Angewandte Chemie (International ed. in English)Jul 13, 2026

Using Targeted Molecules to Redirect Liver-Directed Lipid Nanoparticles for Lung-Selective mRNA Delivery

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 14, 2026

Abstract

Ligand7-2-t6b-lipid-functionalized lipid nanoparticles achieved over 200-fold higher mRNA translation in the lungs compared to liver-tropic nanoparticles.

A ligand-mediated lipid reprogramming approach was developed to redirect liver-targeting lipid nanoparticles for lung-specific mRNA delivery.
From a library of 90 degradable lipidoids, 2-t6b was identified as a potent liver-targeting platform.
Small molecule ligands were site-specifically displayed onto the 2-t6b headgroup to create modified lipidoids for improved targeting.
Enhanced binding to vitronectin was observed, which is associated with improved cellular uptake and translation efficiency.
The modified lipid nanoparticles outperformed a previously constructed system in lung-specific genome editing.

Simplified

Systemic delivery of messenger RNA (mRNA) to target tissues and cells using lipid nanoparticles (LNPs) holds transformative potential for gene therapy. However, most clinically validated LNP exhibit strong liver tropism, and redirecting their organ specificity without redesigning entirely new chemistries remains challenging. Here we present a ligand-mediated lipid reprogramming approach that repurposes chemically defined, liver-tropic, ionizable lipids (lipidoids) for mRNA delivery beyond the liver. From a library of 90 degradable lipidoids, we identified 2-t6b as a potent liver-targeting platform. By site-specific displaying of small molecule ligands onto 2-t6b headgroup, we engineered a series of reconfigured lipidoids that achieve lung-specific targeting while retaining the parent delivery scaffold. Ligand7-2-t6b-lipid-functionalized LNP achieved over 200-fold higher mRNA translation in the lungs compared to the parent liver-tropic LNP. Proteomics and molecular docking analysis revealed enhanced binding of the modified lipid to vitronectin, a serum glycoprotein that improves integrin binding and thus promotes cellular uptake and translation efficiency. Ligand-mediated 2-t6b/ligand7 LNPs achieved outperformed efficacy and therapeutic potential in lung-specific genome editing relative to SORT-constructed 2-t6b LNP system. Our modular reprogramming strategy provides a generalizable framework to upgrade existing liver-biased LNPs into lung-selective mRNA carriers, advancing next-generation tissue-specific mRNA therapies for gene editing, protein replacement therapy, and regenerative medicine.

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A simple ligand swap redirected liver-targeting nanoparticles to the lungs with 200-fold more mRNA delivery

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Using Targeted Molecules to Redirect Liver-Directed Lipid Nanoparticles for Lung-Selective mRNA Delivery

Abstract

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