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

EcN@Se-MHA/BG nanogel coating improved the colonization efficiency of EcN by 560% through sequential pH and ROS-responsive release.

• During digestion, EcN@Se-MHA/BG formed insoluble complexes that protected EcN against acidic pH conditions.
• The diselenide-crosslinked nanogel coating degraded rapidly in response to high levels of reactive oxygen species (ROS) characteristic of inflammatory microenvironments.
• The 560% improvement in colonization efficiency resulted from the combination of acid protection and ROS-triggered release at the site of inflammation.

Se-MHA/BG nanogels were designed with sequential responsiveness to both acidic pH and elevated ROS levels found in IBD inflammatory microenvironments.

• The nanogels incorporated diselenide crosslinks that are sensitive to ROS-mediated degradation.
• Acid conditions during gastric digestion triggered formation of insoluble complexes to shield the probiotic cargo.
• This dual-trigger design enabled site-specific release of EcN at the inflamed colon rather than premature release in the stomach.

Degraded Se-MHA/BG nanogels functionalized with mannose moieties promoted uptake efficiency by M2 macrophages and inhibited their repolarization.

• Mannose moieties on the nanogel surface facilitated targeted uptake by M2 macrophages, which express mannose receptors.
• The nanogel components inhibited repolarization of M2 macrophages by alleviating IBD-related symptoms including epithelial barrier damage, cellular oxidative stress, and inflammation.
• This mechanism addressed multiple pathologic features simultaneously, supporting M2 macrophage-mediated intestinal wound repair.

EcN@Se-MHA/BG exerted both therapeutic and prophylactic effects on colonic pathological symptoms in a DSS-induced murine colitis model.

• The formulation was tested in a dextran sulfate sodium (DSS)-induced murine colitis model.
• Both treatment (therapeutic) and prevention (prophylactic) protocols were evaluated.
• The system improved colonic pathological symptoms and positively regulated gut microbiota composition.

Conventional probiotic therapy for IBD is limited by inefficient oral delivery and inability to simultaneously address multiple pathologic features.

• Multiple pathologic features in IBD persistently disrupt M2 macrophage-mediated intestinal wound repair.
• Probiotic therapy is described as a 'sustainable treatment strategy for IBD' but faces delivery barriers including degradation under acidic gastric conditions.
• The inability to target inflamed tissue and address oxidative stress, barrier damage, and inflammation concurrently limits therapeutic efficacy.

Se-MHA/BG nanogels demonstrated potential as a versatile coating system to enhance clinical therapeutic performance of probiotic-based therapies for IBD.

• The nanogel system was described as 'multifunctional integrated' with both sequential response and diverse bioactivities.
• Escherichia coli Nissle 1917 (EcN) was used as the model probiotic.
• The authors concluded Se-MHA/BG NGs show 'promising potential as a versatile coating system to enhance the clinical therapeutic performance of probiotic-based therapies for IBD.'