Bioengineered Exosome‐Loaded Immunomodulatory Bioadhesive Spray Reverses Liver Fibrosis and Metabolic Dysfunction That Triggers Beneficial Gut‐Liver Crosstalk in Chronic Fatty Liver Disease

ABSTRACT Metabolic dysfunction‐associated fatty liver disease (MAFLD) is a progressive liver disorder with complex pathogenesis and no approved treatments beyond lifestyle changes. Here, we report a sprayable and biodegradable bioadhesive hydrogel loaded with exosomes derived from human mesenchymal stromal cells that provides sustained therapy localized to the liver. In a rat model of chronic MAFLD, a single application of the spray markedly improved liver pathology and systemic metabolic indices over the effects of lifestyle interventions. Specifically, collagen deposition, liver‐enzyme levels, insulin resistance, and chronic inflammation were all attenuated. Furthermore, the spray led to an increase in markers of gut‐barrier integrity and gut bacterial diversity and modulated key pathways of lipid metabolism, inflammation, and fibrosis, as we show via multi‐omics profiling of liver tissue. Our findings strongly suggest that exosomes delivered to the liver via a sprayable anti‐inflammatory hydrogel can address the multifactorial pathology of MAFLD, yielding improvements in liver histology and function, and inducing systemic metabolic homeostasis.