The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index.
Targeted Delivery of RNAi Therapeutics With Endogenous and Exogenous Ligand-Based Mechanisms
Open accessAbstract
Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) to hepatocytes in vivo; however, the precise mechanism by which this efficient delivery occurs has yet to be elucidated. We found that apolipoprotein E (apoE), which plays a major role in the clearance and hepatocellular uptake of physiological lipoproteins, also acts as an endogenous targeting ligand for ionizable LNPs (iLNPs), but not cationic LNPs (cLNPs). The role of apoE was investigated using both in vitro studies employing recombinant apoE and in vivo studies in wild-type and apoE(-/-) mice. Receptor dependence was explored in vitro and in vivo using low-density lipoprotein receptor (LDLR(-/-))-deficient mice. As an alternative to endogenous apoE-based targeting, we developed a targeting approach using an exogenous ligand containing a multivalent N-acetylgalactosamine (GalNAc)-cluster, which binds with high affinity to the asialoglycoprotein receptor (ASGPR) expressed on hepatocytes. Both apoE-based endogenous and GalNAc-based exogenous targeting appear to be highly effective strategies for the delivery of iLNPs to liver.
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“At blood pH, LNPs exhibit a net neutral surface charge but become positively charged in acidified endosomes following ApoE-mediated endocytosis by hepatocytes in vivo, resulting in endosome disruption and release of mRNA into the cytoplasm.28,41,45”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [45]
In the citing paper
“Previous work has shown that LNP systems with this lipid composition can silence target genes in hepatocytes following IV injection at dose levels as low as 0.01 mg siRNA/kg body weight8,9 in an apolipoprotein E (ApoE)–dependent fashion.10”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [10]
In the citing paper
“Detailed studies have shown that the ability of LNP-siRNA systems containing related ionizable cationic lipids to induce hepatocyte gene knockdown in vivo is ApoE dependent.10”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [10]
In the citing paper
“In ApoE knockout mice, LNP-siRNA gene silencing activity is inhibited in hepatocytes and can be reestablished by incubating the LNPs with ApoE before IV administration.”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [10]
In the citing paper
“Upon intravenous administration, Akinc et al. found that the surface of neutrally-charged LNPs is strongly enriched with apolipoprotein E (ApoE), which leads to enhanced uptake by hepatocytes through low density lipoprotein (LDL) receptor-mediated endocytosis [40]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [40]
In the citing paper
“As example, Akinc et al. found that the selective adsorption of apolipoprotein E onto an ionizable (neutral) LNP was responsible for the specific and potent delivery of (si)RNA to hepatocytes through receptor mediated endocytosis [156].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [156]
In the citing paper
“one potential mechanism of hepatocyte targeting effect by LNPs involves the interaction of ionizable LNPs with apolipoprotein E (apoE), a protein that facilitates the transport of molecules such as lipids and cholesterol.[59, 60] Binding on the surface of LNPs, apoE mediated the hepatocellular uptake of LNPs through multiple receptors, such as the low-density lipoprotein receptor (LDLR).[59, 60]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [60]
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Metadata
- Authors
- Akinc, A., Querbes, W., De, S., Qin, J., Frank-Kamenetsky, M., Jayaprakash, K. N., Jayaraman, M., Rajeev, K. G., Cantley, W. L., Dorkin, J. R., Butler, J. S., Qin, L., Racie, T., Sprague, A., Fava, E., Zeigerer, A., Hope, M. J., Zerial, M., Sah, D. W., Fitzgerald, K., Tracy, M. A., Manoharan, M., Koteliansky, V., Fougerolles, A. D., & Maier, M. A.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Corresponding author
- Akinc, Akin
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 18
- Issue
- 7
- Pages
- 1357-1364
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC2911264
- OpenAlex
- W2143743183
- Cited by
- 1,261
- References
- 32
- Citations by year
- 2026: 147 · 2025: 141 · 2024: 164 · 2023: 129 · 2022: 120 · 2021: 83 · 2020: 72 · 2019: 63 · 2018: 39 · 2017: 41 · 2016: 47 · 2015: 46 · 2014: 51 · 2013: 46 · 2012: 44
- FWCI
- 15.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Alnylam Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- RNAi therapeutics, lipid nanoparticles, apolipoprotein E, N-acetylgalactosamine, asialoglycoprotein receptor, hepatocyte targeting, LDL receptor, nanoparticle clearance
- MeSH terms
- Animals, Apolipoproteins E, Female, HeLa Cells, Humans, Ligands, Mice, Inbred C57BL, Receptors, LDL, Hepatocytes, RNA Interference, Asialoglycoprotein Receptor, Mice, Nanoparticles
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