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New Transferrin Receptor-Targeting Conjugate Effectively Delivers DNA to Mouse Brain.

Min-Sun Song1, Adrian H Bustos2, Lise Bastue2

  • 1Department of Molecular and Cellular Biology, City of Hope National Medical Center, City of Hope, 1500 East Duarte Road, Duarte, 91010, USA.

Angewandte Chemie (International Ed. in English)
|April 7, 2025
PubMed
Summary
This summary is machine-generated.

A novel RNA aptamer conjugate effectively delivers DNA oligonucleotides across the blood-brain barrier (BBB), surpassing previous methods. This breakthrough offers a promising new tool for treating brain diseases like glioblastoma and neurodegenerative disorders.

Keywords:
Anti‐miRAptamerBBBNucleic acid deliveryTransferrin receptor

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Area of Science:

  • Biopharmaceutics
  • Neuroscience
  • Molecular Biology

Background:

  • Blood-brain barrier (BBB) presents a significant challenge for drug delivery to the brain.
  • Existing methods for brain drug delivery exhibit limited efficacy.
  • Targeting the transferrin receptor (TfR) is a known strategy for enhancing brain uptake.

Purpose of the Study:

  • To develop and evaluate a novel RNA aptamer-lipid conjugate for enhanced brain delivery.
  • To assess the efficacy and safety of this new conjugate in preclinical models.
  • To explore its potential for treating various brain diseases.

Main Methods:

  • Conjugation of a transferrin receptor-targeting (TfR) RNA aptamer with DSPE lipid.
  • In vivo studies in Balb/cJ mice using fluorescence whole body imaging, PCR, and FISH.
  • Histopathological assessment of mouse organs to evaluate acute toxicity.
  • In vitro testing in human cells.

Main Results:

  • The novel RNA aptamer-lipid conjugate achieved unprecedented effective brain uptake in mice, with brain-to-serum ratios up to 6.5.
  • This delivery efficacy significantly outperformed antibody conjugates and nanovesicles (<1).
  • High concentrations of DNA oligonucleotides were confirmed in mouse brains, with demonstrated efficacy in human cells and no observed acute toxicity.

Conclusions:

  • The developed TfR-targeting RNA aptamer-lipid conjugate is a highly potent and effective tool for brain drug delivery.
  • Its enhanced lipophilicity and TfR targeting contribute to superior brain penetration.
  • This conjugate holds significant therapeutic potential for glioblastoma, neurodegenerative diseases, and brain infections.