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Title: Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here in this paper we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [1]
  1. Stanford Univ., CA (United States). Dept. of Chemistry
  2. Stanford Univ., CA (United States). Dept. of Pediatrics; Stanford Univ., CA (United States). Molecular Imaging Program at Stanford
  3. Stanford Univ., CA (United States). Dept. of Pediatrics; Stanford Univ., CA (United States). Molecular Imaging Program at Stanford
  4. Stanford Univ., CA (United States). Dept. of Pediatrics; Stanford Univ., CA (United States). Molecular Imaging Program at Stanford; Stanford Univ., CA (United States). Dept. of Microbiology & Immunology; Stanford Univ., CA (United States). Dept. of Bioengineering; Stanford Univ., CA (United States). Dept. of Radiology
  5. Stanford Univ., CA (United States). Dept. of Chemistry, and Dept. of Chemical and Systems Biology
Publication Date:
Grant/Contract Number:
SC0005430
Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 4; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Stanford Univ., CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cell-penetrating; gene therapy; nanoparticle; organocatalysis; stimuli-responsive
OSTI Identifier:
1338628
Alternate Identifier(s):
OSTI ID: 1465128

McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., and Waymouth, Robert M.. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. United States: N. p., Web. doi:10.1073/pnas.1614193114.
McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., & Waymouth, Robert M.. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. United States. doi:10.1073/pnas.1614193114.
McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., and Waymouth, Robert M.. 2017. "Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals". United States. doi:10.1073/pnas.1614193114.
@article{osti_1338628,
title = {Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals},
author = {McKinlay, Colin J. and Vargas, Jessica R. and Blake, Timothy R. and Hardy, Jonathan W. and Kanada, Masamitsu and Contag, Christopher H. and Wender, Paul A. and Waymouth, Robert M.},
abstractNote = {Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here in this paper we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.},
doi = {10.1073/pnas.1614193114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 4,
volume = 114,
place = {United States},
year = {2017},
month = {1}
}