A mucosal mRNA-LNP vaccine platform for broad-spectrum protection against Mycoplasma pneumoniae

Mycoplasma pneumoniae (MP) remains a leading cause of community-acquired pneumonia in children and older adults, yet no licensed vaccine exists and intramuscular approaches fail to intercept infection at its mucosal portal. Here, we engineered an mRNA vaccine encoding four conserved MP antigens, formulated in tamibarotene-loaded lipid nanoparticles optimized for both intramuscular (IM) and intranasal (IN) administration. In mice, IM vaccination elicited high serum IgG and splenic T cell responses but generated negligible mucosal immunity. By contrast, IN administration induced robust bronchoalveolar IgA and expanded lung-resident memory T cells, while systemic IgG levels remained lower than with IM. Functionally, IN immunization conferred superior protection against MP challenge compared to IM immunization, reducing pulmonary MP load and lung pathology while demonstrating broad–spectrum efficacy against both MP strains 1 and 2. These head-to-head comparisons position intranasal mRNA‐LNP vaccination as a transformative strategy for safe, broadly protective vaccine for MP.