Dual-Targeting Protein-Based Delivery System for Enhanced Drug Therapy of Neurodegenerative Disorders

Conventional drugs for Alzheimer's disease (AD) treatment often suffer from low bioavailability due to the blood-brain barrier (BBB). In this investigation, we developed a dual-brain targeting protein-based drug delivery system for nose-to-brain drug delivery. The dual-brain targeting drug delivery system, Donepezil@Tf/cRGD-CS, was prepared using a simple self-assembly method. Donepezil was encapsulated in transferrin (Tf) nanoparticles, which were decorated with cRGD-conjugated chitosan (cRGD-CS), enabling dual-targeted drug delivery. Due to the specific interactions between Tf and the transferrin receptor (TfR) as well as cRGD and integrins, Donepezil@Tf/cRGD-CS exhibited enhanced BBB penetration as well as improved cellular uptake by brain neurons. An in vitro BBB model confirmed the enhanced permeability of the dual-targeted drug-loaded nanoparticles across the BBB. Compared to free donepezil, Donepezil@Tf/cRGD-CS nanoparticles significantly improved therapeutic outcomes, including reduced neurotoxicity induced by Aβ_25-35 and downregulation of apoptosis-related proteins and Tau proteins. This study offers an effective strategy for improving the therapeutic outcomes of central nervous system diseases.