Lipid nanoparticles containing labile PEG-lipids transfect primary human skin cells more efficiently in the presence of apoE

Camilla Hald Gregersen, Razan Mearraoui, Pia Pernille Søgaard, Gael Clergeaud, Karsten Petersson, Andrew J. Urquhart, Jens B. Simonsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Nucleic acid-based therapeutics encapsulated into lipid nanoparticles (LNPs) can potentially target the root cause of genetic skin diseases. Although nanoparticles are considered impermeable to skin, research and clinical studies have shown that nanoparticles can penetrate into skin with reduced skin barrier function when administered topically. Studies have shown that epidermal keratinocytes express the low-density lipoprotein receptor (LDLR) that mediates endocytosis of apolipoprotein E (apoE)-associated nanoparticles and that dermal fibroblasts express mannose receptors. Here we prepared LNPs designed to exploit these different endocytic pathways for intracellular mRNA delivery to the two most abundant skin cell types, containing: (i) labile PEG-lipids (DMG-PEG2000) prone to dissociate and facilitate apoE-binding to LNPs, enabling apoE-LDLR mediated uptake in keratinocytes, (ii) non-labile PEG-lipids (DSPE-PEG2000) to impose stealth-like properties to LNPs to enable targeting of distant cells, and (iii) mannose-conjugated PEG-lipids (DSPE-PEG2000-Mannose) to target fibroblasts or potentially immune cells containing mannose receptors. All types of LNPs were prepared by vortex mixing and formed monodisperse (PDI ∼ 0.1) LNP samples with sizes of 130 nm (±25%) and high mRNA encapsulation efficiencies (≥90%). The LNP-mediated transfection potency in keratinocytes and fibroblasts was highest for LNPs containing labile PEG-lipids, with the addition of apoE greatly enhancing transfection via LDLR. Coating LNPs with mannose did not improve transfection, and stealth-like LNPs show limited to no transfection. Taken together, our studies suggest using labile PEG-lipids and co-administration of apoE when exploring LNPs for skin delivery.

Original languageEnglish
Article number114219
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Number of pages14
Publication statusPublished - 2024


  • Apolipoprotein E
  • Dermal fibroblasts
  • Epidermal keratinocytes
  • Lipid nanoparticles
  • Low-density lipoprotein receptor
  • Mannose
  • PEGylation


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