AGE-RELATED brain inflammation may be reversible, as a novel nasal spray delivering extracellular vesicles has been shown to reduce neuroinflammation and improve memory performance in preclinical models, suggesting a potential strategy to reverse cognitive decline linked to ageing processes.
Neuroinflammaging Targeted by Nasal Spray Strategy
Neuroinflammaging, a chronic hippocampal inflammatory state linked to cognitive decline, has traditionally been viewed as an unavoidable feature of ageing. However, the nasal spray approach using neural stem cell-derived extracellular vesicles has emerged as a potential method to directly target central nervous system inflammation and restore neuronal function in preclinical models.
Preclinical Intranasal Nasal Spray EV Study Design
This preclinical experimental study used late middle-aged 18-month-old male and female C57BL/6J mice to evaluate a two-dose intranasal nasal spray extracellular vesicle therapy derived from human induced pluripotent stem cell neural stem cells, compared with a vehicle-treated control group. Animals received two intranasal administrations and were assessed at 20.5 months of age, with additional single-cell RNA sequencing performed seven days after treatment.
Cognitive and Molecular Effects of Nasal Spray Therapy
Compared with vehicle-treated controls, the nasal spray extracellular vesicle therapy reduced astrocyte hypertrophy, microglial clustering, and oxidative stress within the hippocampus, while increasing antioxidant protein expression and genes supporting mitochondrial respiratory chain integrity. The treatment also decreased activation of NLRP3 inflammasome, p38 MAPK, cGAS-STING, and JAK-STAT signalling pathways. Single-cell RNA sequencing demonstrated widespread microglial transcriptomic reprogramming, including enhanced oxidative phosphorylation and reduced proinflammatory gene expression. Behaviourally, the treated animals showed improved recognition memory and cognitive flexibility, with effects observed in both male and female mice.
Translational Potential of Nasal Spray Brain Therapy
These findings suggest that nasal spray delivery of extracellular vesicle-based therapies may offer a non-invasive strategy to counteract neuroinflammaging and improve cognitive resilience during ageing. The observed reductions in inflammatory signalling and restoration of mitochondrial function indicate potential relevance for neurodegenerative conditions such as Alzheimer’s disease and post-stroke recovery. Further translational studies are required to confirm safety, dosing, and long-term efficacy in humans.
Reference
Madhu LN et al. Intranasal human NSC-Derived EVs therapy can restrain inflammatory microglial transcriptome, and NLRP3 and cGAS-STING signalling, in aged hippocampus. Journal of Extracellular Vesicles. 2026;DOI:10.1002/jev2.70232.
Featured image: Maria Vitkovska on Adobe Stock
