Ribonucleic acid (RNA) has taken the field of drug delivery by storm as an exciting cargo class for gene modulation, particularly in the wake of the global deployment of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The full potential of RNA-based medicines, however, can only be realized through the intracellular delivery of RNA to target cell populations, a feat which has only recently been broadly enabled with the emergence of ionizable lipid nanoparticles (LNPs). This dissertation describes the development of both new LNP-based delivery systems for RNA therapeutics and vaccines and novel approaches to accelerate discovery and evaluation of the next generation of RNA LNPs. The first chapter provides a brief background on RNA therapeutics and vaccines and the nanocarriers that have made them possible, with a particular focus on mRNA LNPs. The second chapter describes the development of an LNP platform for dual RNA delivery to T cells ex vivo for the non-viral production of transient, programmed cell death protein 1 (PD-1) signalling-resistant “super” chimeric antigen receptor (CAR) T cells for improved cancer immunotherapy. The remaining chapters focus on direct in vivo LNP evaluation for immune engineering using high-throughput screening (HTS) technologies. Chapter three discusses the use of established barcoded DNA (b-DNA) technology for highly multiplexed screening of mRNA LNPs to uncover differential influences on immune tropism across administration routes. The last chapter discusses the development of a next-generation HTS platform based on barcoded mRNA (b-mRNA) for high-fidelity in vivo mRNA LNP screening. This novel screening platform is then applied to identify mRNA LNPs for hepatic and extrahepatic transfection of both parenchymal cells and leukocytes, and a lead LNP candidate for splenic myeloid cell transfection is evaluated for mRNA cancer vaccination in a mouse model of melanoma. The work reported herein demonstrates both the promise of RNA delivery for immune engineering and methods to broaden understanding of RNA drug carriers and accelerate the discovery of next-generation RNA LNPs for applications in immunotherapy and beyond.