Prodrug-integrated multifunctional liposome encapsulation enhances probiotic-based bacteriotherapy for inflammatory bowel disease.

Probiotic-based bacteriotherapies show promise for treating inflammatory bowel disease (IBD) by dynamically modulating the intestinal microenvironment. However, their clinical efficacy is hampered by poor gastrointestinal viability, limited intestinal retention, and low bioactivity. To overcome these challenges, we developed a prodrug-integrated multifunctional liposomal coating strategy to enhance probiotic efficacy. This liposomal coating protects probiotics from gastric acid, significantly improving their viability after oral administration. In the acidic stomach environment, protonation of amine groups on the liposomal surface increases the surface positive charge, enhancing probiotic adhesion to the negatively charged intestinal mucus through weakening electrostatic repulsion. Concurrently, PEG2000 chains further promote deep mucus penetration, facilitating enhanced colonization, prolonged intestinal retention, and reinforcement of epithelial barrier function. Additionally, idebenone (IDE), conjugated to the liposomal surface via a ROS-responsive linker, is selectively released in inflamed regions with elevated ROS levels, providing localized antioxidant and anti-inflammatory effects. In multiple colitis models, this engineered probiotic platform demonstrated significant prophylactic and therapeutic efficacy with favorable safety profiles, highlighting its potential as an effective strategy for IBD therapy.