Silibinin-loaded PEGylated niosomal nanoparticles restore hippocampus histological changes, memory and learning, and downregulate the inflammasome pathway in Alzheimer's disease animal models.

Nanoencapsulation, especially in the form of PEGylated niosomes, is considered a novel strategy in drug delivery that improves the solubility and bioavailability of compounds. Silibinin, as a flavonoid, has low bioavailability despite its antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, the present study was designed to investigate the effect of PEGylated niosomal nanoparticles containing Silibinin (Sili-PEG-Nios-NPs) on memory and learning, inflammatory pathways, and morphological changes in the hippocampus in an animal model of Alzheimer's disease. In this study, Sili-PEG-Nios-NPs were synthesized and characterized, followed by Alzheimer's induction in rats via intraventricular Aβ1-42 injection. Rats were divided into five groups (n = 8): a healthy control group, an Alzheimer's model group, a sham group (Alzheimer's model + PBS), an Alzheimer's model group + free Silibinin, and an Alzheimer's model group + Sili-PEG-Nios-NPs. Treatments were administered orally (100 mg/kg for 15 days). Cognitive function was assessed using the Morris water maze and shuttle box tests. Tissue analysis included Real-time PCR for inflammasome genes, Congo red staining for amyloid plaques, and cresyl violet staining for hippocampal pyramidal cells. The results demonstrated that both Silibinin formulations (free and nano-encapsulated) significantly improved spatial memory and learning compared to the disease model group. However, Sili-PEG-Nios-NPs were significantly more effective than free Silibinin and also significantly reduced the expression of inflammasome genes, Aβ plaque formation, and hippocampal neuronal cell destruction. These findings suggest that PEGylated Silibinin-loaded niosomal nanoparticles are an effective option for improving Alzheimer's disease complications by modulating the inflammasome pathway and amyloid plaque aggregation.