Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization
Open accessAbstract
The broadest clinical application of siRNA therapeutics will be facilitated by drug-loaded delivery systems that maintain stability and potency for long times under ambient conditions. In the present study, we seek to better understand the stability and effect of storage conditions on lipidoid nanoparticles (LNPs), which have been previously shown by our group and others to potently deliver RNA to various cell and organ targets both in vitro and in vivo. Specifically, this study evaluates the influence of pH, temperature, and lyophilization on LNP efficacy in HeLa cells. When stored under aqueous conditions, we found that refrigeration (2°C) kept LNPs the most stable over 150 days compared to storage in the -20°C freezer or at room temperature. Because the pH of the storage buffer was not found to influence stability, it is suggested that the LNPs be stored under physiologically appropriate conditions (pH 7) for ease of use. Although aggregation and loss of efficacy were observed when LNPs were subjected to freeze-thaw cycles, their stability was retained with the use of the cryoprotectants, trehalose, and sucrose. Initially, lyophilization of the LNPs followed by reconstitution in aqueous buffer also led to reductions in efficacy, most likely due to aggregation upon reconstitution. Although the addition of ethanol to the reconstitution buffer restored efficacy, this approach is not ideal, as LNP solutions would require dialysis prior to use. Fortunately, we found that the addition of trehalose or sucrose to LNP solutions prior to lyophilization facilitated room temperature storage and reconstitution in aqueous buffer without diminishing delivery potency.
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Particle size and siRNA encapsulation for the lipidoid 306O13 siRNA-LNP formulation did not significantly change.
“Particle size and siRNA encapsulation for this formulation did not significantly change.”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Ball et al., 2016
Aggregation of LNPs during storage and fusion of LNPs has been reported.
“Aggregation of LNPs during storage and fusion of LNPs has been reported (Ayat et al., 2019, Ball et al., 2016).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Ball et al., 2016
siRNA-LNPs composed of the lipidoid 306O13 instead of DLin-MC3-DMA remained stable in aqueous conditions at 2 °C for 156 days at pH 7.
“A study on siRNA-LNPs composed of the lipidoid 306O13 instead of DLin-MC3-DMA, showed that in aqueous conditions the formulation remained stable at 2 °C for 156 days at pH 7 (Ball et al., 2016).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Ball et al., 2016
Ball et al. successfully reconstituted freeze dried LNPs with siRNA/ethanol solutions.
“Ball et al. successfully followed the opposite approach by reconstituting freeze dried LNPs with siRNA/ethanol solutions (Ball et al., 2016).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Ball et al., 2016
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- Authors
- Ball, R., Bajaj, P., & Whitehead, K.
- Affiliations
- Carnegie Mellon University (US)
- Corresponding author
- Whitehead, Kathryn
- ORCID
- Whitehead, Kathryn
- Venue
- International Journal of Nanomedicine
- Publisher
- Informa UK Limited
- Published
- 2016-12
- Volume
- Volume 12
- Pages
- 305-315
- ISSN
- 1176-9114 (ISSN-L)
- 1178-2013
- PMC
- PMC5221800
- OpenAlex
- W2564551688
- Cited by
- 333
- References
- 42
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 64 · 2023: 48 · 2022: 41 · 2021: 28 · 2020: 15 · 2019: 13 · 2018: 9
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Nanomedicine (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Funders
- DSF Charitable Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- lipid nanoparticles, siRNA delivery, long-term storage stability, storage temperature, pH effect, freeze-drying, freeze-thaw cycles, nanoparticle aggregation, cryoprotectants, trehalose, sucrose, HeLa cells, siRNA therapeutics
- MeSH terms
- Cryoprotective Agents, Drug Stability, Freeze Drying, Freezing, HeLa Cells, Humans, Hydrogen-Ion Concentration, Lipids, Sucrose, Temperature, Trehalose, Drug Delivery Systems, RNA, Small Interfering, Nanoparticles
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