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

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.