Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters
Abstract
We report a strategy for generating a combinatorial library of oligonucleotide transporters with varied lipid domains and their use in the efficient transfection of lymphocytes with mRNA in vitro and in vivo. This library is based on amphiphilic charge-altering releasable transporters (CARTs) that contain a lipophilic block functionalized with various side-chain lipids and a polycationic α-amino ester mRNA-binding block that undergoes rearrangement to neutral small molecules, resulting in mRNA release. We show that certain binary mixtures of these lipid-varied CARTs provide up to a ninefold enhancement in mRNA translation in lymphocytes in vitro relative to either a single-lipid CART component alone or the commercial reagent Lipofectamine 2000, corresponding to a striking increase in percent transfection from 9–12% to 80%. Informed by the results with binary mixtures, we further show that CARTs consisting of optimized ratios of the two lead lipids incorporated into a single hybrid-lipid transporter molecule maintain the same delivery efficacy as the noncovalent mixture of two CARTs. The lead lipid CART mixtures and hybrid-lipid CARTs show enhanced lymphocyte transfection in primary T cells and in vivo in mice. This combinatorial approach for rapidly screening mRNA delivery vectors has provided lipid-varied CART mixtures and hybrid-lipid CARTs that exhibit significantmore »
- Authors:
- Publication Date:
- Research Org.:
- Stanford Univ., CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences, and Biosciences Division; National Institutes of Health (NIH)
- OSTI Identifier:
- 1441127
- Alternate Identifier(s):
- OSTI ID: 1540298; OSTI ID: 1594176
- Grant/Contract Number:
- SC0018168; CHE-1607092; NIH-CA031841; NIH-CA031845; S10RR027431-01
- Resource Type:
- Published Article
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 26; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; gene therapy; nanoparticle; polyplex; combinatorial; immunotherapy
Citation Formats
McKinlay, Colin J., Benner, Nancy L., Haabeth, Ole A., Waymouth, Robert M., and Wender, Paul A. Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. United States: N. p., 2018.
Web. doi:10.1073/pnas.1805358115.
McKinlay, Colin J., Benner, Nancy L., Haabeth, Ole A., Waymouth, Robert M., & Wender, Paul A. Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. United States. https://doi.org/10.1073/pnas.1805358115
McKinlay, Colin J., Benner, Nancy L., Haabeth, Ole A., Waymouth, Robert M., and Wender, Paul A. Mon .
"Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters". United States. https://doi.org/10.1073/pnas.1805358115.
@article{osti_1441127,
title = {Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters},
author = {McKinlay, Colin J. and Benner, Nancy L. and Haabeth, Ole A. and Waymouth, Robert M. and Wender, Paul A.},
abstractNote = {We report a strategy for generating a combinatorial library of oligonucleotide transporters with varied lipid domains and their use in the efficient transfection of lymphocytes with mRNA in vitro and in vivo. This library is based on amphiphilic charge-altering releasable transporters (CARTs) that contain a lipophilic block functionalized with various side-chain lipids and a polycationic α-amino ester mRNA-binding block that undergoes rearrangement to neutral small molecules, resulting in mRNA release. We show that certain binary mixtures of these lipid-varied CARTs provide up to a ninefold enhancement in mRNA translation in lymphocytes in vitro relative to either a single-lipid CART component alone or the commercial reagent Lipofectamine 2000, corresponding to a striking increase in percent transfection from 9–12% to 80%. Informed by the results with binary mixtures, we further show that CARTs consisting of optimized ratios of the two lead lipids incorporated into a single hybrid-lipid transporter molecule maintain the same delivery efficacy as the noncovalent mixture of two CARTs. The lead lipid CART mixtures and hybrid-lipid CARTs show enhanced lymphocyte transfection in primary T cells and in vivo in mice. This combinatorial approach for rapidly screening mRNA delivery vectors has provided lipid-varied CART mixtures and hybrid-lipid CARTs that exhibit significant improvement in mRNA delivery to lymphocytes, a finding of potentially broad value in research and clinical applications.},
doi = {10.1073/pnas.1805358115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 26,
volume = 115,
place = {United States},
year = {Mon Jun 11 00:00:00 EDT 2018},
month = {Mon Jun 11 00:00:00 EDT 2018}
}
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1073/pnas.1805358115
https://doi.org/10.1073/pnas.1805358115
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 134 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Gene therapy clinical trials worldwide to 2012 - an update: Gene therapy clinical trials worldwide to 2012 - an update
journal, February 2013
- Ginn, Samantha L.; Alexander, Ian E.; Edelstein, Michael L.
