icariin intranasally to the brain.
- In a human nasal epithelial model, the engineered vesicles showed greater neuronal uptake than unmodified vesicles without disrupting the epithelial barrier.
- In amyloid-beta-injured neurons, the formulation reduced mitochondrial oxidative stress and improved membrane potential and ATP production.
- In APP/PS1 Alzheimer's model mice, intranasal treatment improved cognitive performance and attenuated histopathological and mitochondrial abnormalities.
Original abstract
Alzheimer's disease (AD) is associated with mitochondrial dysfunction, oxidative stress, and disrupted lipid homeostasis, but the therapeutic translation of mitochondrial-protective agents remains limited by inefficient brain delivery, insufficient neuronal selectivity, and poor subcellular precision. Here, we developed an intranasal extracellular vesicle formulation (L-DOPA/TPP-EV-ICA) by loading icariin (ICA) into mesenchymal stem cell-derived extracellular vesicles and post-inserting DSPE-PEG-Levodopa and TPP-PEG-PE to enhance nasal environment, neuronal association, and mitochondria-associated intracellular enrichment. The engineered vesicles retained EV-like morphology, showed measurable ICA encapsulation, and maintained colloidal stability under the tested storage and simulated nasal conditions. In a human nasal epithelial Transwell model, L-DOPA/TPP-EV-ICA showed greater neuronal uptake than unmodified EVs without detectable disruption of epithelial barrier integrity and exhibited preferential colocalization with mitochondria-associated structures after cellular internalization. In Aβ-injured neuronal cells, L-DOPA/TPP-EV-ICA treatment reduced mitochondrial oxidative stress and mPTP opening, improved membrane potential, and enhanced ATP production and redox-related parameters. Following intranasal administration, the engineered formulation generated stronger and more persistent brain-associated fluorescence and showed preferential association with NeuN-positive cells. In APP/PS1 mice, treatment improved cognitive performance, and attenuated histopathological and mitochondrial abnormalities. Integrated proteomic, metabolomic analyses, and protein-level analyses further identified treatment-associated alterations in sphingolipid-related pathways. These findings support L-DOPA/TPP-EV-ICA as a promising preclinical intranasal EV platform for improving mitochondrial function and modulating sphingolipid-associated alterations in AD-related models.
Frequently asked questions
What did this study find?
Alzheimer's disease involves mitochondrial dysfunction, oxidative stress, and disturbed lipid metabolism, but brain-targeted treatments are limited by poor delivery along the nose-to-brain route and low precision at the subcellular level. In this study, researchers loaded icariin, a plant-derived compound, into mesenchymal stem cell-derived extracellular vesicles and engineered the vesicle surface with two modifications: an L-DOPA lipid to improve performance in the nasal environment and association with neurons, and a triphenylphosphonium lipid to steer cargo toward mitochondria after uptake. The engineered vesicles kept their typical size and morphology, remained stable under storage and simulated nasal conditions, and showed greater neuronal uptake than unmodified vesicles in a human nasal epithelial model without disturbing the epithelial barrier. In amyloid-beta-injured neurons, the formulation reduced mitochondrial oxidative stress, improved membrane potential and ATP production, and limited mitochondrial pore opening. After intranasal dosing in mice, brain-associated fluorescence was stronger and longer-lasting, and treated APP/PS1 Alzheimer's model mice performed better in cognitive tests with fewer mitochondrial and histological abnormalities. Proteomic and metabolomic analyses further linked the effects to sphingolipid pathway changes.
Was this tested in humans or in the laboratory?
This is delivery-science work, focused on how the vesicles behave when they are administered.
Where can I read the original paper?
The full text lives with the publisher: https://doi.org/10.1016/j.mtbio.2026.103563
How to cite this paper
Wu Beibei, Wu Junyong, Zhu Lemei, Li An, Fu Yangbo, Lei Zuchao et al.. Intranasal L-DOPA/TPP-engineered extracellular vesicles deliver icariin to ameliorate mitochondrial dysfunction with associated sphingolipid remodeling in Alzheimer's disease models.. Materials today. Bio. 2026, 2026-08-30. DOI: 10.1016/j.mtbio.2026.103563
Source & verification
- Journal: Materials today. Bio
- Published: 30 August 2026
- DOI: 10.1016/j.mtbio.2026.103563
- PubMed ID: 42668476
- Indexed via: pubmed
- MeSH terms: —