Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis

  • Nat Commun. 2023 Jan 17;14(1):75. doi: 10.1038/s41467-022-35637-z.
Xuexiang Han  #  1 ,  Ningqiang Gong  #  1 ,  Lulu Xue  1 ,  Margaret M Billingsley  1 ,  Rakan El-Mayta  1 ,  Sarah J Shepherd  1 ,  Mohamad-Gabriel Alameh  2  3 ,  Drew Weissman  2  3 ,  Michael J Mitchell  4  5  6  7  8  9
Affiliations
  • 1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 2. Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 3. Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 4. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 5. Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 6. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 7. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 8. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 9. Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • # Contributed equally.
PMID: 36650129 DOI: 10.1038/s41467-022-35637-z
Abstract

Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a preclinical model of liver fibrosis, AA-T3A-C12 enables ~65% silencing of Heat Shock Protein 47, a therapeutic target primarily expressed by activated fibroblasts, which is 2-fold more potent than MC3, leading to significantly reduced Collagen deposition and liver fibrosis. These results demonstrate the potential of AA-lipidoids for targeted RNA delivery to activated fibroblasts. Furthermore, these synthetic methods and screening strategies open a new avenue to develop and discover potent lipidoids with targeting properties, which can potentially enable RNA delivery to a range of cell and tissue types that are challenging to access using traditional lipid nanoparticle formulations.

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