Intranasal\nCarrier-Free Nanomodulator Addresses Both\nSymptomatology and Etiology of Alzheimer’s Disease by Restoring\nNeuron Plasticity and Reprogramming Lesion Microenvironment

The\nunsatisfactory treatment outcome of Alzheimer’s disease\n(AD) can be attributed to two primary factors, the intricate pathogenic\nmechanisms leading to restricted treatment effectiveness against single\ntargets and the hindered drug accumulation in brain due to blood–brain\nbarrier obstruction. Therefore, we developed a carrier-free nanomodulator\n(NanoDS) through the self-assembly of donepezil and simvastatin for\ndirect nose-to-brain delivery. This approach facilitated a rapid and\nefficient traversal through the nasal epithelial barrier, enabling\nsubsequent drug release and achieving multiple therapeutic effects.\nAmong them, donepezil effectively ameliorated the symptoms of AD and\nrestored synaptic plasticity. Simvastatin exerted a neurotrophic effect\nand facilitated the clearance of amyloid-β aggregation. At the\nsame time, NanoDS demonstrated effective anti-inflammatory and antioxidative\nstress effects. This therapy for AD is approached from both symptomatic\nand etiological perspectives. In the treatment of FAD<sup>4T</sup> transgenic mice, it highly improved spatial memory impairment and\ncognitive deficits while restoring the homeostasis of brain microenvironment.\nCollectively, our study presented a paradigm for both achieving efficient\nbrain delivery and offering pleiotropic therapies for AD.