Allergen-specific immunotherapy with Der p 1/2 mRNA vaccines relieves house-dust-mite-induced allergic airway inflammation in a mouse model.

Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment for allergic diseases, but current crude-extract-based approaches suffer from poor standardization and variable safety and efficacy. This study developed lipid nanoparticle (LNP)-encapsulated mRNA vaccines encoding Der p 1 and Der p 2, the major house dust mite (HDM) allergens, and evaluated them in a murine model of HDM-induced airway inflammation. LNP-mRNA vaccines triggered potent humoral immunity and exhibited good tolerability. Subcutaneous immunotherapy significantly reduced early allergic responses, airway hyperresponsiveness, eosinophil infiltration, and mucus hypersecretion. Compared with HDM extract, LNP-mRNA more effectively suppressed T helper cell 2 (Th2)-driven inflammation, decreased total and HDM-specific IgE, and induced allergen-specific blocking antibodies. Specifically, Der p 1/2-specific IgG1 and IgG2a titers increased by more than 10-fold, markedly inhibiting basophil activation. Mechanistically, LNP-mRNA enhanced regulatory T cell (Treg) and type 1 Treg (Tr1) populations, restored Th1/Th2 balance with an approximately 2-fold increase in Th1 cells, reduced innate lymphoid cell 2 (ILC2) frequencies, and promoted germinal center B and T follicular helper responses. Innate immune activation was also observed, with elevated dendritic cells type 1 (cDC1), dendritic cells type 2 (cDC2), and plasmacytoid dendritic cells (pDC) frequencies. These results demonstrate that HDM LNP-mRNA vaccines are safe, are immunologically potent, and represent a standardized next-generation approach for AIT.