Conceptual and translational pitfalls of modified messenger RNA drug design with public health impact

Abstract Updated safety warnings for base-modified messenger RNA (mmRNA) vaccines—such as increased risks of life-threatening myo(peri)carditis and the increased appearance of colorectal cancer in young adults—prompted our comprehensive review of this approach. Careful analysis of RNA biology textbook materials and the scientific literature identified serious conceptual, procedural, and translational issues that explain the shortcomings and potential public health risks of these injectables. The primary issues include using artificial pseudo-uridinated and methylated nucleosides based on the misleading information that these modified bases occur naturally and in sufficient numbers in eukaryotic mRNAs. In mmRNA vaccines, approximately 50% of the bases are modified with N1-methyl-pseudouridine, whereas eukaryotic mRNA typically contains a much lower percentage of pseudouridine, ranging from 0.2% to 0.6% (Ψ/U ratio), without methylation with intronic (non-coding) properties. This practice, meant to stabilize mRNA and prolong its half-life, disregards the biological safeguard of rapid natural mRNA breakdown. The modifications prevent the activation of key immune mechanisms and can lead to unwanted reverse transcription, frameshifting, and uncontrolled production of pathogenic spike proteins with an unknown pharmacological half-life. Developers also failed to consider that these structural changes could interfere with the proper function of ribonuclease L (RNase L), a critical enzyme of the innate immune system whose primary role is to degrade viral RNA and limit viral protein synthesis and replication. Furthermore, researchers often conflated the structural and functional differences between non-coding tRNA and coding mRNA as well as between pseudouridine and N6-methyladenosine (m6A) modifications—a fundamental research error. Given these substantial unknowns and pitfalls, a second look is warranted before indiscriminately using mmRNA therapeutics in healthy populations of all ages, including pregnant women.