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Advances in Lipid Nanoparticles for mRNA-Based Cancer Immunotherapy
Maria L. Guevara, Francesca Persano, Stefano Persano
Frontiers in Chemistry · 2020 · Review · CC BY
Abstract
Over the past decade, messenger RNA (mRNA) has emerged as potent and flexible platform for the development of novel effective cancer immunotherapies. Advances in non-viral gene delivery technologies, especially the tremendous progress in lipid nanoparticles’ manufacturing, have made possible the implementation of mRNA-based antitumor treatments. Several mRNA-based immunotherapies have demonstrated antitumor effect in preclinical and clinical studies, and marked successes have been achieved most notably by its implementation in therapeutic vaccines, cytokines therapies, checkpoint blockade and chimeric antigen receptor (CAR) cell therapy. In this review, we summarize recent advances in the development of lipid nanoparticles for mRNA-based immunotherapies and their applications in cancer treatment. Finally, we also highlight the variety of immunotherapeutic approaches through mRNA delivery and discuss the main factors affecting transfection efficiency and tropism of mRNA-loaded lipid nanoparticles in vivo.
References 97
- 1.
Arteta M. Y. Kjellman T. Bartesaghi S. Wallin S. Wu X. Kvist A. J. (2018 ). Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles. Proc. Natl. Acad. Sci. U.S.A. 115, E3351–E3360.
Not in our library10.1073/pnas.1720542115
- 2.
Bailey A. L. Cullis P. R. (1994 ). Modulation of membrane fusion by asymmetric transbilayer distributions of amino lipids. Biochemistry 33, 12573–12580.
Not in our library10.1021/bi00208a007
- 3.
Baldin A. V. Savvateeva L. V. Bazhin A. V. Zamyatnin A. A. Jr (2020 ). Dendritic cells in anticancer vaccination: rationale for ex vivo loading or in vivo targeting. Cancers 12:590
Not in our library10.3390/cancers12030590
- 4.
Ball R. L. Hajj K. A. Vizelman J. Bajaj P. Whitehead K. A. (2018 ). Lipid nanoparticle formulations for enhanced co-delivery of siRNA and mRNA. Nano Lett. 18, 3814–3822.
Not in our library10.1021/acs.nanolett.8b01101
- 5.
Belliveau N. M. Huft J. Lin P. J. C. Chen S. Leung A. K. K. Leaver T. J.. (2012 ). Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Mol. Ther. Nucleic Acids 1:e37.
Not in our library10.1038/mtna.2012.28
- 6.
Billingsley M. M. Singh N. Ravikumar P. Zhang R. June C. H. Mitchell M. J. (2020 ). Ionizable lipid nanoparticle-mediated mRNA delivery for human CAR T cell engineering. Nano Lett. 20, 1578–1589.
Not in our library10.1021/acs.nanolett.9b04246
- 7.
- 8.
Blanco E. Shen H. Ferrari M. (2015 ). Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951.
Not in our library10.1038/nbt.3330
- 9.
Brudno J. N. Kochenderfer J. N. (2016 ). Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330.
Not in our library10.1182/blood-2016-04-703751
- 10.
Cheng Q. Wei T. Farbiak L. Johnson L. T. Dilliard S. A. Siegwart D. J. (2020 ). Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat. Nanotechnol. 15, 313–320.
Not in our library10.1038/s41565-020-0669-6
- 11.
- 12.
Cullis P. R. Hope M. J. (2017 ). Lipid nanoparticle systems for enabling gene therapies. Mol. Ther. 25, 1467–1475.
Not in our library10.1016/j.ymthe.2017.03.013
- 13.
De Beuckelaer A. Pollard C. Van Lint S. Roose K. Van Hoecke L. Naessens T.. (2016 ). Type I interferons interfere with the capacity of mRNA lipoplex vaccines to elicit cytolytic T cell responses. Mol. Ther. 24, 2012–2020.
Not in our library10.1038/mt.2016.161
- 14.
Eygeris Y. Patel S. Jozic A. Sahay G. (2020 ). Deconvoluting lipid nanoparticle structure for messenger RNA delivery. Nano Lett. 20, 4543–4549.
Not in our library10.1021/acs.nanolett.0c01386
- 15.
- 16.
