Abstract

The drug delivery for Alzheimer's disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1%, 1375.0%, and 1144.4%, respectively. In the model of AD induced by amyloid-beta 1-42 (Aβ1-42), it was confirmed that LK4-TGS-PDA NPs can significantly improve cognitive dysfunction, with escape latency reduced by 30.3%, platform crossings increased by 5.4-fold, and target quadrant time extended by 2.4-fold, as well as reduce the effects of inflammation in the brain, with IL-1β, IL-6, and TNF-α decreased by 44.05%, 53.49%, and 84.40%, respectively. The present investigation outcomes reveal that the engineered LK4-TGS-PDA NPs demonstrates effectiveness and efficiency as