Sequentially responsive nanogels enhance probiotic delivery and reprogram M2 macrophage polarization for synergistic...

The interplay of multiple pathologic features in inflammatory bowel disease (IBD) persistently disrupts M2 macrophage-mediated intestinal wound repair. Although probiotic therapy represents a sustainable treatment strategy for IBD, it is still limited by inefficient oral delivery and inability to simultaneously address multiple pathologic features. Accordingly, a multifunctional integrated nanogels (Se-MHA/BG NGs) with both sequential response and diverse bioactivities were designed for coating the model probiotic Escherichia coli Nissle 1917 (EcN@Se-MHA/BG) in this study. During digestion, EcN@Se-MHA/BG formed insoluble complexes to protect EcN against acidic pH conditions, while the diselenide-crosslinked NGs coating degraded rapidly in response to the high levels of reactive oxygen species (ROS) characteristic of inflammatory microenvironments, thereby improving the colonization efficiency of EcN by 560%. Moreover, the degraded NGs, functionalized with mannose moieties, promoted the uptake efficiency of M2 macrophages and inhibited their repolarization by alleviating IBD-related symptoms of epithelial barrier damage, cellular oxidative stress and inflammation. Based on these functions, EcN@Se-MHA/BG exerted both therapeutic and prophylactic effects to improve colonic pathological symptoms and positively regulate gut microbiota in a DSS-induced murine colitis model. Overall, Se-MHA/BG NGs demonstrated promising potential as a versatile coating system to enhance the clinical therapeutic performance of probiotic-based therapies for IBD.