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A Computationally Optimized Ribonucleic Acid Circularization Strategy without Byproducts.

Ruofan Chen1, Yuan Zhuang1,2, Li Zhang3

  • 1Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.

Journal of the American Chemical Society
|August 28, 2025
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Summary
This summary is machine-generated.

Researchers developed a purification-free method for creating circular messenger RNA (mRNA) with enhanced stability and protein translation. This advance simplifies production and boosts potential for mRNA therapeutics.

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Area of Science:

  • Biotechnology
  • Molecular Biology
  • RNA Therapeutics

Background:

  • Circular mRNA (mRNA) offers advantages in stability and protein translation duration for mRNA therapy.
  • Efficient in vitro production methods for circular RNA are in high demand.

Purpose of the Study:

  • To develop a versatile and efficient self-circularization strategy for synthesizing circular RNAs.
  • To optimize circularization efficiency, especially for long RNA sequences, using computational methods.

Main Methods:

  • A self-circularization strategy using simple motifs to synthesize circular RNAs.
  • An automated computational program to optimize lock-key structures for enhanced circularization.
  • Leveraging shared sequence and functionality to eliminate purification steps.

Main Results:

  • Achieved robust circularization efficiencies for RNA sequences from dozens to thousands of nucleotides.
  • Demonstrated superior stability and translation efficiency of produced circular RNAs.
  • Enabled sustained protein expression in vitro and in vivo.

Conclusions:

  • The developed method offers a computationally optimized, purification-free approach for scalable circular RNA production.
  • This strategy significantly advances the development of novel RNA therapeutics and mRNA therapy.
  • The method simplifies circular RNA synthesis, enhancing its therapeutic potential.