A self-crosslinkable, adhesive intestine-derived extracellular matrix hydrogel enhances organoid retention and restores intestinal barrier integrity.

Disruption of the intestinal barrier impairs essential functions of the gastrointestinal tract and triggers severe inflammation. Accordingly, transplantation of intestinal organoids restores the integrity of the injured intestinal barrier by promoting regeneration. However, the dynamic mucosal microenvironment of the intestine hinders effective retention of transplanted organoids, thereby limiting their therapeutic efficacy. To address this challenge, this study introduces a pyrogallol (PG)-conjugated intestine-derived extracellular matrix (IEM) (IEM-PG) as a scaffold for effective organoid transplantation. The dual crosslinking of IEM-based fibrillogenesis and oxidative PG coupling enabled IEM-PG to form a robust hydrogel scaffold without crosslinking agents under physiological conditions. Moreover, the IEM-PG hydrogel exhibited enhanced mechanical properties, superior bio-adhesion, and greater resistance to enzymatic degradation than the pristine IEM. The IEM-PG hydrogel was also highly biocompatible and did not adversely affect the viability and development of colonic organoids. The solution-type IEM-PG was readily injected into colonic tissue, thus allowing IEM-PG to initially spread along the intestinal lining. Transplantation of colonic organoids using IEM-PG in a mouse colonic ulcer model demonstrated effective cell retention in the intestinal tract, thereby restoring the structural integrity and function of the intestinal barrier. The study further demonstrated that the patch-type IEM-PG hydrogel was effective for the transplantation of colonic assembloids and the treatment of colonic perforation. Overall, this study presents the IEM engineered with an adhesive motif as a self-crosslinking hydrogel platform for organoid/assembloid transplantation and intestinal tissue repair.