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Engineering the poly(A) tail for therapeutic mRNA: from expression control to manufacturing robustness.
Yang-Yang Zhang1,2, Jian-Ping Zhang1,2, Xiao-Bing Zhang1,2
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Frontiers in Bioengineering and Biotechnology
|May 29, 2026
Summary
Messenger RNA (mRNA) therapeutics face a Production-Expression paradox. Optimizing the poly(A) tail for expression can hinder manufacturing and immune safety, requiring new engineering strategies.
Area of Science:
- Biotechnology
- Molecular Biology
- Immunology
Background:
- Messenger RNA (mRNA) therapeutics offer great promise but face challenges in design.
- The 3' poly(A) tail is critical for mRNA function but presents a design trade-off.
- Conventional poly(A) tails can negatively impact manufacturing and immune response.
Purpose of the Study:
- To review the functions of the poly(A) tail in mRNA therapeutics.
- To discuss engineering strategies for optimizing poly(A) tail architecture.
- To propose a Quality-by-Design framework for poly(A) tail optimization.
Main Methods:
- Review of literature on poly(A) tail function and engineering.
- Analysis of the Production-Expression paradox in mRNA design.
- Discussion of analytical methods for poly(A) tail characterization.
Main Results:
- The poly(A) tail influences translation, mRNA decay, manufacturing, and immunogenicity.
- Novel engineering strategies beyond homopolymers are emerging.
- A Quality-by-Design framework can link critical quality attributes to analytical methods.
Conclusions:
- Reframing the poly(A) tail as an engineerable parameter is crucial.
- Optimized poly(A) architecture can improve product consistency and reduce immunogenicity.
- This approach supports the clinical translation of mRNA medicines.
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