Durable tolerance to food allergens is physiologically established early in life through mucosal immune education, whereas most current allergen immunotherapies primarily induce treatment-dependent desensitization. Here we evaluate a biomimetic oral immunotherapy designed to recapitulate this process in peanut allergy. INP20 is an oral nanoparticle formulation encapsulating complete peanut extract within hypoallergenic zein particles engineered to produce innate immune activation through allergen delivery in the ileocecal region of the distal intestine. In preclinical studies, INP20 preferentially localized to the ileocecal region, induced coordinated Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) activation with IL-10–dominant immune signatures, and protected sensitized mice from fatal anaphylaxis after peanut challenge. In a randomized, double-blind, placebo-controlled Phase 1 dose-escalation trial in peanut-allergic participants (n=52), INP20 was well tolerated up to 20 mg peanut protein and induced a significant increase in peanut-specific IgG4, reaching a mean 8.9-fold rise by day 28 that persisted beyond dosing. *Sara Gómez and Juan Manuel Irache equally contributed.