“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. <i>Ramulus Mori</i> (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 <i>in vivo</i> and <i>in vitro</i> 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.