EphB1‐Mediated Transient Blood‐Brain Barrier Opening Facilitates a Ferritin‐Based Nanotherapeutic for Alzheimer's Disease

ABSTRACT The treatment of Alzheimer's disease (AD) is severely hampered by the blood‐brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi‐faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain‐targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn‐DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood–brain barrier, enables transient and reversible opening of the blood–brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn‐DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain‐derived neurotrophic factor (BDNF). Consequently, AFn‐DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1‐mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.