Intracellular hydrogelation of macrophage conjugated probiotics for hitchhiking delivery and combined treatment of colitis

Immune cell membrane coated nanomedicine was developed to neutralize cytokines via receptor-ligand interaction, which showed potential for the treatment of inflammatory bowel disease (IBD). However, cell membrane isolation and re-assembly process involved protein loss and spatial disorder, which reduced the sequestration efficiency towards cytokines. In addition, oral administration of probiotics was accepted for IBD treatment via gut microbiota modulation, but most probiotics showed weak adhesion to intestine mucosa and were quickly expelled from gastrointestinal tract. Herein, an intracellular hydrogelation technology was proposed to construct gelated peritoneal macrophage (GPM) with intact membrane structure, resulting from the avoidance of membrane isolation and re-assembly process. GPM efficiently neutralized multiple cytokines in vitro and in vivo to ameliorate inflammatory Caco-2 ​cells and colitis rats by regulating oxidative stress, inflammation level and intestinal barrier repair. Moreover, the probiotics (Nissle1917, EcN) were easily attached on GPM surface through specific recognition, to construct GPM-EcN conjugate for GPM hitchhiking delivery to colitis tissue. Conjugation process of GPM and EcN showed no damage on bacterial physiological function. Due to the chemical attachment on inflammatory cells, GPM carried the attached EcN hand-in-hand to accumulate in the colitis tissue of IBD rat, and enhanced intestine retention time of EcN in comparison to free EcN, which improved bacterial diversity, and shifted the microbiota community and acid metabolites to an anti-inflammatory phenotype. This study transferred the hydrogel synthesis from in vitro to intracellular cytoplasm, and came to a new insight of conjugating strategy of GPM and probiotics for hitchhiking delivery and combined anti-IBD treatment.