Professor Hirohide Saito and his research group achieved a major breakthrough in the field of mRNA therapeutics. Indeed, they generated a microRNA-responsive ON-OFF hybrid mRNA switch. This innovative tool combines two essential functions: an ON-switch that activates protein production in target cells and an OFF-switch that halts production in non-target cells. This development marks an important milestone in the pursuit of more precise mRNA-based treatments.
The microRNA-responsive ON-OFF hybrid mRNA switch distinguishes itself by its ability to respond to specific microRNAs (miRNAs) present in various cell types. Upon signal, when the ON-switch identifies recruited miRNAs linked to specific target cells, it activates protein synthesis. When the OFF-switch runs into miRNAs from unwanted (non-target) cells, it instantly turns off this information factory. This unique dual functionality increases the precision of gene therapy. This serves to protect healthy tissue around the target while decreasing the risk of unintended effects on surrounding tissues.
Key Findings from Research
The research team put their engineered microbes through a progression of tests on living creatures. In combination with natural miRNAs, they proved the effectiveness of the hybrid mRNA switch for the first time. The team recruited a unique U-rich sequence of six copies of UUUA, followed by a short run of Us. This new sequence was very successful at maintaining the switch in the OFF state, when the target miRNA may not be present. Once the correct miRNA is found, this sequence causes the switch from the OFF state to the ON state. Consequently, protein expression starts.
The results of these experiments were promising. In principle, the hybrid switch could distinguish among multiple cell types according to their specific miRNA signatures. In experiments on human cells, the hybrid system yielded as much as 16-fold higher protein levels in the target cells. This astounding improvement well exceeded the production amounts seen in off-target cells. This kind of precision highlights the promise this type of technology holds for applications in the space of precision medicine.
Implications for mRNA Therapeutics
The creation of this microRNA-responsive ON-OFF hybrid mRNA switch greatly enhances the promise of mRNA-based therapeutics. These therapies are already being used to great effect to treat dozens of diseases. Unlike conventional gene therapies that change the DNA inside cells, mRNA therapeutics enable the creation of proteins without these permanent changes. This important trait greatly reduces the risk of long-lasting, unintended consequences resulting from genomic changes.
With this new hybrid switch, researchers can have precise control protein expression. They are provided the freedom to custom design this control to be tissue and condition dependent. Now you can really start to control when and where proteins get expressed. This cutting-edge technology holds tremendous potential for treating diseases that require localized action. The research findings were published in the journal Molecular Therapy Nucleic Acids, providing a detailed account of the methodologies and outcomes associated with this innovative approach (DOI: 10.1016/j.omtn.2025.102609).
