Atopic dermatitis (AD), a prevalent chronic inflammatory skin disorder, severely impairs patients’ quality of life. Mounting evidence indicates that gut microbiomes regulate AD pathogenesis through the gut-skin axis; yet the therapeutic potential of gut microbiomes-derived extracellular vesicles (EVs) remains largely unexplored. Here, we isolated EVs from gut probiotic Akkermansia muciniphila (AKK-EVs) and evaluated their therapeutic efficacy and underlying mechanisms against AD pathogenesis. AKK-EVs exhibited pronounced anti-inflammatory and antioxidant properties in vitro. MicroRNA profiling revealed that miR-21-5p was highly enriched within AKK-EVs and critically mediated their biological activity. Mechanistically, miR-21-5p directly targeted TLR4 gene, thereby suppressing NF-κB signaling pathway and downstream proinflammatory cytokine production. Notably, AKK-EVs exhibited excellent stability in gastrointestinal condition, and upon oral administration, preferentially homed to inflamed skin tissues via the gut-skin axis.

Both oral and subcutaneous administration of AKK-EVs alleviated AD-like phenotypes, reshaped the inflammatory microenvironment and restored compromised skin barrier. Collectively, this study uncovers a previously unrecognized role of AKK-EVs in modulating AD and highlights probiotic-derived EVs as a promising therapeutic strategy for inflammatory skin disorders.