Lipid nanoparticle composition directs systemic trafficking and tissue-specific T cell immunity after intramuscular injection.

Messenger RNA lipid nanoparticles are promising vaccine carriers, yet their movement through the body after intramuscular injection and the resulting tissue-specific immune effects remain poorly defined. Here we show that lipid nanoparticle trafficking from the injection site into systemic organs is a key determinant of localized immunity, particularly the formation of tissue-resident cytotoxic T cells. We compared multiple nanoparticle formulations that differed in lipid composition, including ionizable lipids and helper lipids commonly used in clinical vaccines. These formulations exhibited distinct trafficking behaviours: some remained largely at the injection site, whereas others entered the bloodstream and preferentially accumulated in organs such as the liver or lungs. Organ-specific accumulation resulted in corresponding differences in antigen expression and local cytotoxic T cell responses. Nanoparticles that more efficiently reached the liver elicited stronger liver-resident T cell immunity and improved control of liver tumours in mice. Our findings demonstrate that tuning lipid composition can direct the systemic movement and organ targeting of messenger RNA nanoparticles, enabling the design of vaccines that promote durable, tissue-specific protection for diseases where local immunity is essential.