Felgner P. L. Ringold G. M. (1989 ). Cationic liposome-mediated transfection. Nature 337, 387–388.
Not in our library10.1038/337387a0
- 17.
Fenton O. S. Kauffman K. J. McClellan R. L. Appel E. A. Dorkin J. R. Tibbitt M. W.. (2016 ). Bioinspired alkenyl amino alcohol ionizable lipid materials for highly potent in vivo mRNA delivery. Adv. Mater. 28, 2939–2943.
Not in our library10.1002/adma.201505822
- 18.
Foster J. B. Barrett D. M. Karikó K. (2019 ). The emerging role of in vitro-transcribed mRNA in adoptive T cell immunotherapy. Mol Ther. 27, 747–756.
Not in our library10.1016/j.ymthe.2019.01.018
- 19.
Gall D. (1966 ). The adjuvant activity of aliphatic nitrogenous bases. Immunology 11, 369–386.
Not in our library
- 20.
Gilleron J. Querbes W. Zeigerer A. Borodovsky A. Marsico G. Schubert U.. (2013 ). Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646.
Not in our library10.1038/nbt.2612
- 21.
- 22.
Granot Y. Peer D. (2017 ). Delivering the right message: challenges and opportunities in lipid nanoparticles-mediated modified mRNA therapeutics-An innate immune system standpoint. Semin. Immunol. 34, 68–77.
Not in our library10.1016/j.smim.2017.08.015
- 23.
Guan S. Rosenecker J. (2017 ). Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 24, 133–143.
Not in our library10.1038/gt.2017.5
- 24.
Guevara M. L. Jilesen Z. Stojdl D. Persano S. (2019a ). Codelivery of mRNA with α-Galactosylceramide using a new lipopolyplex formulation induces a strong antitumor response upon intravenous administration. ACS Omega 4, 13015–13026.
Not in our library10.1021/acsomega.9b00489
- 25.
Guevara M. L. Persano S. Persano F. (2019b ). Lipid-based vectors for therapeutic mRNA-based anti-cancer vaccines. Curr Pharm Des. 25, 1443–1454.
Not in our library10.2174/1381612825666190619150221
- 26.
Haabeth O. A. W. Blake T. R. McKinlay C. J. Tveita A. A. Sallets A. Waymouth R. M.. (2019 ). Local delivery of Ox40l, Cd80, and Cd86 mRNA kindles global anticancer immunity. Cancer Res. 79, 1624–1634.
Not in our library10.1158/0008-5472.can-18-2867
- 27.
Hajj K. A. Whitehead K. A. (2017 ). Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2:17056
Not in our library10.1038/natrevmats.2017.56
- 28.
Harper P. E. Mannock D. A. Lewis R. N. A. H. McElhaney R. N. Gruner S. (2001 ). X-ray diffraction of some phosphatidylethanolamine lamellar and inverted hexagonal phases. Biophys. J. 81, 2693–2706.
Not in our library10.1016/s0006-3495(01)75912-7
- 29.
- 30.
Henriksen-Lacey M. Christensen D. Bramwell V. W. Lindenstrom T. Agger E. M. Andersen P.. (2010 ). Liposomal cationic charge and antigen adsorption are important properties for the efficient deposition of antigen at the injection site and ability of the vaccine to induce a cmi response. J. Control Release 145, 102–108.
Not in our library10.1016/j.jconrel.2010.03.027
- 31.
- 32.
Holtkamp S. Kreiter S. Selmi A. Simon P. Koslowski M. Huber C.. (2006 ). Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood 108, 4009–4017.
Not in our library10.1182/blood-2006-04-015024
- 33.
Islam M. A. Xu Y. Tao W. Ubellacker J. M. Lim M. Aum D. (2018 ). Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. Nat. Biomed. Eng. 2, 850–864.
Not in our library10.1038/s41551-018-0284-0
- 34.
Jackson H. J. Rafiq S. Brentjens R. J. (2016 ). Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383.
Not in our library10.1038/nrclinonc.2016.36
- 35.
- 36.
Judge A. McClintock K. Phelps J. R. MacLachlan I. (2006 ). Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes. Mol. Ther. 13, 328–337.
Not in our library10.1016/j.ymthe.2005.09.014
- 37.
