Oral microbiota-regulating and inflammation-targeted polymersome-hydrogels for RNAi therapy of ulcerative colitis

The treatment of ulcerative colitis is harassed by its intricate pathogenesis and the harsh gastrointestinal environment. Herein, oral microbiota-regulating and inflammation-targeted polymersome-hydrogels are developed by incorporating gallic acid and tumor necrosis factor α-specific siRNA-encapsulated polymersomes (GA-siTNFα-PS) into self-healable and eatable hydrogels (SHE-Gel) formed from thiolated sodium alginate and dopamine-modified oxidized inulin (DA-OIn) for oral RNAi therapy of ulcerative colitis. SHE-Gel is stable in stomach, resides in the intestine, and degrades in the colon by colon-specific inulinase. DA-OIn endows SHE-Gel anti-oxidative stress and prebiotic activities that modulate the diversity of gut microbiota. GA-siTNFα-PS released in the colon can adhere to the inflamed sites, resulting in selective delivery of siTNFα to macrophages. GA eliminates ROS and further protects siTNFα from degradation. Remarkably, GA-siTNFα-PS/SHE-Gel not only effectively blocks the progression of inflammation but also maintains the homeostasis of gut microbiota in the ulcerative colitis model. GA-siTNFα-PS/SHE-Gel can further combine with anti-TNFα antibody, restoring the intestinal immune and gut microbiota homeostasis in an advanced model of colitis in mice. The polymersome-hydrogels with effective suppression of intestinal inflammation and modulation of gut microbiota provide a versatile and powerful strategy for treatment of ulcerative colitis.