Tuning mrna-lipid nanoparticle composition to program tissue-specific memory T cell immunity for enhanced antitumor activity

The National Cancer Institute awarded The Johns Hopkins University $100,228 on December 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to engineer messenger RNA–lipid nanoparticle vaccines that direct tissue-specific immune responses to metastatic cancers in vital organs.

The research will optimize lipid nanoparticle composition to alter trafficking after intramuscular injection, enabling antigen expression within systemic organs such as the liver and lungs rather than limiting immune activation to the injection site and draining lymph nodes. The work will engineer composition-optimized mRNA lipid nanoparticles that escape the injection site, reach systemic organs efficiently, and induce durable tissue-resident memory T cell formation—key immune sentinels for long-term tumor control. In parallel, the funded team will characterize how lipid nanoparticle composition influences trafficking, antigen expression, and immune cell recruitment dynamics to establish design rules for future cancer vaccines. Research will correlate immune activation and memory formation with therapeutic and prophylactic efficacy in tumor models.

Performance takes place at The Johns Hopkins University in Baltimore, Maryland. The project runs from December 1, 2026, through November 30, 2029. This is a Project Grant, a training and research support mechanism under the Cancer Research Manpower program, which provides biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research aligned with the National Cancer Program.

Abstract

Metastatic cancers, which spread to vital organs such as the liver and lungs, remain a major challenge in oncology due to the lack of therapies capable of generating strong, localized immune protection. Cancer vaccines that can induce durable, tissue-specific immune responses, therefore, represent a critical unmet need in cancer immunotherapy. Among emerging platforms, mrna lipid nanoparticle (LNP) vaccines have gained significant attention due to the success of covid-19 mrna vaccines and promising clinical data from experimental cancer vaccines. However, current strategies mainly prime immune responses at the injection site and draining lymph nodes, with limited capacity to program immunity directly within systemic organs where metastases occur. Our preliminary studies demonstrate that tuning the LNP composition dramatically alters their trafficking after intramuscular injection, directing antigen expression from primarily within the muscle to also include systemic organs, such as the liver and lungs. This organ-specific delivery promotes the recruitment and formation of tissue-resident memory T (TRM) cells, key sentinels of long-term tumor control. These findings suggest that rational LNP design can be leveraged to tune where and how immune responses are activated, opening new opportunities for targeted cancer immunotherapies. Building on this foundation, the proposed research will engineer composition-optimized mrna lnps that escape the injection site, efficiently reach systemic organs, and induce strong local immune activation and durable TRM formation. In parallel, we will characterize how LNP composition influences trafficking, antigen expression, and immune cell recruitment dynamics to define design rules for future vaccines. Immune activation and memory formation will be correlated with therapeutic and prophylactic efficacy in metastatic tumor models. Meanwhile, analyses of the tumor microenvironment will reveal how effective vaccine delivery reshapes local immunity at the tumor site. To achieve these goals, we will integrate high-throughput screening with machine learning-guided optimization to systematically refine LNP composition and identify predictive design features. Advanced immune profiling techniques, including multiplex spatial imaging and single-cell transcriptomics, will be used to map how local antigen expression drives tissue-specific immunity. Successful completion of this project will establish a tunable and scalable strategy to program TRM-mediated anti-tumor immunity through LNP engineering, offering a blueprint for next-generation vaccines that eradicate tumors while sparing healthy tissue. This study will advance mechanistic insight into LNP-immune interactions, inform vaccine design technologies, and enable clinical translation across tissue-specific cancers and infectious diseases. Ultimately, this work will expand the therapeutic potential of mrna LNP platforms and improve outcomes for patients with organ-targeted diseases.