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

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.