A Colon-Targeted Oral Nanosystem Disrupts the Inflammatory Loop in Enteric Glia to Alleviate Ulcerative Colitis

The gut's inflammation is governed by the enteric nervous system, where enteric glial cells (EGCs) serve as essential intermediaries between the nervous and immune systems. During inflammation, elevated levels of S100 calcium-binding protein B (S100B) from hyperactive EGCs initiate a proinflammatory cascade by inducing the excessive production of reactive oxygen species (ROS) and proinflammatory molecules, including S100B itself, thus establishing a detrimental feedback loop. Herein, we develop a S100B inhibitor pentamidine (PTM)-loaded olsalazine-based nanoneedle, Zn₂(Olsa)/PTM, to break this vicious cycle and alleviate ulcerative colitis. Zn₂(Olsa)/PTM not only enhances the cytocompatibility of PTM but also reduces the level of excessive production of S100B and ROS in EGCs. To enhance colon-targeted delivery, Zn₂(Olsa)/PTM is coated with an enteric polymer Eudragit L100-55 to create ZOP@Eud. The oral administration of ZOP@Eud considerably ameliorates disease severity and restores mucosal barrier integrity and immune homeostasis in a murine ulcerative colitis model, which is evidenced by heightened expression of tight junction proteins and reduced levels of colonic proinflammatory S100B and cytokines. These findings suggest that nanosystems targeting EGCs offer a promising approach for mitigating gut inflammation.