Preparation and evaluation of a non-invasive intranasal luteolin delivery for the management of cognitive dysfunction in Alzheimer’s disease (AD) using novel chitosan decorated nanoparticles. Development of luteolin-loaded chitosomes was followed by full in vitro characterization. In vivo efficacy was evaluated using a sporadic Alzheimer’s disease (SAD) animal model via intracerebroventricular injection of 3 mg/kg streptozotocin (ICV-STZ). Treatment groups of luteolin suspension and chitosomes (50 mg/kg) were then intranasally administered after 5 h of ICV-STZ followed by everyday administration for 21 consecutive days. Behavioral, histological, immunohistochemical, and biochemical studies were conducted. Chitosomes yielded promising quality attributes in terms of particle size (PS) (412.8 ± 3.28 nm), polydispersity index (PDI) (0.378 ± 0.07), Zeta potential (ZP) (37.4 ± 2.13 mv), and percentage entrapment efficiency (EE%) (86.6 ± 2.05%). Behavioral findings showed obvious improvement in the acquisition of short-term and long-term spatial memory. Furthermore, histological evaluation revealed an increased neuronal survival rate with a reduction in the number of amyloid plaques. Biochemical results showed improved antioxidant effects and reduced pro-inflammatory mediators’ levels. In addition, a suppression by half was observed in the levels of both Aβ aggregation and hyperphosphorylated-tau protein in comparison to the model control group which in turn confirmed the capability of luteolin-loaded chitosomes (LUT-CHS) in attenuating the pathological changes of AD. The prepared nanoparticles are considered a promising safe, effective, and non-invasive nanodelivery system that improves cognitive function in SAD albino mice as opposed to luteolin suspension.

Impaired memory and cognitive function are the main features of Alzheimer’s disease (AD). Unfortunately, currently available treatments cannot cure or delay AD progression. Moreover, the blood–brain barrier hampers effective delivery of treatment to the brain. Therefore, we aimed to evaluate the impact of intranasally delivered luteolin on AD using bile-salt-based nano-vesicles (bilosomes). Different bilosomes were prepared using 2³-factorial design. The variables were defined by the concentration of surfactant, the molar ratio of cholesterol:phospholipid, and the concentration of bile salt. Results demonstrated optimized luteolin-loaded bilosomes with particle size (153.2 ± 0.98 nm), zeta potential (−42.8 ± 0.24 mV), entrapment efficiency% (70.4 ± 0.77%), and % drug released after 8 h (80.0 ± 1.10%). In vivo experiments were conducted on an AD mouse model via intracerebroventricular injection of 3 mg/kg streptozotocin. We conducted behavioral, biochemical marker, histological, and immune histochemistry assays after administering a luteolin suspension or luteolin bilosomes (50 mg/kg) intranasally for 21 consecutive days. Luteolin bilosomes improved short-term and long-term spatial memory. They also exhibited antioxidant properties and reduced levels of proinflammatory mediators. They also suppressed both amyloid β aggregation and hyperphosphorylated Tau protein levels in the hippocampus. In conclusion, luteolin bilosomes are an effective, safe, and non-invasive approach with superior cognitive function capabilities compared to luteolin suspension.