Clinical development of therapeutic mRNA applications.

mRNA therapeutics are emerging as a transformative approach in modern medicine, providing innovative, highly adaptable solutions for a wide range of diseases, from viral infections to cancer. Since the approval of the first mRNA therapeutic-the coronavirus disease 2019 vaccines in 2021-we have identified more than 70 current clinical trials utilizing mRNA for various diseases. We propose classifying mRNA therapeutics into four main categories: vaccines, protein replacement therapies, antibodies, and mRNA-based cell and gene therapies. Each category can be further divided into subcategories. Vaccines include those targeting viral antigens, bacterial or parasitic antigens, general and individualized cancer antigens, and self-antigens. Protein replacement therapies include maintenance therapeutics designed to treat genetic disorders and interventional therapeutics, where delivering therapeutic proteins could improve patient outcomes, such as vascular endothelial growth factor A for ischemic heart disease or proinflammatory cytokines in cancer. Therapeutic antibodies are based on mRNA sequences encoding the heavy and light chains of clinically relevant antibodies, enabling patient cells to produce them directly, bypassing the costly and complex process of manufacturing protein-ready antibodies. Another category of mRNA-based therapeutics encompasses cell and gene therapies, including CRISPR with mRNA-mediated delivery of Cas9 and the in vivo generation of cells expressing CAR through mRNA. We discuss examples of mRNA therapeutics currently in clinical trials within each category, providing a comprehensive overview of the field's progress and highlighting key advancements as of the end of 2024.