Challenges and advances towards the rational design of mRNA vaccines

• mRNA vaccines are safer as compared with plasmid DNA or viral vector-based vaccines.
• Antigen presentation via the MHC-I processing route evokes mainly CD8+ T cells.
• mRNA induces innate immune responses by triggering pattern recognition receptors.
• Combination with conventional adjuvants inhibits antigen expression of mRNA vaccines.

In recent years, mRNA vaccines have emerged as a safe and potent approach for the induction of cellular immune responses. Whereas initial studies were limited to the ex vivo loading of dendritic cells (DCs) with antigen-encoding mRNA, recent progress has led to the development of improved mRNA vaccines that enable direct in vivo targeting of DCs. Although preclinical studies demonstrated their potency in inducing antitumor immunity, several bottlenecks hinder the broader application of mRNA vaccines. In this review, we discuss the challenges associated with mRNA-based vaccination strategies, the technological advances that have been made to overcome these limitations, and the hurdles that remain to be tackled for the development of an optimal mRNA vaccine.