- 38.
Kaczmarek J. C. Patel A. K. Kauffman K. J. Fenton O. S. Webber M. J. Heartlein M. W.. (2016 ). Polymer-lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew. Chem. Int. Ed. Engl. 55, 13808–13812.
Not in our library10.1002/anie.201608450
- 39.
Karikó K. Muramatsu H. Ludwig J. Weissman D. (2011 ). Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. 39:e142.
Not in our library10.1093/nar/gkr695
- 40.
Kon E. Hazan-Halevy I. Rosenblum D. Cohen N. Chatterjee S. Veiga N.. (2020 ). Resveratrol enhances mRNA and siRNA lipid nanoparticles primary CLL cell transfection. Pharmaceutics 12:520.
Not in our library10.3390/pharmaceutics12060520
- 41.
Korsholm K. S. Agger E. M. Foged C. Christensen D. Dietrich J. Andersen C. S.. (2007 ). The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes. Immunology 121, 216–226.
Not in our library10.1111/j.1365-2567.2007.02560.x
- 42.
Kowalski P. S. Rudra A. Miao L. Anderson D. G. (2019 ). Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728.
Not in our library10.1016/j.ymthe.2019.02.012
- 43.
Kranz L. M. Diken M. Haas H. Kreiter S. Loquai C. Reuter K. C.. (2016 ). Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401.
Not in our library10.1038/nature18300
- 44.
Kreiter S. Selmi A. Diken M. Koslowski M. Britten C. M. Huber C.. (2010 ). Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity. Cancer Res. 70, 9031–9040.
Not in our library10.1158/0008-5472.can-10-0699
- 45.
Li S. Huang L. (1997 ). In vivo gene transfer via intravenous administration of cationic lipid-protamine-DNA (LPD) complexes. Gene Ther. 4, 891–900.
Not in our library10.1038/sj.gt.3300482
- 46.
Li S. D. Huang L. (2009 ). Nanoparticles evading the reticuloendothelial system: role of the supported bilayer. Biochim. Biophys. Acta 1788, 2259–2266.
Not in our library10.1016/j.bbamem.2009.06.022
- 47.
Lonez C. Bessodes M. Scherman D. Vandenbranden M. Escriou V. Ruysschaert J. M. (2014 ). Cationic lipid nanocarriers activate Toll-like receptor 2 and NLRP3 inflammasome pathways. Nanomedicine 10, 775–782.
Not in our library10.1016/j.nano.2013.12.003
- 48.
Malone R. W. Felgner P. L. Verma I. M. (1989 ). Cationic liposome-mediated RNA transfection. Proc. Natl. Acad. Sci. U.S.A. 86, 6077–6081.
Not in our library10.1073/pnas.86.16.6077
- 49.
Matsui H. Sato Y. Hatakeyama H. Akita H. Harashima H. (2015 ). Size-dependent specific targeting and efficient gene silencing in peritoneal macrophages using a pH-sensitive cationic liposomal siRNA carrier. Int. J. Pharm. 495, 171–178.
Not in our library10.1016/j.ijpharm.2015.08.044
- 50.
- 51.
McKinlay C. J. Benner N. L. Haabeth O. A. Waymouth R. M. Wender P. A. (2018 ). Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. Proc. Natl. Acad. Sci. U.S.A. 115, E5859–E5866.
Not in our library10.1073/pnas.1805358115
- 52.
McKinlay C. J. Vargas J. R. Blake T. R. Hardy J. W. Kanada M. Contag C. H.. (2017 ). Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc. Natl. Acad. Sci. U.S.A. 114, E448–E456.
Not in our library10.1073/pnas.1614193114
- 53.
Miao L. Li L. Huang Y. Delcassian D. Chahal J. Han J.. (2019 ). Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185.
Not in our library10.1038/s41587-019-0247-3
- 54.
- 55.
Mohanty R. Chowdhury C. R. Arega S. Sen P. Ganguly P. Ganguly N. (2019 ). CAR T cell therapy: a new era for cancer treatment (Review). Oncol. Rep. 42, 2183–2195.
Not in our library10.3892/or.2019.7335
- 56.
- 57.
