Hydrogel Microspheres with Gut-Adaptive Structures for Efficient Probiotic Delivery and Gut-Targeted Release

Oral administration of probiotics holds great promise for regulating gut microbiota and maintaining intestinal homeostasis. However, its practical effectiveness can be limited due to the digestive tract’s harsh environment. Natural polysaccharide-based hydrogel microsphere systems are increasingly used for probiotic protection and oral delivery; the conventional materials used in these systems exhibit defects such as poor structural strength and instability in gelation, causing premature probiotic release. Here, we created hydrogel microspheres with gut-adaptive structures (GG/GN-TA HMs) using gellan gum (GG) as the backbone and β-glucan-tannic acid (GN-TA) as the antioxidative, adhesive, and gut-targeting prebiotic donor, involving structural enhancement via TA-Ca 2+ metal–phenol networks during cross-linking. The structurally optimized microspheres exhibited excellent structural integrity at low pH conditions while disassembling in the gut environment to release probiotics. Such advantages of GG/GN-TA HMs enabled the survival of probiotics in harsh environments and subsequent promotion of probiotic colonization in the colon. In colitis mice, EcN@GG/GN-TA exhibited superior therapeutic effects compared to those of other groups. GG/GN-TA HMs promoted probiotic–prebiotic synergy, which resulted in significant alleviation of gut inflammation, gut barrier repair, and gut microbiota remodeling. Given its simple preparation and efficacy, the GG/GN-TA HMs system has great potential for the protection and targeted delivery of probiotics.