A multifunctional probiotic co-delivery platform for the treatment of Clostridium difficile infection.

Clostridioides difficile infection (CDI) is strongly linked to disruptions in gut microbial homeostasis. Although conventional antibiotics effectively inhibit C. difficile proliferation, they frequently fail to reestablish microbial equilibrium, thereby constraining therapeutic outcomes. Probiotic therapy seeks to modulate gut microecology by replenishing beneficial microorganisms; however, its clinical efficacy is hindered by poor gastrointestinal survivability, limited colon-targeted engraftment, and inadequate suppression of C. difficile virulence determinants. To address these challenges, we developed a polysaccharide-based hydrogel platform (HF), named BA@HF-PDAT, designed for the synergistic co-delivery of Bifidobacterium adolescentis (BA) and polydopamine-thymol nanoparticles (PDA-TH NPs). HF-mediated encapsulation substantially enhances probiotic viability, facilitates colon- and inflammation-targeted controlled release, and promotes bacterial engraftment. Concurrently, PDA-TH effectively inhibits C. difficile virulence determinants, synergistically amplifying probiotic therapeutic potential. In vitro and in vivo analyses reveal that BA@HF-PDAT facilitates intestinal repair and mitigates apoptosis through Wnt/β-catenin signaling, exerts potent anti-inflammatory and antioxidant activities, and restores gut microbial composition and metabolic function, thereby effectively ameliorating CDI-induced colitis in murine models. Comparative studies further indicate that BA@HF-PDAT achieves superior therapeutic efficacy compared with vancomycin treatment. Collectively, this integrated co-delivery platform constitutes a promising and translational therapeutic strategy for CDI management.