- The Journal of Gene Medicine, Vol. 15, Issue 2
Towards personalized, tumour-specific, therapeutic vaccines for cancer
journal, December 2017
- Hu, Zhuting; Ott, Patrick A.; Wu, Catherine J.
- Nature Reviews Immunology, Vol. 18, Issue 3
An Efficient Low Cost Method for Gene Transfer to T Lymphocytes
journal, March 2013
- Chicaybam, Leonardo; Sodre, Andressa Laino; Curzio, Bianca Azevedo
- PLoS ONE, Vol. 8, Issue 3
T Cell-Specific siRNA Delivery Using Antibody-Conjugated Chitosan Nanoparticles
journal, May 2012
- Lee, Jangwook; Yun, Kyoung-Soo; Choi, Chang Seon
- Bioconjugate Chemistry, Vol. 23, Issue 6
Non-Viral CRISPR/Cas Gene Editing In Vitro and In Vivo Enabled by Synthetic Nanoparticle Co-Delivery of Cas9 mRNA and sgRNA
journal, December 2016
- Miller, Jason B.; Zhang, Shuyuan; Kos, Petra
- Angewandte Chemie International Edition, Vol. 56, Issue 4
Global Manufacturing of CAR T Cell Therapy
journal, March 2017
- Levine, Bruce L.; Miskin, James; Wonnacott, Keith
- Molecular Therapy - Methods & Clinical Development, Vol. 4
Development of Guanidinium-Rich Protein Mimics for Efficient siRNA Delivery into Human T Cells
journal, September 2015
- deRonde, Brittany M.; Torres, Joe A.; Minter, Lisa M.
- Biomacromolecules, Vol. 16, Issue 10
Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy
journal, June 2016
- Kranz, Lena M.; Diken, Mustafa; Haas, Heinrich
- Nature, Vol. 534, Issue 7607
Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy
journal, December 2016
- Oberli, Matthias A.; Reichmuth, Andreas M.; Dorkin, J. Robert
- Nano Letters, Vol. 17, Issue 3
In Vitro and in Vivo mRNA Delivery Using Lipid-Enveloped pH-Responsive Polymer Nanoparticles
journal, April 2011
- Su, Xingfang; Fricke, Jennifer; Kavanagh, Daniel G.
- Molecular Pharmaceutics, Vol. 8, Issue 3
Clinical manufacturing of CAR T cells: foundation of a promising therapy
journal, January 2016
- Wang, Xiuyan; Rivière, Isabelle
- Molecular Therapy - Oncolytics, Vol. 3
mRNA-based therapeutics — developing a new class of drugs
journal, September 2014
- Sahin, Ugur; Karikó, Katalin; Türeci, Özlem
- Nature Reviews Drug Discovery, Vol. 13, Issue 10
Systemic mRNA Delivery to the Lungs by Functional Polyester-based Carriers
journal, November 2017
- Yan, Yunfeng; Xiong, Hu; Zhang, Xinyi
- Biomacromolecules, Vol. 18, Issue 12
Molecular hurdles in polyfectin design and mechanistic background to polycation induced cytotoxicity☆
journal, December 2006
- Hunter, A.
