Abstract
The effective treatment of Alzheimer's disease (AD) is challenging because of its complex and controversial pathological mechanisms. Moreover, multiple barriers, such as the blood-brain barrier (BBB), reduce drug delivery efficiency. Microglia-related neuroinflammation has recently attracted increasing attention as a possible cause of AD and has become a novel therapeutic target. Therefore, overcoming the BBB and targeted delivery of anti-inflammatory agents to microglia seem to be effective practical strategies for treating AD. A large proportion of natural active extracts possess exceptional immunomodulating capabilities. In this study, the cooperative delivery of berberine (Ber) and palmatine (Pal) by transferrin-decorated extracellular vesicles (Tf-hEVs-Ber/Pal), which can cross the BBB and precisely target microglia, was performed. This nanosystem effectively cleared amyloid β-protein (Aβ) aggregates, significantly regulated the neuroinflammatory environment both in vitro and in vivo and markedly altered the behavior and improved the cognitive and learning abilities of AD model mice. The efficacy of a microglia-targeting combined therapeutic approach for AD was demonstrated, which broadens the potential application of Chinese herbal ingredients.