Brain and Liver Dual‐Targeting Oridonin Nanoparticles to Enhance Aβ Clearance for Alzheimer's Disease Therapy

ABSTRACT The brain and liver are both critical organs involved in the pathogenesis of Alzheimer's disease (AD), particularly in the modulation of amyloid‐beta (Aβ) metabolism and neuroinflammation. Based on this, a multifunctional nanodrug delivery system, termed OAF, was developed by encapsulating oridonin (ORI) into apoferritin (ApoFn), enabling simultaneous targeting of both brain and the liver through transferrin receptor 1 (TfR1). OAF upregulated the expression of low‐density lipoprotein receptor‐related protein 1 (LRP1) in cerebral capillary endothelial cells and hepatic parenchymal cells to promote Aβ clearance from the brain and subsequent hepatic degradation. In AD mice, OAF treatment markedly reduced Aβ deposition, neuroinflammation, and cognitive impairment, while ameliorating inflammation, oxidative stress, and mitochondrial dysfunction in both brain and liver. Overall, OAF synergistically combined Aβ clearance, anti‐inflammatory, and antioxidant mechanisms, offering a novel therapeutic strategy for AD.