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Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation Diagnosis and Treatment

View ORCID ProfileJacob W. Myerson, Priyal N. Patel, Nahal Habibi, Landis R. Walsh, Yi-Wei Lee, David C. Luther, Laura T. Ferguson, Michael H. Zaleski, Marco E. Zamora, Oscar A. Marcos-Contreras, Patrick M. Glassman, Ian Johnston, Elizabeth D. Hood, Tea Shuvaeva, Jason V. Gregory, Raisa Y. Kiseleva, Jia Nong, Kathryn M. Rubey, Colin F. Greineder, Samir Mitragotri, George S. Worthen, Vincent M. Rotello, Joerg Lahann, Vladimir R. Muzykantov, Jacob S. Brenner
doi: https://doi.org/10.1101/2020.04.15.037564
Jacob W. Myerson
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Priyal N. Patel
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Nahal Habibi
2Biointerfaces Institute and Department of Chemical Engineering, University of Michigan at Ann Arbor
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Landis R. Walsh
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Yi-Wei Lee
3Department of Chemistry, University of Massachusetts at Amherst
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David C. Luther
3Department of Chemistry, University of Massachusetts at Amherst
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Laura T. Ferguson
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
4Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania
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Michael H. Zaleski
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Marco E. Zamora
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Oscar A. Marcos-Contreras
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Patrick M. Glassman
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Ian Johnston
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Elizabeth D. Hood
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Tea Shuvaeva
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Jason V. Gregory
2Biointerfaces Institute and Department of Chemical Engineering, University of Michigan at Ann Arbor
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Raisa Y. Kiseleva
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Jia Nong
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Kathryn M. Rubey
5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania
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Colin F. Greineder
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Samir Mitragotri
6Wyss Institute for Biologically Inspired Engineering, Harvard University
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George S. Worthen
5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania
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Vincent M. Rotello
3Department of Chemistry, University of Massachusetts at Amherst
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Joerg Lahann
2Biointerfaces Institute and Department of Chemical Engineering, University of Michigan at Ann Arbor
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Vladimir R. Muzykantov
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
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Jacob S. Brenner
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
4Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania
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  • For correspondence: jacob.brenner@pennmedicine.upenn.edu
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Abstract

Acute lung inflammation has severe morbidity, as seen in COVID-19 patients. Lung inflammation is accompanied or led by massive accumulation of neutrophils in pulmonary capillaries (“margination”). We sought to identify nanostructural properties that predispose nanoparticles to accumulate in pulmonary marginated neutrophils, and therefore to target severely inflamed lungs. We designed a library of nanoparticles and conducted an in vivo screen of biodistributions in naive mice and mice treated with lipopolysaccharides. We found that supramolecular organization of protein in nanoparticles predicts uptake in inflamed lungs. Specifically, nanoparticles with agglutinated protein (NAPs) efficiently home to pulmonary neutrophils, while protein nanoparticles with symmetric structure (e.g. viral capsids) are ignored by pulmonary neutrophils. We validated this finding by engineering protein-conjugated liposomes that recapitulate NAP targeting to neutrophils in inflamed lungs. We show that NAPs can diagnose acute lung injury in SPECT imaging and that NAP-like liposomes can mitigate neutrophil extravasation and pulmonary edema arising in lung inflammation. Finally, we demonstrate that ischemic ex vivo human lungs selectively take up NAPs, illustrating translational potential. This work demonstrates that structure-dependent interactions with neutrophils can dramatically alter the biodistribution of nanoparticles, and NAPs have significant potential in detecting and treating respiratory conditions arising from injury or infections.

Competing Interest Statement

Findings in this study contributed to United States provisional patent application number 62/943469.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 18, 2020.
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Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation Diagnosis and Treatment
Jacob W. Myerson, Priyal N. Patel, Nahal Habibi, Landis R. Walsh, Yi-Wei Lee, David C. Luther, Laura T. Ferguson, Michael H. Zaleski, Marco E. Zamora, Oscar A. Marcos-Contreras, Patrick M. Glassman, Ian Johnston, Elizabeth D. Hood, Tea Shuvaeva, Jason V. Gregory, Raisa Y. Kiseleva, Jia Nong, Kathryn M. Rubey, Colin F. Greineder, Samir Mitragotri, George S. Worthen, Vincent M. Rotello, Joerg Lahann, Vladimir R. Muzykantov, Jacob S. Brenner
bioRxiv 2020.04.15.037564; doi: https://doi.org/10.1101/2020.04.15.037564
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Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation Diagnosis and Treatment
Jacob W. Myerson, Priyal N. Patel, Nahal Habibi, Landis R. Walsh, Yi-Wei Lee, David C. Luther, Laura T. Ferguson, Michael H. Zaleski, Marco E. Zamora, Oscar A. Marcos-Contreras, Patrick M. Glassman, Ian Johnston, Elizabeth D. Hood, Tea Shuvaeva, Jason V. Gregory, Raisa Y. Kiseleva, Jia Nong, Kathryn M. Rubey, Colin F. Greineder, Samir Mitragotri, George S. Worthen, Vincent M. Rotello, Joerg Lahann, Vladimir R. Muzykantov, Jacob S. Brenner
bioRxiv 2020.04.15.037564; doi: https://doi.org/10.1101/2020.04.15.037564

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