Abstract

Engineered bacterial therapeutics have shown promising performance in treating various chronic and inflammatory diseases. However, inadequate colonization of therapeutic bacteria at disease sites, which usually impairs efficacy, remains a critical challenge that needs to be addressed for clinical translation of live biotherapeutics. Herein, we report an innovative approach to enhance the colonization of probiotic Escherichia coli Nissle 1917 (EcN) by genetically replacing its native capsular polysaccharide with hyaluronan, a human glycosaminoglycan that potentiates bacterial stress tolerance, mucoadhesion, and phagocytosis resistance. Using hyaluronan-mediated colonization, the engineered EcN strain expressing recombinant superoxide dismutase (SOD) further exhibited a significantly improved efficacy against dextran sulfate sodium (DSS)-induced colitis in mice, as demonstrated by the remarkable resolution of ulcerative colitis following a single administration. Collectively, hyaluronan-based capsular polysaccharide engineering represents a robust platform to improve bacterial colonization, thus developing effective therapeutic bacteria targeting ulcerative colitis or other bowel diseases.