Liposomal Formulation of Ellagic Acid Counteracts Amyloid‐β Oligomer‐Induced Cellular Stress: Influence of Neuronal Differentiation

Ellagic acid (EA) is a polyphenolic compound with antioxidant and neuroprotective properties whose therapeutic application is limited by poor aqueous solubility, low permeability and limited stability. In this study, EA‐loaded liposomes (F2) were developed and characterized to improve its biopharmaceutical properties and evaluate its protective effects against amyloid‐β (Aβ) oligomer‐induced cellular stress. F2 showed favorable physicochemical characteristics, storage stability, and stability in the presence of human serum albumin, while providing sustained EA release. In the BBB‐PAMPA assay, F2 maintained measurable passive EA permeability while allowing higher EA amount permeated. The biological effects of EA and F2 were subsequently evaluated in undifferentiated and retinoic acid‐differentiated SH‐SY5Y cells (RA‐SH‐SY5Y) exposed to Aβ oligomers. In undifferentiated cells, F2 showed a distinct concentration‐dependent protective profile, particularly at 10 μM, associated with preservation of cellular metabolic activity, attenuation of ROS accumulation and partial preservation of mitochondrial‐associated functional and morphological parameters. In RA‐SH‐SY5Y, EA and F2 showed broadly comparable protective effects. Overall, liposomes improved the biopharmaceutical properties of EA while preserving or enhancing its biological activity against Aβ‐induced cellular stress. The differential responses observed in undifferentiated and RA‐SH‐SY5Y cells further suggest that the biological advantage associated with liposomal formulation may be influenced by cellular phenotype.