Jingjiao Li, Yu Liu, Xinghuan Ma, Sujia Liu, C. C. Yang, Yuzhou Zhang, Xingdi Cheng, Yixing Wen, Shiwei Mi, Haowei Zu, W. Li, Yuanyuan Zhao, Qing Li, Shuai Liu, Haonan Huo, Guizhi Shi, Jiaqi Lin, Xueguang Lu
Gastrointestinal viruses such as rotavirus remain a major cause of childhood gastroenteritis and mortality worldwide. Although current live-attenuated rotavirus vaccines are effective, they face challenges including production, reduced efficacy in low- and middle-income countries, and rare adverse events, highlighting the need for vaccines that can induce strong gut mucosal immunity. Here, we introduce a lipid nanoparticle (LNP) platform that codelivers messenger RNA (mRNA) and the retinoic acid receptor agonist Am80 (Am80-LNP), enabling antigen-specific mucosal immune responses in the gut via parenteral intramuscular vaccination. Am80 incorporation preserved the vaccine's ability to imprint expression of the gut-homing receptors CCR9 and α4β7 on T and B cells, improved mRNA delivery, enhanced lymph node accumulation, and mitigated injection-site inflammation driven by the LNP. In mice and Bama miniature pigs, Am80-LNP induced antigen-specific serum antibody titers, cellular immune responses, and intestinal IgA production. Neonatal mice vaccinated with Am80-LNP exhibited reduced incidence and duration of diarrhea after live rotavirus challenge, whereas LNPs without Am80 conferred negligible protection. These findings highlight the importance of gut mucosal immunity in mediating protection against rotavirus and suggest that Am80-LNP may offer a versatile mRNA vaccine platform against gastrointestinal viruses.