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Published on: January 30, 2019
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Beyond the Sequence: Chemical and Topological Design and Innovations in mRNA Therapeutics
Dangliang Liu1,2, Hongyu Chen1,2, Alisia Pan1,2,3
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, United States.
Chemical Reviews
|March 24, 2026
Summary
Messenger RNA (mRNA) engineering advances, including chemical modifications and topological designs like circular RNAs, enhance therapeutic potential for diseases. These innovations improve mRNA stability, translation, and reduce immune responses.
Area of Science:
- Biochemistry and Molecular Biology
- Synthetic Biology
- RNA Therapeutics
Background:
- Messenger RNA (mRNA) is a rapidly developing therapeutic platform with applications in infectious diseases, oncology, and genetic disorders.
- Current mRNA therapeutics leverage chemical programmability for functional modulation, targeting modifications across the mRNA molecule, including cap structure, untranslated regions (UTRs), coding sequence (CDS), and poly(A) tail.
- Recent innovations extend beyond sequence modification to topological engineering, introducing new control dimensions for RNA molecules.
Purpose of the Study:
- To review recent advances in the chemical and topological engineering of mRNA.
- To highlight key areas including novel modification methodologies, synthesis strategies for diverse mRNA topologies, structure-activity relationships, and implications for next-generation therapeutics.
Main Methods:
- Survey of enzymatic, chemical, and hybrid methodologies for mRNA modification.
- Analysis of synthesis strategies for linear, circular, and branched mRNA topologies.
- Examination of structure-activity relationships influencing translation efficiency, decay, and immune activation.
Main Results:
- Expanded repertoire of accessible mRNA modifications through diverse methodologies.
- Development of synthesis strategies for various mRNA topologies (linear, circular, branched).
- Insights into how mRNA structure impacts its therapeutic properties, including stability, translation, and immunogenicity.
Conclusions:
- Chemical and topological engineering are crucial for unlocking the full therapeutic potential of mRNA.
- Integration of chemical synthesis, synthetic biology, and RNA structural design drives innovation in mRNA therapeutics.
- Engineered mRNA molecules offer promising avenues for next-generation treatments across various diseases.
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