Advances in mRNA‐Lipid Nanoparticle Engineering for Immune Cell Targeting and Immune Modulation

Immunotherapy has transformed therapeutic paradigms, especially in oncology, by leveraging antibodies, cytokines, and cell-based strategies. In recent years, immunotherapy has expanded its impact to combat a broad spectrum of diseases, including fibrotic, autoimmune, and infectious disorders. Messenger RNA (mRNA)-based platforms offer distinct advantages for immunotherapy by enabling in vivo synthesis of proteins with native post-translational modifications to enhance bioactivity and reduce immunogenicity. mRNA also allows non-viral, transient reprogramming of immune cells in vivo, supporting scalable manufacturing and eliminating the risk of insertional mutagenesis. However, naked mRNA faces clinical limitations including inherent instability, poor cellular uptake, and non-targeted delivery. Lipid nanoparticles (LNPs) can overcome these challenges by encapsulating mRNA for protected and efficient delivery to target cells. Importantly, recent advances have demonstrated the potential of mRNA-LNPs to modulate immune cell function with cell-type specificity, enhancing therapeutic precision. This review highlights progress in engineering mRNA-LNPs for targeted immune cell delivery, strategies for immune cell-specific modulation, and applications across immune-related pathologies. Design considerations to improve delivery efficiency and immunological outcomes are also discussed, supporting the clinical translation of mRNA-LNP immunotherapies.