Targeted Nanodelivery of <scp>WGX50</scp> and Curcumin via Gold Nanoparticles for Alzheimer's Therapy

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood-brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%-90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.