Alzheimer's disease (AD) is a common neurodegenerative disease of the central nervous system. Due to its complex pathogenesis and the difficulty of drugs to cross the blood brain barrier (BBB), no effective clinical drugs are currently available that prevent the development of the course of AD. Silibinin (Slb) is known to exert dual therapeutic effects on reducing amyloid-β (Aβ) aggregation and deactivating astrocytes to improve behaviour and cognitive performance in subjects with Alzheimer's disease (AD). However, the poor brain targeting ability and low bioavailability limit its wide application. We aimed to encapsulate Slb in macrophage-derived exosomes (Exo-Slb) to improve its brain targeting ability. After entering the brain, exosomal Slb selectively interacted with Aβ monomers to reduce its aggregation. At the same time, Exo-Slb was internalized in astrocytes to inhibit their activation and alleviate astrocyte inflammation-mediated neuronal damage. Finally, Exo-Slb potently ameliorated cognitive deficits in AD mice.

阿尔茨海默病 (AD) 是一种常见的中枢神经系统神经退行性疾病。由于其复杂的发病机制和药物难以穿过血脑屏障（BBB），目前尚无有效的临床药物来阻止 AD 病程的发展。已知水飞蓟宾 (Slb) 在减少淀粉样蛋白 β (Aβ) 聚集和使星形胶质细胞失活方面发挥双重治疗作用，以改善阿尔茨海默病 (AD) 患者的行为和认知能力。然而，脑靶向能力差和生物利用度低限制了其广泛应用。我们旨在将 Slb 封装在巨噬细胞衍生的外泌体 (Exo-Slb) 中，以提高其大脑靶向能力。进入大脑后，外泌体 Slb 选择性地与 Aβ 单体相互作用以减少其聚集。同时，Exo-Slb 被内化在星形胶质细胞中以抑制其活化并减轻星形胶质细胞炎症介导的神经元损伤。最后，Exo-Slb 有效改善了 AD 小鼠的认知缺陷。