Colon‐Targeted Adhesive Hydrogel Microsphere for Regulation of Gut Immunity and Flora

Intestinal immune homeostasis and microbiome structure play a critical role in the pathogenesis and progress of inflammatory bowel disease (IBD), whereas IBD treatment remains a challenge as the first‐line drugs show limited therapeutic efficiency and great side effect. In this study, a colon‐targeted adhesive core–shell hydrogel microsphere is designed and fabricated by the ingenious combination of advanced gas‐shearing technology and ionic diffusion method, which can congregate on colon tissue regulating the gut immune‐microbiota microenvironment in IBD treatment. The degradation experiment indicates the anti‐acid and colon‐targeted property of the alginate hydrogel shell, and the in vivo imaging shows the mucoadhesive ability of the thiolated‐hyaluronic acid hydrogel core of the microsphere, which reduces the systematic exposure and prolongs the local drug dwell time. In addition, both in vitro and in vivo study demonstrate that the microsphere significantly reduces the secretion of pro‐inflammatory cytokines, induces specific type 2 macrophage differentiation, and remarkably alleviates colitis in the mice model. Moreover, 16S ribosomal RNA sequencing reveals an optimized gut flora composition, probiotics including Bifidobacterium and Lactobacillus significantly augment, while the detrimental communities are inhibited, which benefits the intestinal homeostasis. This finding provides an ideal clinical candidate for IBD treatment. A colon‐targeting and mucoadhesive hydrogel core–shell microsphere is fabricated by advanced gas‐shearing technology for treatment of inflammatory bowel disease. The oral‐administrated microsphere targets the colon where the alginate shell collapses and the HA‐SH‐Ag hydrogel core is released, which congregates on the inflamed colon mucosa for regulation of macrophage differentiation and optimization of gut flora.