Marginal-zone B cells as promising targets of an mRNA-loaded, lipid-nanoparticle cancer vaccine

Combining mRNA-based cancer vaccines and lipid nanoparticles (LNPs) is a highly versatile and effective delivery technology that achieves efficient mRNA delivery to antigen-presenting cells (APCs). Marginal zone B (MZB) cells have been recognized as a promising APC target for cancer vaccines. However, no report has yet introduced a carrier that could efficiently deliver mRNA to MZB cells; hence, their potential as a target for cancer vaccines has yet to be demonstrated. In this study, we describe our application of an LNP formulation containing 15 mol% DSPC (15%DSPC) as a systemically administered cancer vaccine. The 15%DSPC selectively delivered mRNA to MZB cells, and the MZB cells subsequently accumulated in splenic follicles, which suggests a concentration of antigen proteins in the follicles. In addition, the delivery of antigen-coding mRNA to MZB cells induced MZB cell-specific major histocompatibility complex class I antigens, which was followed by cytotoxic T lymphocyte responses. Furthermore, with no signs of significant toxicity, 15%DSPC shows an anti-tumor effect that is equal to, or perhaps even better than, mRNA cancer vaccines that target dendritic cells in clinical trials. In summary, the results of this study demonstrate the efficacy of using an LNP formulation to target splenic MZB cells as a cancer vaccine. Antigen presentation and cellular immune responses were induced in an MZB cell-dependent manner, which proves that mRNA-based cancer vaccines could be effective at targeting MZB cells as APCs. ● DSPC-rich LNP (15%DSPC) targeted splenic marginal zone B (MZB) cells known as antigen presenting cells. ● 15%DSPC induced MZB cell-specific antigen presentation and enhanced CTL responses. ● 15%DSPC induced tumor suppression comparable to formulation in clinical trials. ● 15%DSPC showed no observable toxicity. ● MZB cell targeting 15%DSPC identified MZB cells as a potential target for mRNA-based cancer vaccines.