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A Rapid High-throughput Method for Mapping Ribonucleoproteins (RNPs) on Human pre-mRNA
Published on: December 2, 2009
Backbone-Ionized Polymers for Quantitatively Guided Extra-Hepatic mRNA Expression via Differential Local Structural
Yiwan Geng1, Dongfang Zheng2, Jun Yang1
1State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing100190, PR China.
Journal of the American Chemical Society
|August 12, 2026
Summary
This study introduces an ionized polymer platform for extra-hepatic mRNA delivery, establishing quantitative structure-activity relationships (QSARs) and a targeting mechanism (DIGIT) for improved organ selectivity and therapeutic outcomes.
Area of Science:
- Biomaterials Science
- Drug Delivery Systems
- Molecular Biology
Background:
- Lack of quantitative structure-activity relationships (QSARs) hinders rational design of extra-hepatic mRNA carriers.
- Microscopic mechanisms of carrier-mRNA interfacial interactions are poorly understood, limiting delivery efficiency.
Purpose of the Study:
- To develop a single-component backbone-ionized polymer platform for extra-hepatic mRNA delivery.
- To establish QSARs for extra-hepatic mRNA expression and elucidate carrier-mRNA interaction mechanisms.
Main Methods:
- Developed ionized poly(β-amino ester) (iPβAE) variants by tuning ionization proportion and side-chain chemistry.
- Utilized in vivo screening to identify QSAR and the differential ionization gradient-induced targeting (DIGIT) mechanism.
- Investigated the rearrangement-mediated affinity control and translation (RE-ACT) mechanism for mRNA release and translation.
Main Results:
- Established DIGIT, a QSAR summarizing side-chain-regulated, ionization-dependent organ-selective mRNA expression.
- Elucidated RE-ACT mechanism, where side chains control mRNA release via 'Electrostatic Pincer' or 'Electrostatic-Hydrogen Tethering' modes.
- Demonstrated efficient delivery of antigen and p53 mRNA to spleen and lung, respectively, using lyophilized iPβAE formulations.
Conclusions:
- The iPβAE platform provides a framework for engineering next-generation mRNA carriers with predictable organ targeting.
- Achieved significant therapeutic benefits, including extended lifespan via vaccine immunotherapy and enhanced chemosensitivity via protein replacement therapy.
- This work establishes a broadly applicable strategy for advancing mRNA-based therapeutics.
