A Nose-to-Brain Delivery System for Taxifolin Ameliorates Alzheimer's Disease via Synergistic Attenuation of Oxidative Stress and Mitochondrial Dysfunction.

The blood-brain barrier (BBB) presents the principal obstacle to drug delivery for Alzheimer's disease (AD), severely restricting brain bioavailability and therapeutic efficacy. Taxifolin (TF) is a potent natural antioxidant with significant therapeutic potential. To enhance its efficacy in treating AD, we developed a brain-targeted delivery system based on a taxifolin-loaded thermosensitive hydrogel (TF-Gel). This platform integrates TF with a poly(N-isopropylacrylamide)-based thermosensitive hydrogel to enhance brain delivery, tissue penetration, and intracerebral retention via intranasal administration. TF-Gel exhibits excellent structural stability and functional performance, enabling efficient bypass of the BBB through the nasal-brain pathway. Furthermore, it regulates mitochondrial dysfunction, reverses abnormal levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), and malondialdehyde (MDA) in neuronal mitochondria, repairs mitochondrial energy metabolism, restores mitochondrial dynamic balance, improves oxidative stress damage, and blocks cell apoptosis pathways. Collectively, these results highlight the strong potential of the TF-Gel nasal delivery system as a mitochondria-targeted therapeutic strategy for AD.