In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors

Xuexiang Han, Junchao Xu, Ying Xu, Mohamad-Gabriel Alameh, Lulu Xue, Ningqiang Gong, Rakan El-Mayta, Rohan Palanki, Claude C. Warzecha, Gan Zhao, Andrew E. Vaughan, James M. Wilson, Drew Weissman and Michael J. Mitchell ()
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Xuexiang Han: University of Pennsylvania
Junchao Xu: University of Pennsylvania
Ying Xu: Case Western Reserve University
Mohamad-Gabriel Alameh: University of Pennsylvania
Lulu Xue: University of Pennsylvania
Ningqiang Gong: University of Pennsylvania
Rakan El-Mayta: University of Pennsylvania
Rohan Palanki: University of Pennsylvania
Claude C. Warzecha: University of Pennsylvania
Gan Zhao: University of Pennsylvania
Andrew E. Vaughan: University of Pennsylvania
James M. Wilson: University of Pennsylvania
Drew Weissman: University of Pennsylvania
Michael J. Mitchell: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.

Date: 2024
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DOI: 10.1038/s41467-024-45537-z

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