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Next-generation mRNA vaccines: strategies to overcome stability challenges
Abdullah Algaissi1,2, Sivakumar S Moni3,4
1Department of Medical Laboratories Technology, College of Nursing and Health Sciences, Jazan University, Jazan, Saudi Arabia. aalgaissi@jazanu.edu.sa.
NPJ Vaccines
|June 25, 2026
Summary
Messenger RNA (mRNA) vaccines face storage challenges due to molecular instability. Innovations in RNA engineering and delivery systems are crucial for developing thermostable vaccines for global deployment.
Area of Science:
- Vaccinology
- Nanotechnology
- Biochemistry
Background:
- Messenger RNA (mRNA) vaccines offer rapid development and manufacturing capabilities.
- Current mRNA vaccine deployment is limited by extreme cold-chain storage requirements due to molecular and nanoparticle instability.
Purpose of the Study:
- To provide a mechanistic analysis of the factors contributing to mRNA vaccine instability.
- To critically evaluate strategies for enhancing mRNA vaccine stability for improved global distribution.
Main Methods:
- Mechanistic analysis of RNA degradation pathways (hydrolysis, oxidation).
- Evaluation of lipid nanoparticle (LNP) vulnerabilities (lipid peroxidation, PEG-lipid desorption, aggregation).
- Review of diverse engineering strategies for stability enhancement.
Main Results:
- Identified key molecular liabilities including RNA backbone lability and oxidative damage.
- Highlighted LNP structural vulnerabilities and freeze-thaw induced aggregation as critical issues.
- Assessed various stabilization techniques: optimized LNPs, lyophilization, antioxidants, hybrid nanocarriers, saRNA, and circRNA.
Conclusions:
- Overcoming ultra-cold dependence requires integrated innovation in RNA engineering, delivery systems, and manufacturing.
- Enhanced formulation robustness is essential for resilient, globally deployable mRNA vaccine technologies.
- Stability modeling and CMC considerations are vital for real-world vaccine distribution.
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