Successful mRNA vaccine deployment hinges on delivery systems such as lipid nanoparticles (LNPs), which are the most commonly used systems in research and human-use approved mRNA vaccines. LNPs facilitate the delivery of mRNA and provide robust immune-stimulating adjuvant activity. Modifications to or substitution of any of the four lipid components of an LNP can alter the destiny of an mRNA vaccine in vivo. This may involve altered vaccine-induced immune profiles, vaccine biodistribution to favour specific tissues, or dampened reactogenicity. The development of novel lipid components has greatly expanded in recent years, driving the need for methods and tools to screen potential LNP formulations for mRNA delivery. These updated LNP formulations, which utilise modified or novel lipid components, ideally exhibit improved safety profiles and induce immune responses associated with protection against a target pathogen. Additionally, traditional pathogen-first, platform-second approaches to vaccine design can limit in-depth characterisation of LNP immunogenicity in cases where ideal vaccine antigens have not yet been identified or the common antigens have limited epitopes for one or multiple immune compartments. Therefore, we chose an alternative, “pathogen-agnostic” LNP screening approach to characterise and compare alternative LNP formulations. To do this, we designed an mRNA reporter system that allows for simultaneous observation of LNP uptake, mRNA expression, and vaccine-specific immune responses. The construct encodes Cre recombinase which when expressed in transgenic reporter mice (Ai9), leads to the production of intracellular tdTomato fluorescent protein, enabling the detection of mRNA vaccine antigen expression at a cellular level. The construct also encodes fused B cell and T cell epitopes known to induce vaccine-specific cells in C57BL/6 mice. Combined with high-dimensional spectral flow cytometry panels, this system allows for thorough evaluation of vaccine-induced immunity following mRNA-LNP vaccination at a cell population level in both myeloid and lymphoid immune compartments. Preliminary data indicates substantial induction of tdTomato+ immune cells in the site of vaccination and draining lymph nodes 48 hours after intramuscular vaccination. Additionally, circulating T cells produce pro-inflammatory cytokines in response to stimulation with vaccine-specific peptides, providing proof of concept for the system. Ultimately, we aim to determine whether modified LNP formulations can lead to induction of localised tissue immunity. Of particular interest to us is the induction of localised resident immune cells within the lung following intramuscular vaccination. More broadly, this system will allow for streamline in-depth characterisation of novel LNP formulations and more strategic and informed mRNA vaccine design.