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.