DNA Nanopatch-Specific Modification of Probiotics for Ultrasound-Triggered Inflammatory Bowel Disease Therapy

Probiotics offer promising results for treating inflammatory bowel disease, yet precision therapy remains challenging, particularly in manipulating probiotics spatially and temporally and shielding them from oxidative stress. To address these limitations, herein we synthesized bacteria-specific DNA nanopatches to modify ultrasound-triggered engineered <i>Escherichia coli</i> Nissle 1917. These probiotics produced the anti-inflammatory cytokine interleukin-10 when stimulated by ultrasound and were fortified with DNPs for oxidative stress resistance. The DNPs were composed of rectangular DNA origami nanosheets with reactive oxygen species' scavenging ability and bacterial targeting ligands of maltodextrin molecules. We systematically demonstrated that the DNPs could selectively attach to bacterial surface but not mammalian cell surface via the maltodextrin transporter pathway. To further enhance the bioavailability of engineered probiotics in the gastrointestinal tract, we employed a self-assembly strategy to encapsulate them using chitosan and sodium alginate. In a murine model of ulcerative colitis, this system significantly improved the gut barrier integrity and reduced inflammation. Our results indicate that this DNA nanopatch-bacteria system holds substantial promise for mitigating oxidative stress, correcting microbiota dysbiosis, and enhancing the intestinal barrier function in colitis.