Biomimetic silibinin-loaded macrophage-derived exosomes induce dual inhibition of Aβ aggregation and astrocyte activation to alleviate cognitive impairment in a model of Alzheimer's disease

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. • Silibinin was loaded in macrophage-derived exosomes to improve its brain targeting. • Internalization of Exo-Slb in astrocytes can alleviate inflammation mediated neuronal damage. • Exo-Slb can selectively prevent the transition of astrocytes to the active state. • High selectively binding to Aβ1–42 to improve the cognitive behaviour of Aβ-induced AD mice.