Dual-Targeting Mn@CeO₂ Nanozyme-Modified Probiotic Hydrogel Microspheres Reshape Gut Homeostasis in Inflammatory Bowel Disease

Oral microecological agents show potential in reshaping intestinal microbiota and treating inflammatory bowel disease (IBD), but their clinical application is hindered by gastrointestinal challenges, antioxidant instability, and ineffective targeted delivery. In this study, we proposed a protective modification strategy utilizing a nanozyme coating and an alginate microsphere system to enhance the delivery efficiency, effectiveness, and precision of probiotics. By incorporating Mn into CeO₂, Mn@CeO₂ nanozyme was synthesized, significantly boosting ROS scavenging activity both <i>in vitro</i> and <i>in vivo</i> at safe dosages. Following the coincubation of Mn@CeO₂ with <i>Limosilactobacillus reuteri</i>, the nanozymes were successfully distributed onto the surface of the probiotics. MnCe@LR/AMs were then fabricated using the electrostatic spray method, enhancing their tolerance to the acidic environment of the stomach. Notably, sodium alginate (SA), through electrostatic interactions and binding to mannose receptors highly expressed at inflamed sites, conferred a dual-targeting property to MnCe@LR/AMs. In the treatment of colitis in mice, MnCe@LR/AMs were shown to function through the synergistic antioxidant and anti-inflammatory activities of their components. They also effectively reinforced the intestinal barrier, while improving gut microbial diversity and increasing the relative abundance of probiotics. Furthermore, we demonstrated that MnCe@LR/AMs contribute to the maintenance of intestinal homeostasis by enhancing the absorption of amino acids in the gut and modulating macrophage polarization to regulate the immune response. These findings suggest that MnCe@LR/AMs hold significant promise for developing advanced IBD therapies, offering improved precision and efficacy in probiotic delivery.