Multilayered Silica-Core/Chitosan-Coated Nanostructures Co-Delivering Tamoxifen and Quercetin Mitigate LPS-Associated Neurodegenerative and Alzheimer's Disease-Like Alterations.

Cholinergic dysfunction, oxidative stress, neuroinflammation, and proteinopathies are among the major hallmarks of Alzheimer's disease (AD). This study aimed to develop and evaluate the therapeutic potential of multilayered silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with quercetin (QUR) and tamoxifen (TAM) in an LPS-induced neuroinflammatory murine model exhibiting AD-like neuropathological alterations associated with bacterial endotoxin exposure. Molecular docking and target prediction analyses suggested that TAM may exert partial cholinesterase inhibitory activity and potentially interact with muscarinic receptor- and epidermal growth factor receptor (EGFR)-associated pathways, which are implicated in neuroinflammation and oxidative stress regulation. The resulting silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with QUR and TAM (QUR/TAM-Si@CsNPs) were spherical in shape, exhibited a core-shell architecture, and demonstrated high loading efficiencies for QUR (93.1% ± 2.56) and TAM (84.27 ± 3.66), with a mean particle diameter of approximately 135 nm as determined by TEM. Behavioral assessment using Morris Water Maze revealed that lipopolysaccharide (LPS) administration impaired spatial learning and memory in rats; these effects were significantly ameliorated by QUR/TAM-Si@CsNPs treatment, to a greater extent than Si@CsNPs loaded individually with QUR or TAM. Biochemical, apoptotic, and histopathological analyses further demonstrated that treatment with QUR/TAM-Si@CsNPs normalized acetylcholinesterase activity, Tau protein level, β-amyloid accumulation, pro-inflammatory mediators, and apoptotic indices while preserving hippocampal architecture. Collectively, these findings demonstrate that QUR/TAM-Si@CsNPs exert combined anti-inflammatory and neuroprotective effects, highlighting their promise as a multifunctional nanotherapeutic strategy against LPS-associated neurodegenerative and AD-like neuropathological alterations.