- Advanced Drug Delivery Reviews, Vol. 58, Issue 14
In Situ Functionalized Polymers for siRNA Delivery
journal, April 2016
- Priegue, Juan M.; Crisan, Daniel N.; Martínez-Costas, José
- Angewandte Chemie International Edition, Vol. 55, Issue 26
Lipid composition of cationic nanoliposomes implicate on transfection efficiency
journal, March 2013
- Ghanbari Safari, Maryam; Hosseinkhani, Saman
- Journal of Liposome Research, Vol. 23, Issue 3
Toxicity of cationic lipids and cationic polymers in gene delivery
journal, August 2006
- Lv, Hongtao; Zhang, Shubiao; Wang, Bing
- Journal of Controlled Release, Vol. 114, Issue 1
A Combinatorial Polymer Library Approach Yields Insight into Nonviral Gene Delivery
journal, June 2008
- Green, Jordan J.; Langer, Robert; Anderson, Daniel G.
- Accounts of Chemical Research, Vol. 41, Issue 6
Transfecting the hard-to-transfect lymphoma/leukemia cells using a simple cationic polymer nanocomplex
journal, April 2012
- Zhao, Nianxi; Qi, Jianjun; Zeng, Zihua
- Journal of Controlled Release, Vol. 159, Issue 1
Transgene expression, but not gene delivery, is improved by adhesion-assisted lipofection of hematopoietic cells
journal, May 1999
- Keller, H.; Yunxu, C.; Marit, G.
- Gene Therapy, Vol. 6, Issue 5
Materials for non-viral intracellular delivery of messenger RNA therapeutics
journal, October 2016
- Kauffman, Kevin J.; Webber, Matthew J.; Anderson, Daniel G.
- Journal of Controlled Release, Vol. 240
Small Interfering RNA-Mediated Gene Silencing in T Lymphocytes
journal, November 2002
- McManus, Michael T.; Haines, Brian B.; Dillon, Christopher P.
- The Journal of Immunology, Vol. 169, Issue 10
Thiourea-Based Bifunctional Organocatalysis: Supramolecular Recognition for Living Polymerization
journal, October 2005
- Dove, Andrew P.; Pratt, Russell C.; Lohmeijer, Bas G. G.
- Journal of the American Chemical Society, Vol. 127, Issue 40
Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery
journal, February 2016
- Fenton, Owen S.; Kauffman, Kevin J.; McClellan, Rebecca L.
- Advanced Materials, Vol. 28, Issue 15
An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo
journal, November 2015
- Li, Bin; Luo, Xiao; Deng, Binbin
- Nano Letters, Vol. 15, Issue 12
Nanoparticulate Nonviral Agent for the Effective Delivery of pDNA and siRNA to Differentiated Cells and Primary Human T Lymphocytes
journal, September 2012
- Schallon, Anja; Synatschke, Christopher V.; Jérôme, Valérie
- Biomacromolecules, Vol. 13, Issue 11
An Inverted Hexagonal Phase of Cationic Liposome-DNA Complexes Related to DNA Release and Delivery
journal, July 1998
- Koltover, I.
- Science, Vol. 281, Issue 5373
Functional DNA Delivery Enabled by Lipid-Modified Charge-Altering Releasable Transporters (CARTs)
journal, May 2018
- Benner, Nancy L.; Near, Katherine E.; Bachmann, Michael H.
- Biomacromolecules, Vol. 19, Issue 7
Lipid-like materials for low-dose, in vivo gene silencing
journal, January 2010
- Love, K. T.; Mahon, K. P.; Levins, C. G.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 5
Peptide/Cas9 nanostructures for ribonucleoprotein cell membrane transport and gene edition
journal, January 2017
- Lostalé-Seijo, Irene; Louzao, Iria; Juanes, Marisa
- Chemical Science, Vol. 8, Issue 12
Multi-Emissive Difluoroboron Dibenzoylmethane Polylactide Exhibiting Intense Fluorescence and Oxygen-Sensitive Room-Temperature Phosphorescence
journal, July 2007
- Zhang, Guoqing; Chen, Jianbin; Payne, Sarah J.
