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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
New-Concept Chemotherapy by Nanoparticles of Biodegradable Polymers: Where Are We Now?
Feng, S.-S. (2006) · Nanomedicine · doi:10.2217/17435889.1.3.297 · Cited by 1,951
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822
Allen, T. M., Hansen, C., Martin, F., Redemann, C. T., & Yau‐Young, A. O. (1991) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(91)90246-5 · Cited by 1,392
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357
A combinatorial library of lipid-like materials for delivery of RNAi therapeutics
Akinc, A., Zumbuehl, A., Goldberg, M., Leshchiner, E. S., Busini, V., Hossain, N., Bacallado, S. A., Nguyen, D. N., Fuller, J., Alvarez, R., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1402 · Cited by 1,150
Lipid-like materials for low-dose, in vivo gene silencing
Love, K. T., Mahon, K. P., Levins, C. G., Whitehead, K. A., Querbes, W., Dorkin, J. R., Qin, J., Cantley, W., Qin, L. L., Racie, T., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910603106 · Cited by 969
Mahley, R. W., & Ji, Z.-S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33334-4 · Cited by 693
The LDL–receptor–related protein, LRP, is an apolipoprotein E-binding protein
Beisiegel†, U., Weber, W. T., Ihrke, G., Herz, J., & Stanley, K. K. (1989) · Nature · doi:10.1038/341162a0 · Cited by 680
Frank-Kamenetsky, M. D., Grefhorst, A., Anderson, N. N., Racie, T., Bramlage, B., Akinc, A., Butler, D., Charissé, K., Dorkin, J. R., Fan, Y., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805434105 · Cited by 645
Research works printed but not linked: 1
- Immordino, 2006, Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential, Int J Nanomedicine, 1, 297
Cited by
Sorted by citations
Liposomal drug delivery systems: From concept to clinical applications
Allen, T. M., & Cullis, P. R. (2013) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.09.037 · Cited by 4,839
mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667
Non-viral vectors for gene-based therapy
Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3763 · Cited by 3,123
Self-citationCheng, Q., Wei, T., Farbiak, L., Johnson, L. T., Dilliard, S. A., & Siegwart, D. J. (2020) · Nature Nanotechnology · doi:10.1038/s41565-020-0669-6 · Cited by 2,383
Advances in oligonucleotide drug delivery
Roberts, T. C., Langer, R., & Wood, M. J. A. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0075-7 · Cited by 2,121
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
