Cellular Nanoparticle–Probiotic Biohybrid for Multimodal Oral Therapy of Food Allergy

Food allergies, driven by abnormal immune responses to dietary allergens, can cause severe and potentially life-threatening reactions. Current treatments remain limited by partial efficacy and prolonged regimens. Here, we present a biohybrid formulation composed of macrophage membrane-derived nanoparticles and <i>Escherichia coli</i> Nissle 1917 probiotics for targeted, multimodal oral therapy of food allergies. The nanoparticles are loaded with an allergen-degrading enzyme and conjugated onto probiotics via click chemistry. This design enables the biohybrid to neutralize pro-inflammatory cytokines, degrade allergens, and enhance intestinal targeting and retention. In vitro, the formulation demonstrated strong cytokine binding and effective allergen degradation. In mouse models of casein- and gluten-induced allergies, oral treatment with the biohybrid suppresses inflammatory cytokines, restores gut microbiota diversity, and alleviates symptoms such as weight loss, diarrhea, and elevated immunoglobulin <i>E</i> levels. Histological analysis shows preserved intestinal structure, and no systemic or gastrointestinal toxicity is observed, indicating good tolerability of the biohybrid system.