Resveratrol-loaded macrophage exosomes alleviate multiple sclerosis through targeting microglia.

Despite exosome promise as endogenous drug delivery vehicles, the current understanding of exosome may be insufficient to develop their various applications. Here we synthesized five sialic acid analogues with different length N-acyl side chains and screened out the optimal metabolic precursor for exosome labeling via bio-orthogonal click chemistry. In proof-of-principle labeling experiments, exosomes derived from macrophages (RAW-Exo) strongly co-localized with central nervous system (CNS) microglia. Inspired by this discovery, we developed a resveratrol-loaded RAW-Exo formulation (RSV&Exo) for multiple sclerosis (MS) treatment. Intranasal administration of RSV&Exo significantly inhibited inflammatory responses in the CNS and peripheral system in a mouse model of MS and effectively improved the clinical evolution of MS in vivo. These findings suggested the feasibility and efficacy of engineered RSV&Exo administration for MS, providing a potential therapeutic strategy for CNS diseases.