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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
Summary
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.
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.
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