Engineering <i>Escherichia coli</i> Nissle 1917 Carrying PD1 Agonists Resolves Intestinal Inflammation via Local Immune Modulation

Immunological imbalance is a key factor in the progression of intestinal inflammation, yet effective treatments remain elusive. Using a radiation-induced intestinal injury model, we investigated the causes of inflammation at the single-cell level and identified abnormal T-cell activation as a major contributor. To address this, we targeted the PD1 signaling pathway to suppress T-cell activation and evaluated the anti-inflammatory and intestinal repair effects of the PD1 agonist displaying probiotic <i>Escherichia coli</i> Nissle 1917 (EcN^MP1-M) in two mouse models. Encapsulated in Eudragit L100-55 for pH-dependent release, EcN^MP1-M and its bacterial outer membrane vesicles (OMVs) expressed PD1 agonists, which inhibited excessive immune activation and reduced inflammatory cytokines. EcN^MP1-M promoted the expression of proteins that maintain intestinal epithelial barrier integrity, improving gut function and immune responses in colitis mice. Furthermore, 16S rDNA microbiome sequencing revealed that EcN^MP1-M enhanced intestinal microbiota diversity, increased beneficial bacteria, and reduced harmful bacteria. This study proposes a localized EcN-based immunosuppressive therapy for radiation-induced enteritis and inflammatory bowel disease with promising potential for clinical applications.