Intestine‐Targeted Controlled Hydrogen‐Releasing MgH2 Microcapsules for Improving the Mitochondrial Metabolism of Inflammatory Bowel Disease

Abstract The development of efficient therapeutic agents with low side effects for inflammatory bowel disease management is a longstanding challenge. Recently, hydrogen molecule (H2) is identified as an emerging spectrum‐wide, effective, and biosafe anti‐inflammatory agent, but intestine‐targeted H2 delivery is still challenging. Here, an intestine‐targeted controlled hydrogen‐releasing microcapsule (MgH2@EC@ES) is developed by confining abundant MgH2 microparticles in the hydrophobic network of ethyl cellulose (EC) before being encapsulated with Eudragit S100 (ES) by a multistep microemulsion method. The pH‐responsive swelling feature of ES enables MgH2@EC@ES microcapsules to escape from the stomach after oral administration and to hydrolytically produce a high amount of H2 in the intestinal tract in a sustained way. High‐dose oral administration of MgH2@EC@ES microcapsules exhibits a high outcome of colitis prevention, which is comparable to the first‐line drug 5‐aminosalicylic acid (5‐ASA) in the changes of body/spleen weights and disease activity and even better in the recovery of colon length and the improvement of histopathological change in the colon than 5‐ASA in a colitis mouse model. Mechanically, it is innovatively revealed that H2 released from MgH2@EC@ES microcapsules protects the complexes in the mitochondrial electron transfer chain from oxidative damage to enhance the energy metabolism of intestinal cells in support of mucosal restoration in colitis.