“Precision‐Guided Killer” Engineered Phage for Combating Carbapenem‐Resistant Klebsiella Pneumoniae Induced Inflammatory Bowel Disease

Abstract Carbapenem‐resistant Klebsiella pneumoniae (CRKP) poses a significant global health challenge, recognized by the World Health Organization as a critical priority pathogen necessitating new therapeutic approaches. Phages have emerged as a promising treatment option for CRKP‐infected inflammatory bowel disease (IBD) due to their targeted properties. However, the rapid evolution of phage‐resistant bacteria and the elevated levels of reactive oxygen species in inflamed colons pose significant challenges that can limit the effectiveness of phage therapy. Herein, this study develops a novel engineered phage (phage@CeO 2 ) designed to target and eliminate CRKP, inhibit the emergence of phage‐resistant mutants, and restore intestinal redox and microbiota balance. The mechanism behind the suppression of phage resistance involves downregulating capsule‐encoding genes and inhibiting efflux pumps. Besides, multi‐omic analysis reveals that the increased diversity of intestinal probiotics enhances metabolite production, such as organic acids and indole derivatives, which boost intestinal immunity and restore barrier function through tryptophan metabolism and aminoacyl‐tRNA biosynthesis. This innovative approach using phage@CeO 2 nanoparticles effectively targeted and eradicated the CRKP strain, alleviated inflammation, and repaired intestinal barrier in mice. The engineered phage offers a precise and personalized therapy for pathogenic bacteria, providing a flexible and effective method to combat diverse bacterial infections and improve clinical outcomes.