Oral <i>Akkermansia muciniphila</i> Biomimetic Nanotherapeutics for Ulcerative Colitis Targeted Treatment by Repairing Intestinal Epithelial Barrier and Restoring Redox Homeostasis

The structural disruption of intestinal barrier and excessive reactive oxygen/nitrogen species (RONS) generation are two intertwined factors that drive the occurrence and development of ulcerative colitis (UC). Synchronously restoring the intestinal barrier and mitigating excess RONS is a promising strategy for UC management, but its treatment outcomes are still hindered by low drug accumulation and retention in colonic lesions. Inspired by intestine colonizing bacterium, we developed a mucoadhesive probiotic <i>Akkermansia muciniphila</i>-mimic entinostat-loaded hollow mesopores prussian blue (HMPB) nanotherapeutic (AM@HMPB@E) for UC-targeted therapy via repairing intestinal barrier and scavenging RONS. After oral administration, the negatively charged AM@HMPB@E specifically bind to the positively charged inflamed colon lesions via electrostatic interactions and <i>Akkermansia muciniphila</i> membrane-mediated bioadhesion mechanism. Subsequently, the superoxide dismutase (SOD)-, and catalase (CAT)-like HMPB eliminated RONS, thereby alleviating RONS-mediated inflammation and intestinal epithelial damage. Meanwhile, the UC-site locally released entinostat could repair the damaged intestinal epithelial barrier by inhibiting intestinal endothelial cell apoptosis and up-regulating the expression of tight junctions. Both <i>in vitro</i> and <i>in vivo</i> results shown that AM@HMPB@E not only exhibited an exceptional retention in the colitis site but also demonstrated superior therapeutic efficacy compared to the first-line drug sulfasalazine, as evidenced by the longer colon, less rectal bleeding and body weight loss. Collectively, our findings highlight the clinical application prospects of this synchronous nanotherapeutic strategy for UC treatment, offering a paradigm for the rational design of oral nanomedicine.