A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR sites for Improved Treatment of Depression.

Ketamine (KA), commonly used as an anesthetic, is now widely-used as an antidepressant for the treatment of clinical depression. However, due to its side effects, such as dependence, addiction, and cognitive impairment, the dosage and frequency of (S)-ketamine approved by the FDA for the treatment of refractory depression is very low, which limits its efficacy. Here, we developed a new multifunctional nanocarrier system (AC-RM@HA-MS) with specific targeting capabilities to improve the efficacy of KA treatment. KA-loaded NPs (AC-RM@HA-MS-KA) were constructed with a multilayer core-shell structure. KA-loaded mesoporous silica NPs were prepared, conjugated with hyaluronic acid (HA) as pore gatekeepers, and sheathed with an RBC-membrane for camouflage. Finally, the surface was tagged with bifunctional peptides (Ang-2-Con-G, AC) to achieve specific targeting. One peptide (Ang-2) acted as a guide to facilitate the crossing of the blood-brain barrier (BBB), while the other (Con-G) functioned as a ligand for the targeted delivery of KA to the N-methyl-D-aspartate receptor sites. Animal experiments revealed that AC-RM@HA-MS-KA NPs effectively crossed the BBB and directionally accumulated in the curing areas, thereby alleviating the depressive symptoms and improving the cognitive functions of depressed mice. After treatment, the depressed mice almost completely returned to normal without obvious symptoms of addiction. This article is protected by copyright. All rights reserved.