In situ gut microbiota editing: enhancing therapeutic efficacy for bacterial colitis by compatible oral hydrogel microspheres with phages

Gut microbiota editing represents a promising therapeutic strategy for dysbiosis-associated diseases. Bacteriophages (phages), with their host specificity, enable precise microbial manipulation but face challenges such as environmental vulnerability and low bioavailability, which limit their in vivo efficacy. Here, we develop double-responsive hydrogel microspheres (HMs) via electrohydrodynamic spraying to enhance oral phage delivery. Composed of sodium alginate, hyaluronic acid, and Eudragit S100, these HMs achieve 90% encapsulation efficiency for a Salmonella-targeting phage cocktail. Such formulation significantly protects phages from gastric conditions, prolongs their intestinal retention, and enables responsive payload release in the colon. In a murine model of Salmonella Typhimurium (STm)-induced colitis, HMs-encapsulated phages (HMs-Phages) reduce intestinal STm burden by nearly 2000-fold and lower levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) to 60% of those in infected group. Notably, HMs-Phages achieve potent antibacterial efficacy comparable to ciprofloxacin while selectively targeting STm. This targeted strategy circumvents antibiotics-associated microbiota dysbiosis and diarrhea, thereby effectively restoring gut homeostasis and improving host physical health. By integrating targeted pathogen eradication with microbiota conservation, this work provides a precise toolkit for gut microbiota editing and phage therapy, offering substantial advantages over antibiotics for managing dysbiosis-related diseases.