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<p>Circular RNAs (circRNAs) are covalently closed single-stranded RNA molecules generated through canonical or non-canonical backsplicing events and have garnered attention as innovative therapeutic platforms owing to their exceptional stability and low immunogenicity. Here, we highlighted the diverse functions of circRNA, including microRNA sequestration, scaffolding of RNA-binding proteins, and cap-independent protein translation mediated by internal ribosome entry sites (IRESs) or N6-methyladenosine (m6A), all of which contribute to disease modulation and sustained protein expression. Recent advances in circularization strategies have enabled the production of high-purity synthetic circRNAs with precisely controlled translational efficiency and reduced immunogenicity. We highlighted a variety of preclinical studies which demonstrated the robust and durable efficacy of circmRNA vaccines, protein replacement therapies, circular interfering RNAs (ciRNAs) for gene silencing, and circular guide RNAs (cgRNAs) for genome editing and circRNA aptamer-based PKR inhibition. Nonetheless, challenges persist in standardizing large-scale manufacturing processes, preventing off-target effects, and comprehensively evaluating immunological responses and safety profiles. This review proposes a future perspective incorporating automated purification, high-throughput screening, and artificial intelligence-driven design to accelerate the clinical application of circRNA-based therapeutics.</p>

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Biomanufacturing of Synthetic circRNAs for Therapeutic Applications

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Sunghyun Moon,
  • Iksoo Jang,
  • Jong Bum Lee

摘要

Circular RNAs (circRNAs) are covalently closed single-stranded RNA molecules generated through canonical or non-canonical backsplicing events and have garnered attention as innovative therapeutic platforms owing to their exceptional stability and low immunogenicity. Here, we highlighted the diverse functions of circRNA, including microRNA sequestration, scaffolding of RNA-binding proteins, and cap-independent protein translation mediated by internal ribosome entry sites (IRESs) or N6-methyladenosine (m6A), all of which contribute to disease modulation and sustained protein expression. Recent advances in circularization strategies have enabled the production of high-purity synthetic circRNAs with precisely controlled translational efficiency and reduced immunogenicity. We highlighted a variety of preclinical studies which demonstrated the robust and durable efficacy of circmRNA vaccines, protein replacement therapies, circular interfering RNAs (ciRNAs) for gene silencing, and circular guide RNAs (cgRNAs) for genome editing and circRNA aptamer-based PKR inhibition. Nonetheless, challenges persist in standardizing large-scale manufacturing processes, preventing off-target effects, and comprehensively evaluating immunological responses and safety profiles. This review proposes a future perspective incorporating automated purification, high-throughput screening, and artificial intelligence-driven design to accelerate the clinical application of circRNA-based therapeutics.