Cascade-triggered oral gelatin-alginate micro-nano carriers integrate dual targeting and microbiota restoration for anti-Salmonella therapy.

Foodborne pathogens such as Salmonella enterica serovar Typhimurium remain a major threat to public health and food safety. Conventional antibiotic therapy is often ineffective due to intracellular persistence and biofilm protection. We developed a cascade-responsive oral micro-nano carrier (EQM@MS) that combines the food-derived flavonoid quercetin and enrofloxacin within dual-targeted micelles encapsulated by gelatin-alginate microspheres. The system provides gastric protection, enzyme-triggered intestinal release, and ligand-mediated targeting of epithelial cells and macrophages. EQM@MS achieved a 4-log reduction of intracellular S. typhimurium in vitro, eradicated 80% of biofilms, and elevated mouse survival to 80% with a 1000-fold bacterial load reduction in vivo. Notably, the treatment rebalanced the gut microbiota by enriching Firmicutes and Bacteroidetes, mitigating inflammation and promoting host recovery. These findings provide a basis for designing functional oral formulations that combine food-derived bioactive and antibacterial agents to combat foodborne pathogens and support gut health.