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

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

  • Nat Commun. 2024 Feb 29;15(1):1884. doi: 10.1038/s41467-024-45422-9.
Lulu Xue 1,  Alex G Hamilton 1,  Gan Zhao 2,  Zebin Xiao 2,  Rakan El-Mayta 1 3,  Xuexiang Han 1,  Ningqiang Gong 1,  Xinhong Xiong 4,  Junchao Xu 1,  Christian G Figueroa-Espada 1,  Sarah J Shepherd 1,  Alvin J Mukalel 1,  Mohamad-Gabriel Alameh 3 5,  Jiaxi Cui 4,  Karin Wang 6,  Andrew E Vaughan 2,  Drew Weissman 3 5,  Michael J Mitchell 7 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 2 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 4 Yangtze Delta Region Institute (Huzhou), University of Electronic Science and Technology of China, Huzhou, Zhejiang, 313001, China.
  • 5 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 6 Department of Bioengineering, Temple University, Philadelphia, PA, 19122, USA.
  • 7 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 8 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 9 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 10 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 11 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19014, USA. mjmitch@seas.upenn.edu.
  • 12 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
PMID: 38424061 DOI: 10.1038/s41467-024-45422-9
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.

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