Researchers from The University of Texas at Austin, in collaboration with Eli Lilly and Company, have discovered that optimizing storage buffers—the chemical solutions used to stabilize mRNA-lipid nanoparticles (LNPs)—can significantly increase the potency and stability of mRNA therapies after they are frozen and shipped globally.
The stability of mRNA-LNP therapeutics is a primary hurdle in global medicine. If the internal structure of the nanoparticle shifts during the freeze-thaw cycle, the mRNA "cargo" can leak or the particles can aggregate, rendering the treatment ineffective by the time it reaches the patient.
This research, published in ACS Nano, identifies a specific mechanism of action—the way a chemical interacts with a biological system—where the choice of buffer directly shapes the nanoparticle’s nanostructure. By refining these buffers, scientists can ensure that a higher percentage of the mRNA actually enters the target cells and produces the necessary proteins, potentially allowing for lower doses and fewer side effects.
In Plain English: The Clinical Takeaway
- Better Stability: New research shows that using the right storage liquid (buffer) prevents mRNA medicines from breaking down during freezing and shipping.
- Lower Doses, Fewer Side Effects: Increasing the efficiency of mRNA delivery means patients may need smaller doses to get the same result, which could reduce the “rough” feeling often felt after vaccination.
- Global Access: These improvements make it easier to distribute life-saving gene therapies and vaccines to remote areas without losing potency.
How Storage Buffers Dictate mRNA Delivery Efficiency
Lipid nanoparticles (LNPs) act as microscopic delivery vehicles. Their job is to protect fragile mRNA from enzymes in the body and ferry it across the cell membrane. However, these vehicles are susceptible to environmental stress. When a vaccine is frozen, the physical arrangement of the lipids can shift, leading to a loss of uniformity.
The research team tested three specific storage buffers: Tris, histidine, and citrate. They found that the chemical environment provided by these buffers determines whether the LNP remains a cohesive unit or collapses during temperature fluctuations. This structural integrity is what governs transfection efficiency—the success rate at which the mRNA is delivered into the cell and translated into protein.
In contrast, Tris buffer preserved the desired internal structure and potency even after the freeze-thaw process, ensuring the mRNA remained encapsulated and ready for delivery.
Reducing the “Dose-to-Effect” Ratio to Minimize Side Effects
A critical revelation in this study is the current inefficiency of mRNA delivery. According to Alex Marras, an assistant professor at the Cockrell School of Engineering, roughly 5-10% of mRNA is properly delivered to the target. This means the vast majority of the administered dose does not reach its destination but still interacts with the body’s immune system.
When delivery is inefficient, the standard pharmaceutical response is to increase the dose. However, higher concentrations of LNPs can trigger stronger inflammatory responses, which explains why patients often experience systemic side effects—such as fever or fatigue—after an RNA vaccine. By optimizing the storage buffer to increase the percentage of successful delivery, manufacturers can achieve the same therapeutic outcome with a lower total dose, thereby reducing the physiological burden on the patient.
Comparative Impact of Storage Buffers on LNP Stability
| Buffer Type | Refrigeration Performance | Freeze-Thaw Stability | Clinical Outcome |
|---|---|---|---|
| Citrate | High Efficiency | Poor | Ineffective for long-term frozen storage. |
| Histidine | Moderate | Variable | Intermediate stability. |
| Tris | High Efficiency | High | Preserves internal structure and potency. |
Bridging Academic Research and Pharmaceutical Scale
This study was made possible through a multi-year collaboration between UT Austin and Eli Lilly and Company. This partnership provided the academic team with access to pharmaceutically relevant samples and the ability to scale up nanoparticle synthesis beyond what is typically possible in a university lab. The researchers tested their findings across four different human cell lines to ensure the results were consistent across various biological environments.
By providing a mechanistic understanding of how buffers influence RNA-lipid interactions, this research helps manufacturers design more stable therapeutics that are less likely to fail during the "last mile" of delivery to the patient.
The research was funded and supported through the collaboration between the University of Texas at Austin and Eli Lilly and Company, ensuring that the academic insights into nanostructure could be directly applied to industrial pharmaceutical design.
Contraindications & When to Consult a Doctor
The Future of Stabilized Genetic Medicine
The ability to maintain the structural integrity of mRNA-LNPs through optimized buffers marks a shift toward more personalized and accessible medicine. As we move beyond COVID-19 vaccines toward gene-editing therapies and targeted cancer treatments, the “cold chain”—the temperature-controlled supply chain—remains a vulnerability. Solving the stability puzzle at the molecular level reduces the risk of treatment failure and opens the door to more potent, lower-dose medicines that are easier on the human body.
References
- Mohammadi-Zerankeshi, M., et al. (2026). Storage Buffer Composition Impacts Internal Structure, Freeze–Thaw Stability, and Transfection Efficiency of mRNA-Lipid Nanoparticles. ACS Nano. DOI: 10.1021/acsnano.5c22170.
- University of Texas at Austin. (2026). Research on mRNA lipid nanoparticles and storage buffers.
