Oral delivery of layer-by-layer coated exosomes for colitis therapy

Mesenchymal stem cell-derived exosomes (MSC-Exos) have attracted much attention as a potential cell-free therapy for ulcerative colitis (UC), mainly due to their anti-inflammatory, tissue repair, and immunomodula-tory properties. Although intravenous injection of MSC-Exos is able to improve UC to a certain extent, oral administration of exosomes is the preferred method to treat gastrointestinal diseases such as UC. However, exosomes contain proteins and nucleic acids that are vulnerable to degradation by the gastrointestinal envi-ronment, making oral administration difficult to implement. Layer-by-layer (LbL) self-assembly technology provides a promising strategy for the oral delivery of exosomes. Therefore, an efficient LbL-Exos self-assembly system was constructed in this study for the oral delivery of exosomes targeted to the colon to improve UC treatment. Biocompatible and biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) and oxidized konjac glucomannan (OKGM) polysaccharides were used as the outer layers to provide colon targeting and to protect exosomes from degradation. Similar to plain exosomes, LbL-Exos had a similar structure and features, but LbL provided controlled release of exosomes in the inflammatory colon. Compared with intravenous administration, oral administration of LbL-Exos could effectively alleviate UC using half the number of exosomes. Mechanistic studies showed that LbL-Exos were internalized by macrophages and intestinal epithelial cells to exert anti-inflammatory and tissue repair effects and therefore alleviate UC. Furthermore, the LbL-Exos system was able to improve UC via MAPK/NF-kappa B signaling pathway inhibition. Overall, our data show that LbL-MSC-Exos can alleviate UC after oral administration and therefore may constitute a new strategy for UC treatment in the future.