Oberli M. A. Reichmuth A. M. Dorkin J. R. Mitchell M. J. Fenton O. S. Jaklenec A. (2017 ). Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 17, 1326–1335.
Not in our library10.1021/acs.nanolett.6b03329
- 58.
Pardi N. Hogan M. J. Porter F. W. Weissman D. (2018 ). mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 17, 261–279.
Not in our library10.1038/nrd.2017.243
- 59.
- 60.
Parhiz H. Shuvaev V. V. Pardi N. Khoshnejad M. Kiseleva R. Y. Brenner J. S.. (2018 ). PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake. J. Control Release 291, 106–115.
Not in our library10.1016/j.jconrel.2018.10.015
- 61.
- 62.
Pastor F. Berraondo P. Etxeberria I. Frederick J. Sahin U. Gilboa E.. (2018 ). An RNA toolbox for cancer immunotherapy. Nat Rev Drug Discov. 17, 751–767.
Not in our library10.1038/nrd.2018.132
- 63.
Patel S. Ashwanikumar N. Robinson E. DuRoss A. Sun C. Murphy-Benenato K. E.. (2017 ). Boosting intracellular delivery of lipid nanoparticle-encapsulated messenger RNA. Nano Lett. 17, 5711–5718.
Not in our library10.1021/acs.nanolett.7b02664
- 64.
- 65.
Persano S. Guevara M. L. Li Z. Mai J. Ferrari M. Pompa P. P.. (2017 ). Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination. Biomaterials 125, 81–89.
Not in our library10.1016/j.biomaterials.2017.02.019
- 66.
Pozzi D. Marchini C. Cardarelli F. Amenitsch H. Garulli C. Bifone A.. (2012 ). Transfection efficiency boost of cholesterol-containing lipoplexes. Biochim. Biophys. Acta 1818, 2335–2343.
Not in our library10.1016/j.bbamem.2012.05.017
- 67.
Reichmuth A. M. Oberli M. A. Jaklenec A. Langer R. Blankschtein D. (2016 ). mRNA vaccine delivery using lipid nanoparticles. Ther. Deliv. 7, 319–334.
Not in our library10.4155/tde-2016-0006
- 68.
Rybakova Y. Kowalski P. S. Huang Y. Gonzalez J. T. Heartlein M. W. DeRosa F.. (2019 ). mRNA delivery for therapeutic anti-HER2 antibody expression in vivo. Mol. Ther. 27, 1415–1423.
Not in our library10.1016/j.ymthe.2019.05.012
- 69.
Sahin U. Karikó K. Türeci Ö. (2014 ). mRNA-based therapeutics–developing a new class of drugs. Nat Rev Drug Discov. 13, 759–780.
Not in our library10.1038/nrd4278
- 70.
Sato Y. Okabe N. Note Y. Hashiba K. Maeki M. Tokeshi M.. (2020 ). Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles. Acta Biomater. 102, 341–350.
Not in our library10.1016/j.actbio.2019.11.022
- 71.
Schlake T. Thess A. Thran M. Jordan I. (2019 ). mRNA as novel technology for passive immunotherapy. Cell Mol. Life Sci. 76, 301–328,
Not in our library10.1007/s00018-018-2935-4
- 72.
Stadler C. R. Bähr-Mahmud H. Celik L. Hebich B. Roth A. S. Roth R. P. (2017 ). Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nat. Med. 23, 815–817.
Not in our library10.1038/nm.4356
- 73.
Suzuki M. Kato C. Kato A. (2015 ). Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. J. Toxicol. Pathol. 28, 133–139.
Not in our library10.1293/tox.2015-0031
- 74.
- 75.
Thomas A. Garg S. M. De Souza R. A. G. Ouellet E. Tharmarajah G. Reichert D.. (2018 ). Microfluidic production and application of lipid nanoparticles for nucleic acid transfection. Methods Mol. Biol. 1792, 193–203.
Not in our library10.1007/978-1-4939-7865-6_14
- 76.
- 77.
- 78.
Turnis M. E. Rooney C. M. (2010 ). Enhancement of dendritic cells as vaccines for cancer. Immunotherapy 2, 847–862.
Not in our library10.2217/imt.10.56
- 79.
