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

Xuexiang Han, Ningqiang Gong, Lulu Xue, Margaret M. Billingsley, Rakan El-Mayta, Sarah J. Shepherd, Mohamad-Gabriel Alameh, Drew Weissman and Michael J. Mitchell ()
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Xuexiang Han: University of Pennsylvania
Ningqiang Gong: University of Pennsylvania
Lulu Xue: University of Pennsylvania
Margaret M. Billingsley: University of Pennsylvania
Rakan El-Mayta: University of Pennsylvania
Sarah J. Shepherd: University of Pennsylvania
Mohamad-Gabriel Alameh: University of Pennsylvania
Drew Weissman: University of Pennsylvania
Michael J. Mitchell: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35637-z

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