An overview of rational design of mRNA-based therapeutics and vaccines.

INTRODUCTION: Messenger RNA (mRNA)-based therapeutics and vaccines have emerged as a disruptive new drug class for various applications, including regenerative medicine, cancer treatment, and prophylactic and therapeutic vaccinations. AREAS COVERED: This review provides an update about the rational structure-based design of various formats of mRNA-based therapeutics. The authors discuss the recent advances in the mRNA modifications that have been used to enhance stability, promote translation efficiency and regulate immunogenicity for specific applications. EXPERT OPINION: Extensive research efforts have been made to optimize mRNA constructs and preparation procedures to unleash the full potential of mRNA-based therapeutics and vaccines. Sequence optimization (untranslated region and codon usage), chemical engineering of nucleotides and modified 5'cap, and optimization of in vitro transcription and mRNA purification protocols have overcome the major obstacles (instability, delivery, immunogenicity and safety) hindering the clinical applications of mRNA therapeutics and vaccines. The optimized design parameters should not be applied as default to different biological systems, but rather individually optimized for each mRNA sequence and intended application. Further advancement in the mRNA design and delivery technologies for achieving cell type- and organ site-specificity will broaden the scope and usefulness of this new class of drugs.