"Golden cicada-escape" style colon-targeted pellets for ulcerative colitis by balancing oxidative stress and repairing colonic barrier.

Ulcerative colitis (UC) is a chronic, recurrent inflammatory disease of the colon with a complex and unknown etiology. Oxidative stress and impaired colonic barrier function are key factors in the pathogenesis of UC. Ramulus Mori (Sangzhi) Alkaloids (SZ-A), a group of natural plant-derived compounds, exhibit multiple pharmacological activities, including modulating anti-inflammatory immune responses, attenuating oxidative stress, and restoring intestinal barrier integrity. These properties highlight their great potential in the treatment of UC. However, SZ-A is prone to intestinal flatulence after oral administration due to its interaction with α-glucosidase in the small intestine, and high doses may pose a risk of weight loss, which is detrimental to patients with UC. To address these challenges, this study developed a pH-sensitive, colon-targeted pellet with colonic mucosal adhesion for the oral delivery of SZ-A, representing the inaugural successful application of this approach in the treatment of UC. The pH sensitivity and mucosal adhesion properties of the system were validated through both in vivo and in vitro experiments. Under colonic pH conditions, the outer shells of the pellets dissolved and were completely dislodged, thereby exposing the pellet cores and achieving the "golden cicada-escape" effect. The pellet cores rapidly adhered to and aggregated at the colonic lesion site due to the action of chitosan, followed by a slow release of SZ-A. The colon-targeted adhesion pellets effectively mitigated the progression of UC in rats through multiple mechanisms, including anti-inflammatory effects, reduction of oxidative stress, repair of the intestinal barrier, and optimization of intestinal flora composition. This system offers a precise, efficient, and translationally promising delivery strategy for the oral treatment of UC and is anticipated to be an ideal clinical candidate.