A Spleen-Targeted Tolerogenic mRNA-LNPs Vaccine for the Treatment of Experimental Asthma

Lipid nanoparticles (LNPs)-based mRNA vaccines have witnessed their great advantages in the fight against infectious diseases. However, the pro-inflammatory properties of mRNA-LNPs vaccines may hinder the induction of antigen-specific tolerogenic immune responses. Here, it is demonstrated that stearic acid-doped LNPs co-loaded with nucleoside-modified mRNA and celastrol selectively target spleen, convert their adjuvanticity and promote a tolerogenic rather than immunogenic DCs phenotype. Furthermore, the tolerogenic mRNA vaccine also invokes the generation of antigen-specific regulatory T cells (Tregs) in the spleen and migration of the induced Tregs to the lung. In a mouse model of allergic asthma, immunization with the tolerogenic mRNA vaccine significantly alleviated symptom induction, reducing eosinophilic granulocyte accumulation and mucus secretion. In conclusion, this spleen-targeted mRNA-LNPs vaccine platform induces tolerogenic immune responses, offering promise for the development of therapeutics against allergic asthma and other conditions requiring immune tolerance modulation.