Chitosan-coated cyclodextrin-based niosomes enable enhanced nose-to-brain delivery of rivastigmine and asiaticoside for Alzheimer's disease.

The co-delivery of rivastigmine hydrogen tartrate (RHT) and asiaticoside (AS) offers a promising strategy for enhancing acetylcholinesterase (AChE) inhibition in Alzheimer's disease (AD) by targeting both cholinergic deficits and neurodegeneration. However, formulating a combined delivery system is challenging due to the hydrophilic nature of RHT and poor solubility of AS. Accordingly, we developed a scalable intranasal delivery system using cyclodextrin-enabled niosomes. Inclusion complexes of RHT, AS, and 2-hydroxypropyl-β-cyclodextrin were prepared and encapsulated into niosomes via thin-film hydration, followed by surface modification with chitosan (CS) to produce CS-coated RA@N. Characterization confirmed the successful complexation and nanoscale encapsulation. CS-coated RA@N exhibited a biphasic release pattern for RHT and sustained release for AS. Compared to uncoated niosomes, CS-coated RA@N showed a 3.1-fold increase in mucoadhesion and enhanced ex vivo permeation across porcine nasal mucosa (2.1-fold for RHT, 1.8-fold for AS). The formulation exhibited excellent biocompatibility, efficient uptake by RPMI 2650 and SH-SY5Y cells, and improved epithelial-to-neuronal transport. In vivo mouse studies demonstrated significantly higher brain-to-plasma ratios and a more sustained reduction in brain AChE activity following intranasal administration of the formulation. Importantly, co-administration of RHT and AS produced an enhanced pharmacodynamic response, surpassing the effects of single-drug formulations. These findings support CS-coated RA@N as a robust nanocarrier for enhanced nose-to-brain delivery, with strong potential for effective AD symptom management.