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

Jun 12, 2026Nature biomedical engineering

Lipid nanoparticle makeup controls body-wide movement and tissue-targeted T cell immune responses after muscle injection

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Abstract

Lipid nanoparticle formulations exhibit distinct trafficking behaviors, influencing immune responses in specific organs.

Different lipid compositions in nanoparticles led to varying degrees of movement from the injection site to systemic organs.
Some formulations remained localized, while others entered the bloodstream and accumulated in organs like the liver and lungs.
The accumulation of nanoparticles in specific organs was associated with differences in antigen expression and local immune responses.
Enhanced delivery to the liver correlated with stronger immunity from liver-resident T cells and improved control of liver tumors in mice.
Adjusting lipid composition may enable the design of vaccines that provide targeted, lasting protection in tissues where local immunity is crucial.

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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.