During the COVID-19 pandemic, mRNA vaccines such as Moderna and Pfizer-BNT have demonstrated tremendous potential in vaccine development. However, the natural instability and susceptibility to degradation of linear RNA remain significant challenges in mRNA applications. Dr. Chia-Yi Yu and his team at the National Institute of Infectious Diseases and Vaccinology, supported by the NSTC Outstanding Young Scholar Grant and the National Health Research Institutes intramural funding, have developed a novel circular RNA (circRNA) synthesis method. This groundbreaking approach utilizes a cis-acting ligase ribozyme (RzL) to circularize linear RNA, significantly improving the purity and efficiency of circRNA synthesis. This innovation not only enhances vaccine safety and efficacy but also paves the way for new opportunities in gene therapy, cancer treatment, and beyond. The research findings were published in the prestigious journal Nature Communications in August 2024.
Conventional circRNA synthesis methods often suffer from low efficiency, poor product purity, and residual small RNA byproducts. Dr. Yu's team has addressed these challenges by integrating a cis-acting RzL into the RNA transcription process. This enables the linear RNA to autonomously undergo circularization by connecting its 5' and 3' ends, ensuring a highly efficient and straightforward synthesis process. The method also minimizes byproduct formation and improves the precision of circRNA preparation, yielding highly pure circRNA and significantly increasing synthesis efficiency. This technological breakthrough holds great promise for enhancing the safety and efficacy of RNA vaccines and advancing the clinical potential of circRNA applications.
In addition, the research team discovered that circRNA containing an internal ribosome entry site (IRES) can drive the translation of broad-spectrum antiviral proteins, demonstrating antiviral potential in a cell culture model. Furthermore, circRNA encoding Cas13, an RNA-cleaving enzyme, can be guided to target and degrade specific viral RNA sequences, providing a novel approach for developing specific antiviral therapies.
CircRNA not only overcomes the instability of linear RNA but also retains the advantages of sequence modifiability and versatility. Dr. Yu's newly developed synthesis method significantly enhances circRNA purity and production efficiency, breaking through existing RNA application limitations. This advancement positions circRNA as a next-generation biomedical tool with significant implications for vaccine development, gene therapy, cancer treatment, and antiviral strategies.
