In recent years, mRNA vaccine has achieved increasing interest owing to its high potency, safety, ease of production, and low-cost manufacturing. Currently approved mRNA vaccines are administered intramuscularly to transfect local antigen-presenting cells (APCs) to initiate low to moderate immune responses. Spleen, the largest secondary lymphoid organ in the body which contains a large number of APCs close to B and T lymphocytes, could be the ideal site for effective initiation of an enhanced immune response. Here, we provide an overview of the recent advances in the development of synthetic materials for spleen-specific mRNA delivery, and lipid nanoparticle-based approaches will be highlighted. We further discuss the main challenges for spleen-specific mRNA delivery to provide a reference for the development of next-generation synthetic nanomaterials with optimal properties.