Engineered probiotics for inflammatory bowel disease therapy: mechanisms, delivery strategies, and precision medicine

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is a prevalent chronic gastrointestinal disorder. Conventional therapies are often limited by adverse effects and suboptimal long-term efficacy. Probiotics have emerged as promising therapeutic alternatives for IBD because of their ability to modulate the gut microbiota, reinforce intestinal barrier integrity, and regulate immune responses. However, their clinical translation is hampered by challenges within the harsh gastrointestinal milieu, including low viability, poor colonization, and insufficient target specificity. This review focuses on the engineering of probiotics designed to overcome these limitations for IBD management. We outline the therapeutic potential and mechanisms of action of probiotics in IBD, with a critical emphasis on discrepancies between preclinical and clinical observations. We subsequently discuss the drawbacks of conventional probiotic therapies, highlighting gaps between <i>in vitro</i> efficacy and <i>in vivo</i> performance. We then highlight cutting-edge engineering strategies, encompassing advanced encapsulation techniques, genetic engineering approaches, novel delivery systems, and molecular-targeting modifications, with quantitative comparisons of their advantages, limitations, and translational potential. The application of these engineered probiotics specifically in UC and CD treatment is explored, with detailed analyses of preclinical models and clinical trials. We also address personalized interventions tailored to individual gut microbiome profiles. Despite significant promise, critical challenges remain, including long-term safety, stability, and accurate prediction of therapeutic responses for engineered probiotics in IBD. Nevertheless, with ongoing advancements in gene editing, synthetic biology, and microbial safety engineering, engineered probiotics represent a promising direction in IBD therapy that will enable more precise, effective, and personalized treatment modalities, provided that safety, reproducibility, and regulatory compliance are prioritized.