Targeted Delivery of RNAi Therapeutics With Endogenous and Exogenous Ligand-Based Mechanisms.

By Akin Akinc, W. Querbes, Soma De, June Qin, M. Frank-Kamenetsky, K. Jayaprakash, M. Jayaraman, K. G. Rajeev, William L. Cantley, J. R. Dorkin and 15 more. Molecular Therapy, 2010

955 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/041a320b5ab2c61e31eaed607c0bdf49a1eb775d

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In Cancer Research

1. R. Juliano
2. Theresa M. Allen

In Molecular Biology

1. P. Cullis
2. M. Hope
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4. J. Kulkarni
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Citations in the corpus

• Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. (2019, positive): “92 For APEs, it was found that the core structure of the tertiary amino alcohol of the polymers could play an important role in targeting speci fi c organs.”
• Lipid Nanoparticle Systems for Enabling Gene Therapies. (2017, background): “Adapted from Semple et al.16 The LNP is accumulated into target cells by endocytosis following adsorption of ApoE.23 As the pH of the endosome is reduced by inwardly directed proton pumps the ionizable cationic lipid becomes progressively protonated (positively charged).”
• Liposomal drug delivery systems: from concept to clinical applications. (2013, background): “Further, it has been shown that the potency of these systems arises in part due to the association of apolipoprotein E with the LNP siRNA system in vivo, which stimulates uptake into hepatocytes via the scavenging receptor and LDL receptors [210].”
• The role of lipid components in lipid nanoparticles for vaccines and gene therapy (2022, positive): “PEG-lipids with short lipid tails tend to desorb from LNPs [6,51,63], allowing the particles to adsorb apoE [34].”
• First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. (2013, background): “Various nanoparticle formulations have been evaluated for their ability to silence targets in vivo (6-10); among these, lipid nanoparticles (LNPs) have been shown to be highly effective in delivering siRNAs to the liver and silencing a number of different hepatocyte gene targets across multiple spec”