Ellagic acid (EA) is a natural compound characterized by neuroprotective potential, although it shows poor pharmacokinetic profile. A valid approach could be delivering the drug in non-ionic surfactant vesicles (NSVs) through the nose to brain (N2B) route. Our aim was to load EA inside NSVs and explore EA-NSVs capability, compared to free-EA, to restore the impairment induced by Aβ1-42 on synaptic plasticity through electrophysiological recordings in ex-vivo model.Empty and loaded NSVs were prepared, and a physicochemical characterization were carried out. We performed field and whole cell patch clamp recordings to measure LTP, PPR, sEPSC amplitude and frequency, and AMPA/NMDA ratio, in area CA1-CA3 of hippocampus using C57BL6/J mice of both sexes (30-40 days). Empty and loaded NSVs present an appropriate range of size suitable for N2B delivery. Results show that EA up to 30 µM did not affect LTP while at 100 µM EA was able to increase significantly LTP compared to vehicle. EA restores LTP impairment following Aβ application, PPR alteration and it was able to reverse the changes induced by Aβ on both the amplitude and frequency of sEPSC at 10 µM, while when EA is loaded in NSVs the same neuroprotective effect is showed at a lower dose (3 µM).Our data show a dose dependent neuroprotective effect of EA against Aβ mediated synaptic impairment. Physicochemical characterization results of EA-NSVs suggest that the drug delivery system is suitable N2B administration, representing a promising therapeutic approach to overcome the pharmacokinetic limitations associated with EA administration.