In a recent Nature Communications paper published on November 8, 2023, Dr. Zhen Xie’s team from Tsinghua University introduced the PROMITAR platform, designed to enable programmable translational control in circular mRNA, a significant innovation in RNA-based therapeutics.

RNA-based therapeutics, including antisense oligonucleotides, small interfering RNA, and mRNA vaccines, have emerged as promising tools in biomedicine. Among these, circular RNA (circRNA) stands out for its stability and low immunogenicity compared to linear mRNA. Addressing the challenges of manipulating circRNA, this paper introduces the PROMITAR platform, a programmable miRNA-responsive system for controlling IRES-mediated translation in circRNA. This innovative platform facilitates the construction of logic gates and cell-type classifiers, showcasing its potential for identifying specific mammalian cell types and targeted cancer cell treatments.

The PROMITAR platform utilizes hepatitis C virus (HCV) IRES to advance the development of miRNA-responsive IRES translation activators (MITAs). By strategically inserting sequences into key IRES regions, researchers achieved reversible control over protein synthesis in response to specific miRNAs, a process validated in HEK293 and Huh7 cells. The MITAs, crafted with structures like toehold-like, stem-loop, and 3-arm-junctions, enable precise miRNA-specific translation regulation.

Employed further, the platform demonstrates its utility in creating cellular logic gates and classifiers that respond to specific miRNAs, like miR-FF4 and miR-199a, implementing OR, AND, and NOT functions. Moreover, the platform’s adaptation to circRNAs has led to significant strides in cancer therapy, particularly in identifying and eliminating cancer cells through MITAs responsive to miRNAs like miR-21.

PROMITAR’s flexibility is further underscored by extending its principles to the classical swine fever virus (CSFV) IRES, proving its capability for diverse IRES sequence engineering. This adaptability is critical, especially for IRES sequences with less understood structure-activity relationships, where effective distorting sequences can be screened.

The platform’s capacity for integrating both translation activation and repression mechanisms within a single RNA construct marks a novel breakthrough in RNA translational control. This dual functionality, combined with its potential for sophisticated RNA circuit integration and protein-level regulation, positions PROMITAR as a powerful tool in precision medicine, synthetic biology, and targeted cancer therapy. The prospects of this platform in enhancing gene expression control and advancing biomedical applications highlight its potential to revolutionize future therapeutic strategies.

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Ning, H., Liu, G., Li, L. et al. Rational design of microRNA-responsive switch for programmable translational control in mammalian cells. Nat Commun 14, 7193 (2023).

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