@article{01K921TP2R9ARD59XJGHTATN2E,
  abstract     = {{mRNA-based therapeutics formulated in lipid nanoparticles (mRNA-LNPs) have emerged as a groundbreaking platform technology for vaccination, immunotherapy, protein replacement therapy, and gene editing. However, a major bottleneck in their application is the lack of cell-specific delivery methods, which limits their efficacy and safety. To overcome this challenge, we developed a novel mRNA-LNP platform with targeted delivery capabilities. To this end, lipid nanoparticles were functionalized with nanobodies (VHH) specific to aminopeptidase N (APN), a cell surface protein on gut epithelial cells. These nanobodies were produced in genetically engineered E. coli, incorporating the non-canonical amino acid azido-phenylalanine into the VHH sequence to enable their precise conjugation onto lipid nanoparticles containing DSPE-PEG2000-TCO via a two-step click chemistry (SPAAC and IEDDA) reaction. Our findings demonstrate that APN-targeted, mRNA-loaded LNPs selectively target APN-expressing cells, enhancing LNP uptake and mRNA delivery to these cells. Furthermore, we show that directing the nanobody-functionalized mRNA-LNPs toward APN promotes their transcytosis across the gut epithelial barrier in porcine apical-out intestinal organoids and in vivo. Together, these findings highlight the potential of this programmable platform for the cell-specific delivery of mRNA-based vaccines and therapeutics. While this study focuses on porcine APN, the approach is adaptable across species, providing a versatile and customizable solution for the precise delivery of mRNA payloads to specific cells.}},
  articleno    = {{114365}},
  author       = {{Chen, Linglong and Van Der Weken, Hans and Zwaenepoel, Olivier and Okkelman, Irina and Aelvoet, Justine and Van Denberghe, Emma and Gettemans, Jan and Dmitriev, Ruslan and De Geest, Bruno and Cox, Eric and Devriendt, Bert}},
  issn         = {{0168-3659}},
  journal      = {{JOURNAL OF CONTROLLED RELEASE}},
  keywords     = {{mRNA-lipid nanoparticles,Cell-specific delivery,Aminopeptidase N,Nanobodies,Apical-out intestinal organoids,FC-RECEPTOR,TRAFFICKING,ANTIBODIES,VACCINES,IMMUNE}},
  language     = {{eng}},
  number       = {{part 2}},
  pages        = {{17}},
  title        = {{Cell-specific mRNA delivery via nanobody-functionalized lipid nanoparticles}},
  url          = {{http://doi.org/10.1016/j.jconrel.2025.114365}},
  volume       = {{388}},
  year         = {{2025}},
}

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