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Using Lipid Nanoparticles for the Delivery of Chemically Modified mRNA into Mammalian Cells
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Cell-specific mRNA delivery via nanobody-functionalized lipid nanoparticles.

Linglong Chen1, Hans Van Der Weken1, Olivier Zwaenepoel2

  • 1Laboratory of Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|October 29, 2025
PubMed
Summary

Researchers developed targeted messenger RNA–lipid nanoparticle (mRNA-LNP) delivery systems. These novel systems enhance mRNA delivery to specific cells, improving therapeutic efficacy and safety for mRNA-based treatments.

Keywords:
Aminopeptidase NApical-out intestinal organoidsCell-specific deliveryNanobodiesmRNA-lipid nanoparticles

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Area of Science:

  • Biotechnology
  • Nanomedicine
  • Molecular Biology

Background:

  • Messenger RNA–lipid nanoparticle (mRNA-LNP) formulations are a powerful platform for various therapies.
  • A key limitation is the absence of targeted delivery, hindering efficacy and safety.
  • Cell-specific delivery is crucial for advancing mRNA therapeutic applications.

Purpose of the Study:

  • To engineer a novel mRNA-LNP platform with targeted delivery capabilities.
  • To functionalize lipid nanoparticles with nanobodies targeting aminopeptidase N (APN) on gut epithelial cells.
  • To demonstrate enhanced cellular uptake and delivery of mRNA payloads via targeted functionalization.

Main Methods:

  • Lipid nanoparticles were functionalized with nanobodies (VHH) specific to aminopeptidase N (APN).
  • Nanobodies were engineered in E. coli to incorporate azido-phenylalanine for click chemistry conjugation.
  • Targeted conjugation onto lipid nanoparticles was achieved using SPAAC and IEDDA click chemistry.
  • The efficacy of targeted delivery was assessed in porcine intestinal organoids and in vivo models.

Main Results:

  • APN-targeted mRNA-LNPs demonstrated selective uptake by APN-expressing cells.
  • Functionalized LNPs enhanced mRNA delivery to target cells.
  • Nanobody-mediated targeting promoted transcytosis across the gut epithelial barrier.
  • The platform showed successful delivery in both in vitro and in vivo models.

Conclusions:

  • The developed nanobody-functionalized mRNA-LNP platform enables targeted delivery of mRNA payloads.
  • This programmable system enhances cellular uptake and delivery across the gut barrier.
  • The approach offers a versatile solution for cell-specific mRNA delivery, adaptable across species.
  • This technology holds significant potential for advancing mRNA-based vaccines and therapeutics.