- Journal of the American Chemical Society, Vol. 129, Issue 29
Engineered T cells: the promise and challenges of cancer immunotherapy
journal, August 2016
- Fesnak, Andrew D.; June, Carl H.; Levine, Bruce L.
- Nature Reviews Cancer, Vol. 16, Issue 9
Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals
journal, January 2017
- McKinlay, Colin J.; Vargas, Jessica R.; Blake, Timothy R.
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 4
Mapping Optimal Charge Density and Length of ROMP-Based PTDMs for siRNA Internalization
journal, September 2016
- Caffrey, Leah M.; deRonde, Brittany M.; Minter, Lisa M.
- Biomacromolecules, Vol. 17, Issue 10
Modulated Protonation of Side Chain Aminoethylene Repeats in N-Substituted Polyaspartamides Promotes mRNA Transfection
journal, August 2014
- Uchida, Hirokuni; Itaka, Keiji; Nomoto, Takahiro
- Journal of the American Chemical Society, Vol. 136, Issue 35
Boosting Intracellular Delivery of Lipid Nanoparticle-Encapsulated mRNA
journal, August 2017
- Patel, Siddharth; Ashwanikumar, N.; Robinson, Emily
- Nano Letters, Vol. 17, Issue 9
mRNA vaccines — a new era in vaccinology
journal, January 2018
- Pardi, Norbert; Hogan, Michael J.; Porter, Frederick W.
- Nature Reviews Drug Discovery, Vol. 17, Issue 4
Cationic liposome-mediated RNA transfection.
journal, August 1989
- Malone, R. W.; Felgner, P. L.; Verma, I. M.
- Proceedings of the National Academy of Sciences, Vol. 86, Issue 16
Transfection efficiency boost of cholesterol-containing lipoplexes
journal, September 2012
- Pozzi, Daniela; Marchini, Cristina; Cardarelli, Francesco
- Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1818, Issue 9
Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems
journal, January 2017
- Guan, S.; Rosenecker, J.
- Gene Therapy, Vol. 24, Issue 3
Rational design of cationic lipids for siRNA delivery
journal, January 2010
- Semple, Sean C.; Akinc, Akin; Chen, Jianxin
- Nature Biotechnology, Vol. 28, Issue 2
Lymphocyte apoptosis: induction by gene transfer techniques
journal, April 1997
- Ebert, O.; Finke, S.; Salahi, A.
- Gene Therapy, Vol. 4, Issue 4
Polyamine-Mediated Stoichiometric Assembly of Ribonucleoproteins for Enhanced mRNA Delivery
journal, September 2017
- Li, Jiahe; He, Yanpu; Wang, Wade
- Angewandte Chemie International Edition, Vol. 56, Issue 44
Dynamic Amphiphile Libraries To Screen for the “Fragrant” Delivery of siRNA into HeLa Cells and Human Primary Fibroblasts
journal, June 2013
- Gehin, Charlotte; Montenegro, Javier; Bang, Eun-Kyoung
- Journal of the American Chemical Society, Vol. 135, Issue 25
In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers
journal, April 2017
- Smith, Tyrel T.; Stephan, Sirkka B.; Moffett, Howell F.
- Nature Nanotechnology, Vol. 12, Issue 8
Tagging alcohols with cyclic carbonate: a versatile equivalent of (meth)acrylate for ring-opening polymerization
journal, January 2008
- Pratt, Russell C.; Nederberg, Fredrik; Waymouth, Robert M.
- Chem. Commun., Issue 1
Biodegradable polyamino acid-based polycations as safe and effective gene carrier minimizing cumulative toxicity
journal, May 2010
- Itaka, Keiji; Ishii, Takehiko; Hasegawa, Yoko
- Biomaterials, Vol. 31, Issue 13
Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA
journal, February 2016
- Li, Bin; Luo, Xiao; Deng, Binbin
- Scientific Reports, Vol. 6, Issue 1
Gene therapy returns to centre stage
journal, October 2015
- Naldini, Luigi
- Nature, Vol. 526, Issue 7573
Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes
journal, July 2017
- Fenton, Owen S.; Kauffman, Kevin J.; Kaczmarek, James C.
