mRNA-based therapeutics: powerful and versatile tools to combat diseases

Abstract

The therapeutic use of messenger RNA (mRNA) has fueled great hope to combat a wide range of incurable diseases. Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any functional protein/peptide in the human body by introducing mRNA as a vaccine or therapeutic agent. This represents a rising precision medicine field with great promise for preventing and treating many intractable or genetic diseases. In addition, in vitro transcribed mRNA has achieved programmed production, which is more effective, faster in design and production, as well as more flexible and cost-effective than conventional approaches that may offer. Based on these extraordinary advantages, mRNA vaccines have the characteristics of the swiftest response to large-scale outbreaks of infectious diseases, such as the currently devastating pandemic COVID-19. It has always been the scientists’ desire to improve the stability, immunogenicity, translation efficiency, and delivery system to achieve efficient and safe delivery of mRNA. Excitingly, these scientific dreams have gradually been realized with the rapid, amazing achievements of molecular biology, RNA technology, vaccinology, and nanotechnology. In this review, we comprehensively describe mRNA-based therapeutics, including their principles, manufacture, application, effects, and shortcomings. We also highlight the importance of mRNA optimization and delivery systems in successful mRNA therapeutics and discuss the key challenges and opportunities in developing these tools into powerful and versatile tools to combat many genetic, infectious, cancer, and other refractory diseases.

Poly(aspartic acid)-Based Polymeric Nanoparticle for Local and Systemic mRNA Delivery

“…Messenger RNA (mRNA)-based gene therapies demonstrate great promise for treating various diseases, especially after the COVID-19 mRNA vaccines led to numerous studies focused on the development of mRNA therapeutics. − mRNA therapeutics are mainly explored in antigen production, protein replacement therapy, and genome engineering. , In contrast to DNA, intracellularly delivered mRNA can be translated into an encoded protein in the cytoplasm without integrating the host gene, reducing the risk of biosafety. However, the efficient delivery of intact mRNA to the cytoplasm of target cells after systemic administration is a challenging step.…”

“…1−3 mRNA therapeutics are mainly explored in antigen production, protein replacement therapy, and genome engineering. 4,5 In contrast to DNA, intracellularly delivered mRNA can be translated into an encoded protein in the cytoplasm without integrating the host gene, reducing the risk of biosafety. However, the efficient delivery of intact mRNA to the cytoplasm of target cells after systemic administration is a challenging step.…”

Lipid Nanoparticles: A Novel Gene Delivery Technique for Clinical Application

“…In mRNA, native bases of RNA strongly activate innate immunity [ 16 , 17 ]. Thus, these must be modified by an analog with low immunogenicity for therapeutic purposes [ 18 , 19 , 20 ]. Uridine is a well-known example.…”

“…In addition, to replace uridine to its analog, an in silico procedure to reduce the number of uridines, codon optimization, may be performed. For the polyA tail, its length is correlated with mRNA stability [ 18 ].…”

“…Usually these are used as a single strand RNA of approximately 100 nt. When extended half-life is desired, 2′-O-methylation and 5′/3′-phosphorothioation are performed [ 18 , 21 , 22 ] ( Figure 2 C). These modifications decrease susceptibility to exonucleases.…”