Engineering tolerogenic mRNA-LNPs for allergen-specific immune reprogramming in pollen allergy.

Pollen allergy is a prevalent respiratory allergic disease, yet current allergen immunotherapy (AIT) remains limited by safety concerns and insufficient induction of durable immune tolerance. Here, we develop an engineered mRNA-LNP platform for allergen-specific tolerance induction by integrating allergen and delivery system optimization. A non-secretory mRNA encoding the major mugwort pollen allergen Art v 1 fused with invariant chain (mArt v 1) was designed to reduce IgE-mediated activation while promoting tolerogenic allergen processing. This antigen was delivered using a mannose-functionalized LNP formulation (mAr-C18mann) optimized for low inflammatory activation and enhanced immune regulation. The engineered platform promotes a tolerance-associated hepatic immune environment, regulates antigen-presenting cell responses, and enhances allergen-specific regulatory T-cell induction. In a murine model of pollen allergy, both mAr-C18mann and a simplified epitope-based variant (mdT-C18mann) attenuate allergic inflammation and allergen-specific IgE levels. Consistently, mAr-C18mann reprograms immune responses toward Treg- and Th1-dominated profiles, providing effective protection in a prophylactic allergy model. These findings support the mRNA-LNP platform as a modular next-generation AIT strategy for inducing durable immune tolerance to pollen allergy.