- Advanced Materials, Vol. 29, Issue 33
Organocatalytic Ring-Opening Polymerization of Morpholinones: New Strategies to Functionalized Polyesters
journal, June 2014
- Blake, Timothy R.; Waymouth, Robert M.
- Journal of the American Chemical Society, Vol. 136, Issue 26
A brief history of gene therapy
journal, October 1992
- Friedmann, Theodore
- Nature Genetics, Vol. 2, Issue 2
Novel Protein Transduction Domain Mimics as Nonviral Delivery Vectors for siRNA Targeting NOTCH1 in Primary Human T cells
journal, January 2013
- Tezgel, A. Özgül; Gonzalez-Perez, Gabriela; Telfer, Janice C.
- Molecular Therapy, Vol. 21, Issue 1
Engineering liposomal nanoparticles for targeted gene therapy
journal, May 2017
- Zylberberg, C.; Gaskill, K.; Pasley, S.
- Gene Therapy, Vol. 24, Issue 8
Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells
journal, July 2012
- Geihe, E. I.; Cooley, C. B.; Simon, J. R.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 33
A new developing class of gene delivery: messenger RNA-based therapeutics
journal, January 2017
- Meng, Zhao; O'Keeffe-Ahern, Jonathan; Lyu, Jing
- Biomaterials Science, Vol. 5, Issue 12
mRNA-based therapeutics–Advances and perspectives
journal, July 2016
- Sergeeva, O. V.; Koteliansky, V. E.; Zatsepin, T. S.
- Biochemistry (Moscow), Vol. 81, Issue 7
A combinatorial library of lipid-like materials for delivery of RNAi therapeutics
journal, April 2008
- Akinc, Akin; Zumbuehl, Andreas; Goldberg, Michael
- Nature Biotechnology, Vol. 26, Issue 5
Effective Non-Viral Delivery of siRNA to Acute Myeloid Leukemia Cells with Lipid-Substituted Polyethylenimines
journal, August 2012
- Landry, Breanne; Aliabadi, Hamidreza Montazeri; Samuel, Anuja
- PLoS ONE, Vol. 7, Issue 8
High-Efficiency Transfection of Primary Human and Mouse T Lymphocytes Using RNA Electroporation
journal, January 2006
- Zhao, Yangbing; Zheng, Zhili; Cohen, Cyrille J.
- Molecular Therapy, Vol. 13, Issue 1
mRNA vaccine delivery using lipid nanoparticles
journal, May 2016
- Reichmuth, Andreas M.; Oberli, Matthias A.; Jaklenec, Ana
- Therapeutic Delivery, Vol. 7, Issue 5
Polycation-based nanoparticle delivery of RNAi therapeutics: Adverse effects and solutions
journal, December 2012
- Ballarín-González, Borja; Howard, Kenneth Alan
- Advanced Drug Delivery Reviews, Vol. 64, Issue 15
Messenger RNA-based therapeutics for the treatment of apoptosis-associated diseases
journal, October 2015
- Matsui, Akitsugu; Uchida, Satoshi; Ishii, Takehiko
- Scientific Reports, Vol. 5, Issue 1
Structurally Programmed Assembly of Translation Initiation Nanoplex for Superior mRNA Delivery
journal, February 2017
- Li, Jiahe; Wang, Wade; He, Yanpu
- ACS Nano, Vol. 11, Issue 3
Organocatalysis: Opportunities and Challenges for Polymer Synthesis
journal, March 2010
- Kiesewetter, Matthew K.; Shin, Eun Ji; Hedrick, James L.
- Macromolecules, Vol. 43, Issue 5