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Enhanced-mRNA Delivery Using Ultrasound-Delivered Anchors for Bioorthogonal Ligation.

Emilio Di Ianni1, Jueun Jeon2, Sedra Mohammadi2

  • 1Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

Angewandte Chemie (International Ed. in English)
|January 22, 2026
PubMed
Summary
This summary is machine-generated.

This study introduces a novel ultrasound-guided pre-targeting strategy to enhance messenger RNA (mRNA) delivery to extrahepatic tissues using lipid nanoparticles (LNPs). This method significantly improves targeted delivery and gene expression in vivo.

Keywords:
Bioorthogonal pre‐targetingFocused ultrasound (FUS)Nucleic acid deliveryTargeted drug delivery

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Area of Science:

  • Biomedical Engineering
  • Molecular Biology
  • Drug Delivery Systems

Background:

  • Targeting extrahepatic tissues for nucleic acid therapy remains a significant challenge.
  • Current methods lack flexibility and precise image-guided control.
  • Developing advanced delivery systems is crucial for therapeutic applications.

Purpose of the Study:

  • To develop a bioorthogonal pre-targeting strategy using focused ultrasound (FUS) for enhanced mRNA-LNP delivery.
  • To improve the targeting efficiency and gene expression in extrahepatic tissues.
  • To present a modular and ultrasound-enabled approach for nucleic acid delivery.

Main Methods:

  • Synthesized amphiphilic click reactive anchors (ACRAs) with trans-cyclooctene (TCO) or methyltetrazine (mTz).
  • Utilized nanobubbles encapsulating ultrasound-responsive gas for ACRA-TCO delivery via FUS.
  • Employed mRNA-loaded lipid nanoparticles (mRNA-LNP) functionalized with companion ACRA-mTz for subsequent delivery.

Main Results:

  • Ultrasound pre-targeting enhanced mTz-functionalized nanoparticle accumulation by 75% in cell cultures and up to 3.6-fold in mice.
  • Achieved increased gene expression using mRNA-LNP in vivo.
  • Microbubbles with ACRA doubled mRNA delivery to the heart, outperforming ultrasound alone.

Conclusions:

  • The developed strategy offers a modular and ultrasound-enabled approach for targeted nucleic acid delivery.
  • This method shows significant potential for enhancing therapeutic mRNA-LNP delivery to specific tissues.
  • The bioorthogonal pre-targeting strategy provides a flexible and image-guided solution for extrahepatic tissue targeting.