High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models

Lulu Xue, Alex G. Hamilton, Gan Zhao, Zebin Xiao, Rakan El-Mayta, Xuexiang Han, Ningqiang Gong, Xinhong Xiong, Junchao Xu, Christian G. Figueroa-Espada, Sarah J. Shepherd, Alvin J. Mukalel, Mohamad-Gabriel Alameh, Jiaxi Cui, Karin Wang, Andrew E. Vaughan, Drew Weissman and Michael J. Mitchell ()
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Lulu Xue: University of Pennsylvania
Alex G. Hamilton: University of Pennsylvania
Gan Zhao: University of Pennsylvania
Zebin Xiao: University of Pennsylvania
Rakan El-Mayta: University of Pennsylvania
Xuexiang Han: University of Pennsylvania
Ningqiang Gong: University of Pennsylvania
Xinhong Xiong: University of Electronic Science and Technology of China
Junchao Xu: University of Pennsylvania
Christian G. Figueroa-Espada: University of Pennsylvania
Sarah J. Shepherd: University of Pennsylvania
Alvin J. Mukalel: University of Pennsylvania
Mohamad-Gabriel Alameh: University of Pennsylvania
Jiaxi Cui: University of Electronic Science and Technology of China
Karin Wang: Temple University
Andrew E. Vaughan: University of Pennsylvania
Drew Weissman: University of Pennsylvania
Michael J. Mitchell: University of Pennsylvania

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

Abstract: Abstract Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.

Date: 2024
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DOI: 10.1038/s41467-024-45422-9

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