BioTech IP Review

Published in Nature Biotechnology (February 19, 2025) — this study introduces a novel internal cap-initiated mechanism that significantly enhances the efficiency of protein production from circular mRNA therapeutics.

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What it covers

Traditionally, circular mRNAs — promising as next-generation RNA medicines because they are more stable and immunologically quiet than linear mRNAs — suffer from inefficient translation inside cells because they lack the typical 5′ cap that recruits the ribosome.

This paper introduces two molecular designs that solve this problem:

1. Covalent internal cap (cap-circ mRNA):
   The authors attached an N⁷-methylguanosine (m⁷G) cap directly within the circular RNA backbone. This allows the cellular translational machinery to recognize and initiate protein synthesis more effectively than previous IRES-dependent approaches.
2. Non-covalent cap recruitment via hybridization:
   A complementary oligonucleotide carrying an m⁷G cap binds to the circular mRNA and enhances translation — in some cases more than 50-fold compared with uncapped circular mRNA.

Both designs also incorporate a modified nucleotide (N¹-methylpseudouridine) that reduces innate immune activation while maintaining high translation efficiency, important for therapeutic safety.

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Why it is important

• Enhanced protein expression: The internal cap mechanism dramatically improves the translation efficiency of circular mRNAs — a persistent challenge for RNA-based therapeutics.
• Broader therapeutic potential: With better translation, circular mRNA could be used not only for vaccines but for long-acting protein replacement therapies, cancer treatments, and gene regulation applications.
• Lower immunogenicity: Modified nucleotides reduce immune responses compared with conventional linear mRNA designs, improving tolerability.
• Sustained protein production: In vivo experiments showed that circular mRNAs with internal caps can yield durable protein expression, improving therapeutic effectiveness.

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Summary

This work tackles a foundational obstacle in RNA therapeutics: coupling the stability advantages of circular mRNA with efficient translation. By doing so, it opens the door to a new class of RNA-based treatments that could outperform current linear mRNA drugs in efficacy, duration, and safety — making it one of the most influential biotechnology advances in Nature Biotechnology.