Oral delivery of chitosan/hyaluronic-acid-coated milk-derived exosomes for ulcerative-colitis amelioration.

Restoring intestinal-barrier homeostasis is crucial in treating ulcerative colitis (UC). Milk-derived exosomes, known for their potent biological properties, hold promise in promoting intestinal-barrier repair. However, their stability and targeting ability during gastrointestinal transit remain challenging. To address this, we engineered exosomes via layer-by-layer (LBL) encapsulation, enhancing their stability, controlled release, and targeted delivery. In a C57BL/6 J mouse model of UC induced by dextran sulfate sodium, oral administration of LBL-encapsulated milk-derived exosomes (LBL-Exos) significantly improved the intestinal barrier, including the physical, mucus, and immune barriers, thereby effectively alleviating the symptoms of UC, even at half the exosome dosage. These effects were also associated with reduced apoptosis and inhibition of the PI3K/AKT signaling pathway. This study demonstrates the therapeutic potential of engineered milk-derived exosomes in UC treatment, offering a promising approach for treating colitis and paving the way for the broader use of natural exosomes in related diseases.