Abstract Luteolin (LUT) is a biologically active flavonoid exhibiting significant therapeutic potential against neurodegenerative disorders such as cognitive impairment. Nonetheless, its clinical application is limited by poor aqueous solubility, extensive first-pass metabolism and diminished permeability across the blood–brain barrier (BBB) and consequently, low oral bioavailability. This study aimed to develop PEGylated LUT nano-vesicular delivery systems to enhance brain delivery and therapeutic efficacy. PEGylated LUT-Aspasomes were prepared via thin-film hydration, using Brij 52 for PEGylation. Sixteen formulations were designed using a 2 4 full factorial design, varying the weights of Ascorbyl Palmitate (AP), Cholesterol (CH), Brij 52, and Span (Sp) type. The optimized formulation (F14) is composed of 40 mg AP and CH, 10 mg Brij 52, and 50 mg Sp 60 with a desirability value (0.747). F14 demonstrated entrapment efficiency (EE%) (86.24 ± 1.16%), particle size (PS) (188.30 ± 1.50 nm), and zeta potential (ZP) (-25.31 ± 0.84 mV). TEM confirmed spherical, nanosized vesicles with uniform morphology. XRD analysis revealed transformation of LUT from crystalline to amorphous form, supporting successful encapsulation. Drug release and ex-vivo nasal permeation were enhanced 3.4- and fourfold, respectively, compared to free LUT. In-vivo studies in chronic unpredictable stress (CUS) rats revealed that the optimized PEGylated LUT-Aspasomes significantly enhanced neuroprotective effects compared to free LUT. Treated rats exhibited improved spatial memory and a 1.7-fold greater attenuation of depressive-like behavior relative to free LUT. Biochemically, F14 produced 1.15-, 1.23-, and 1.06-fold superior reductions in hippocampal acetylcholinesterase (AChE) activity, serum corticosterone (CORT), and increased brain-derived neurotrophic factor (BDNF) levels, respectively, compared to LUT suspension. Histopathological examination confirmed nearly preserved hippocampal architecture in PEGylated LUT-Aspasome–treated rats. These effects are attributed to LUT encapsulation within PEGylated Aspasomes, which enhanced stability, brain delivery, and neuroprotective efficacy. Thus, PEGylated LUT-Aspasomes are a promising strategy for managing stress-related neurobehavioral disorders. Graphical Abstract
Aladoly et al. (Wed,) studied this question.