M_2026_Pharm.Nanotechnol__

BACKGROUND: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative condition characterized by cognitive decline, oxidative stress, and amyloid plaque accumulation. Current therapies, including cholinesterase inhibitors, mainly provide symptomatic relief and are limited by suboptimal brain delivery, necessitating multifunctional nanocarrier-based strategies. This study aimed to formulate and evaluate a Taxifolin-decorated Rivastigmine liposomal nanocarrier (Tax-Riva-Lipo) to achieve synergistic neuroprotection through combined cholinesterase inhibition, antioxidant defense, and anti-amyloid activity. METHODS: Taxifolin was covalently conjugated to DSPE-PEG using EDC/NHS chemistry and incorporated into Rivastigmine-loaded liposomes prepared by thin-film hydration. The optimized formulation was characterized by DLS, TEM, FTIR, and DSC. In vitro evaluations included release kinetics, cholinesterase inhibition, antioxidant assays, and neuroprotection studies, followed by in vivo assessment in an ICV-STZ-induced AD rat model. RESULTS: Tax-Riva-Lipo formed uniform nanosized vesicles (~145 nm) with high encapsulation efficiency (=85%) and sustained drug release up to 48 h. The formulation showed enhanced AChE and BuChE inhibition (IC50: 0.08 microM and 0.52 microM), strong free radical scavenging activity, and significant protection of SH-SY5Y cells (92% viability). In vivo studies demonstrated improved cognitive performance, restoration of antioxidant enzymes (SOD, CAT, GSH), suppression of proinflammatory cytokines (TNF-alpha, IL-6), and preservation of hippocampal architecture without detectable toxicity. DISCUSSION: These findings indicate that Taxifolin functionalization enables complementary multitarget actions, integrating antioxidant and anti-amyloid effects with sustained cholinesterase inhibition. CONCLUSION: Tax-Riva-Lipo represents a promising synergistic nanotherapeutic platform for improved management of Alzheimer's disease.