Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

Roslyn M. Ray, Anders Højgaard Hansen, Maria Taskova, Bernhard Jandl, Jonas Hansen, Citra Soemardy, Kevin V. Morris, Kira Astakhova*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert and can be produced in a cost effective and scalable manner. However, targeting and delivery of LNPs across the blood–brain barrier (BBB) has proven challenging. In an effort to target LNPs composed of an ionizable cationic lipid (DLin-MC3-DMA), cholesterol, the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000) to particular cell types, as well as to generate LNPs that can cross the BBB, we developed and assessed two approaches. The first was centered on the BBB-penetrating trans-activator of transcription (Tat) peptide or the peptide T7, and the other on RNA aptamers targeted to glycoprotein gp160 from human immunodeficiency virus (HIV) or C-C chemokine receptor type 5 (CCR5), a HIV-1 coreceptor. We report herein a CCR5-selective RNA aptamer that acts to facilitate entry through a simplified BBB model and that drives the uptake of LNPs into CCR5-expressing cells, while the gp160 aptamer did not. We further observed that the addition of cell-penetrating peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB.

Original languageEnglish
JournalBeilstein Journal of Organic Chemistry
Pages (from-to)891-907
Publication statusPublished - 2021

Bibliographical note

Funding Information:
This project was supported by NIMH R01 113407-01 to K. V. M. and by Villum YIP grant 40851 to K. A. The Analytical Pharmacology is supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572.

Publisher Copyright:
© 2021 Ray et al.; licensee Beilstein-Institut. License and terms: see end of document.


  • Aptamer
  • Blood–brain barrier
  • Gene therapy
  • HIV-1
  • Lipid nanoparticle


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