Messenger RNA (mRNA) delivery has revolutionized the therapeutic landscape, allowing for precise, intracellular control of previously undruggable targets through potent therapeutic protein expression. However, the mRNA platform also contains several intrinsic inefficiencies, including low stability, immunogenicity, and delivery challenges. Throughout mRNA’s history, researchers have worked to overcome these limitations by re-engineering the in vitro mRNA transcription (IVT) process, resulting in significant improvements in immunogenicity, stability, and translational efficiency. Furthermore, mRNA delivery platforms like lipid nanoparticles (LNPs) help shield the mRNA from degradation and enable controlled release to target tissues. Despite these advancements, widespread challenges related to immunogenicity and stability remain, limiting broader clinical application in diseases that would otherwise benefit from mRNA’s favorable pharmacokinetics. Innate immunomodulation is a critically underexplored area for mRNA application, stemming from our limited understanding of how mRNA delivery’s intrinsic immunogenicity results in inefficient expression, or worse yet, unexpected off-target exacerbations in disease state. Therefore, the primary objective of this dissertation is to broaden this understanding and enable therapeutic applications in the innate immune system and inflammatory disease. In Aim 1, we investigate how LNP lipid composition influences activation of the NLRP3 inflammasome, a highly dysregulated and disease-relevant innate immune pathway. We demonstrate that mRNA-LNPs activate the NLRP3 inflammasome in a lipid-formulation dependent manner, yielding key insights for future therapeutic and clinical design. In Aim 2, we focus on the mRNA cargo itself, assessing how production method, nucleotide modifications, and purification influence immunogenicity and therapeutic viability. Using novel co-tethered transcription systems, we perform comprehensive in vitro and in vivo screening, and also explore the potential of unmodified IVT RNA, coined immunoagonist non-coding RNA (incRNA), to act as a combination toll-like receptor agonist for cancer immunotherapy. In Aim 3, we integrate all our previous LNP design and mRNA engineering insights to develop the first mRNA therapeutic systems targeting gouty arthritis, a localized inflammatory disease mediated by NLRP3 activation. Together, these findings establish new principles for designing mRNA therapeutics that either evade or harness innate immune signaling and lay considerable groundwork for future clinical applications in chronic inflammatory disease and cancer.