Abstract

Oral probiotics have shown great potential in treating ulcerative colitis (UC). However, gastrointestinal obstacles substantially inactivate probiotics, impeding delivery and colonization in the colon. Here, we developed robust oral living therapeutics with high colon-accumulating effect via surface decoration of probiotic ( Escherichia coli Nissle 1917, EcN ) using a layer-by-layer approach. Calcium ions and carboxymethyl-modified lignin (CML) were sequentially coated on EcN to generate an acid-resistant and colitis microenvironment-responsive system (CML@ EcN ). After oral administration in a male C57BL/6 N mouse model, EcN were specifically delivered to the site of colitis and successfully colonized. The CML@ EcN notably alleviated colitis by modulating immune dysfunction, reshaping gut microbiota (GM), and repairing the intestinal barrier. The delivery mechanism was explored based on experiments and mathematical models. Interestingly, this engineering approach can be further used to decorate other bacteria. Consequently, the robust CML@ EcN shows high colon-targeting delivery efficacy and great potential in UC therapy.