Mannan-based oral nanovaccine rebalances intestinal immunity against food allergy.

Food allergy is an escalating global health challenge. Although oral immunotherapy is clinically promising, its efficacy is limited by gastrointestinal adverse effects, allergen instability, and transient desensitization. We developed mannan-decorated allergen nanoparticles (Mann/Allergen NPs) that protected allergen integrity, prolonged intestinal residence (>8 h), and selectively targeted tolerogenic antigen-presenting cells in the small intestinal lamina propria. Mann/Allergen NPs exhibited uniform size, excellent stability, and enhanced dendritic cell uptake compared with free allergen. In mouse models of food allergy, the nanoparticles induced robust immune reprogramming, including preferential uptake by macrophage-like dendritic cells (DCs), induction of tolerogenic DCs, rebalancing of Th1/Th2 responses, expansion of regulatory T cells (Tregs), and marked suppression of jejunal mast cell infiltration and allergen-specific IgE. In a translational peanut allergy model, a single treatment course conferred durable protection for over four weeks while preserving gut microbial diversity and short-chain fatty acid (SCFA)-producing commensals. These findings establish receptor-targeted nanodelivery as a promising strategy for safe and durable food allergy immunotherapy.