Van der Jeught K. De Koker S. Bialkowski L. Heirman C. Joe P. T. Perche F.. (2018 ). Dendritic cell targeting mRNA lipopolyplexes combine strong antitumor T-cell immunity with improved inflammatory safety. ACS Nano 12, 9815–9829.
Not in our library10.1021/acsnano.8b00966
- 80.
Van Lint S. Goyvaerts C. Maenhout S. Goethals L. Disy A. Benteyn D.. (2012 ). Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy. Cancer Res. 72, 1661–1671.
Not in our library10.1158/0008-5472.can-11-2957
- 81.
Verbeke R. Lentacker I. Wayteck L. Breckpot K. Van Bockstal M. Descamps B.. (2017 ). Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: restoring the immunogenicity of immunosilent mRNA. J. Control Release 266, 287–300.
Not in our library10.1016/j.jconrel.2017.09.041
- 82.
Vitale C. Strati P. (2020 ). CAR T-cell therapy for B-cell non-hodgkin lymphoma and chronic lymphocytic leukemia: clinical trials and real-world experiences. Front Oncol. 10:849.
Not in our library10.3389/fonc.2020.00849
- 83.
- 84.
- 85.
Wang Y. Huang L. (2013 ). A window onto siRNA delivery. Nat. Biotechnol. 31, 611–612.
Not in our library10.1038/nbt.2634
- 86.
Wang Y. Zhang L. Xu Z. Miao L. Huang L. (2018 ). mRNA vaccine with antigen-specific checkpoint blockade induces an enhanced immune response against established melanoma. Mol. Ther. 26, 420–434.
Not in our library10.1016/j.ymthe.2017.11.009
- 87.
Weissman D. (2014 ). mRNA transcript therapy. Expert Rev. Vaccines 14, 265–281.
Not in our library10.1586/14760584.2015.973859
- 88.
Weng Y. Li C. Yang T. Hu B. Zhang M. Guo S.. (2020 ). The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40:107534.
Not in our library10.1016/j.biotechadv.2020.107534
- 89.
Wiesinger M. März J. Kummer M. Schuler G. Dörrie J. Schuler-Thurner B.. (2019 ). Clinical-scale production of CAR-T cells for the treatment of melanoma patients by mRNA transfection of a CSPG4-specific CAR under full GMP compliance. Cancers 11:1198.
Not in our library10.3390/cancers11081198
- 90.
Wilk A. J. Benner N. L. Vergara R. Haabeth O. A. W. Levy R. Waymouth R. M. (2020 ). Charge-altering releasable transporters enable specific phenotypic manipulation of resting primary natural killer cells. bioRxiv.
Not in our library10.1101/2020.02.28.970491
- 91.
Xue H. Y. Guo P. Wen W. C. Wong H. L. (2015 ). Lipid-based nanocarriers for RNA Delivery. Curr. Pharm. Des. 21, 3140–3147.
Not in our library10.2174/1381612821666150531164540
- 92.
Zelphati O. Szoka F. C. Jr. (1996 ). Mechanism of oligonucleotide release from cationic liposomes. Proc. Natl. Acad. Sci. U.S.A. 93, 11493–11498.
Not in our library10.1073/pnas.93.21.11493
- 93.
- 94.
Zhao Z. Chen Y. Francisco N. M. Zhang Y. Wu M. (2018 ). The application of CAR-T cell therapy in hematological malignancies: advantages and challenges. Acta Pharm. Sin. B 8, 539–551.
Not in our library10.1016/j.apsb.2018.03.001
- 95.
Zhigaltsev I. V. Belliveau N. Hafez I. Leung A. K. K. Huft J. Hansen C.. (2012 ). Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing. Langmuir 28, 3633–3640.
Not in our library10.1021/la204833h
- 96.
Zhong Z. McCafferty S. Combes F. Huysmans H. De Temmerman J. Gitsels A. (2018 ). mRNA therapeutics deliver a hopeful message. Nano Today 23, 16–39.
Not in our library10.1016/j.nantod.2018.10.005
- 97.
Zhu X. Tao W. Liu D. Wu J. Guo Z. Ji X.. (2017 ). Surface De-PEGylation controls nanoparticle-mediated siRNA delivery in vitro and in vivo. Theranostics 7, 1990–2002.
Not in our library10.7150/thno.18136
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