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Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery
Open accessAbstract
Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. Here, we use a multiparametric approach for the evaluation of lipid nanoparticles (LNPs) to identify relationships between structure, biological function, and biological activity. Our results indicate that evaluation of multiple parameters associated with barriers to delivery such as siRNA entrapment, pK a , LNP stability, and cell uptake as a collective may serve as a useful prescreening tool for the advancement of LNPs in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro–in vivo translation by minimizing false negatives. For the LNPs used in this work, the evaluation of multiple parameters enabled the identification of LNP pK a as one of the key determinants of LNP function and activity both in vitro and in vivo. It is anticipated that this type of analysis can aid in the identification of meaningful structure–function–activity relationships, improve the in vitro screening process of nanoparticles before in vivo use, and facilitate the future design of potent nanocarriers.
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“Endosomal escape can be increased by optimizing the pKa values of ionizable lipids66,76–78,88,100,140.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [140]
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“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [140]
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Chittari, S. S., & Gormley, A. J. (2026) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6c00447
Metadata
- Authors
- Alabi, C. A., Love, K. T., Sahay, G., Yin, H., Luly, K. M., Langer, R., & Anderson, D. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of Rochester (US)
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;
- Harvard–MIT Division of Health Sciences and Technology (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-07-23
- Volume
- 110
- Issue
- 32
- Pages
- 12881-12886
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3740846
- OpenAlex
- W2155534998
- Cited by
- 188
- References
- 39
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 26 · 2023: 9 · 2022: 13 · 2021: 18 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 17 · 2015: 16 · 2014: 15 · 2013: 3
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (4r37eb000244-34)
- National Cancer Institute (P30CA014051)
- National Institute of Biomedical Imaging and Bioengineering (R37-EB000244)
- 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, cellular uptake, in vitro to in vivo translation, nanocarrier design
- MeSH terms
- Animals, Factor VII, Flow Cytometry, HeLa Cells, Hemolysis, Humans, Lipids, Luciferases, Mice, Inbred C57BL, Reproducibility of Results, Gene Transfer Techniques, Microscopy, Confocal, Fluorescence Resonance Energy Transfer, RNA Interference, RNA, Small Interfering, Mice, Nanoparticles
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