An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo
Open accessAbstract
Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications.
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Increasing the ionizable lipid molar ratio in an LNP formulation can augment mRNA delivery.
“In our prior studies, we found that the increase in ionizable lipid molar ratio in the LNP formulation can augment mRNA delivery44.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [44]
In the formulation-optimization passage (labeled Abstract; page unavailable), the paper says that reduced levels of the lipid-like component TT3 may facilitate mRNA delivery and describes decreasing its ratio from 40 to 10. It does not report increased delivery from increasing the TT3 ratio; its reported trend runs in the opposite direction. (LLM, conf=0.84)
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Experimental — accuracy not yet measuredmRNA-based protein replacement therapies have been applied to haematological diseases, central nervous system disorders, skin diseases and hearing loss in preclinical studies.
“In addition, mRNA-based protein replacement therapies have been applied to haematological diseases (for example, haemophilia A232, haemophilia B91,104,233 and thrombotic thrombocytopaenic purpura234), central nervous system disorders67,152 (for example, Friedreich’s ataxia67), skin diseases235,236 (for example, elastin deficiency235) and hearing loss237 in preclinical”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [104]
After 6 hours of i.v. injection of TT3-delivered hFIX mRNA, plasma FIX concentration was 1740 ng/mL and activity was 791 mIU/mL, within normal physiological values.
“After 6 hours of i.v. injection, the plasma concentration of FIX was 1740 ng/mL and the activity was 791 mIU/mL, which were well within the normal physiological values.[40]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [40]
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- Authors
- Li, B., Luo, X., Deng, B., Wang, J., McComb, D. W., Shi, Y., Gaensler, K. M. L., Tan, X., Dunn, A. L., Kerlin, B. A., & Dong, Y.
- Affiliations
- The Ohio State University (US)
- University of California, San Francisco (US)
- Center for Life Sciences (CN)
- Nationwide Children's Hospital (US)
- Corresponding author
- Dong, Yizhou
- ORCID
- Venue
- Nano Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-11-06
- Volume
- 15
- Issue
- 12
- Pages
- 8099-8107
- ISSN
- 1530-6984 (ISSN-L)
- 1530-6992
- PMC
- PMC4869688
- OpenAlex
- W2405541722
- Cited by
- 261
- References
- 39
- Citations by year
- 2026: 19 · 2025: 35 · 2024: 31 · 2023: 31 · 2022: 36 · 2021: 32 · 2020: 32 · 2019: 12 · 2018: 17 · 2017: 9 · 2016: 7
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nano Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bayer HealthCare (GRT00039254)
- 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
- mRNA delivery, orthogonal experimental design, factor IX, hemophilia B, in vivo gene therapy, luciferase expression, knockout mice
- MeSH terms
- Humans, Lipids, RNA, Messenger, Nanoparticles
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