Self-degradable lipid-like materials based on “hydrolysis accelerated by the intra-particle enrichment of reactant (HyPER)” for messenger RNA delivery
Open accessAbstract
Abstract RNA‐based therapeutics is a promising approach for curing intractable diseases by manipulating various cellular functions. For eliciting RNA (i.e., mRNA and siRNA) functions successfully, the RNA in the extracellular space must be protected and it must be delivered to the cytoplasm. In this study, the development of a self‐degradable lipid‐like material that functions to accelerate the collapse of lipid nanoparticles (LNPs) and the release of RNA into cytoplasm is reported. The self‐degradability is based on a unique reaction “Hydrolysis accelerated by intra‐Particle Enrichment of Reactant (HyPER).” In this reaction, a disulfide bond and a phenyl ester are essential structural components: concentrated hydrophobic thiols that are produced by the cleavage of the disulfide bonds in the LNPs drive an intraparticle nucleophilic attack to the phenyl ester linker, which results in further degradation. An oleic acid‐scaffold lipid‐like material that mounts all of these units (ssPalmO‐Phe) shows superior transfection efficiency to nondegradable or conventional materials. The insertion of the aromatic ring is unexpectedly revealed to contribute to the enhancement of endosomal escape. Since the intracellular trafficking is a sequential process that includes cellular uptake, endosomal escape, the release of mRNA, and translation, the improvement in each process synergistically enhances the gene expression.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Other researchers propose that the outer shell of mRNA-LNPs consists of one or multiple bilayers.
“Other researchers propose that the outer shell of mRNA-LNPs consists of one or multiple bilayers, based on cryo-TEM analysis (Fig. 2) (Patel et al., 2020, Tanaka et al., 2020) or SANS (Sebastiani et al., 2021).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Tanaka et al., 2020
Cites
mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667 · see citing works
Schafer, F. Q., & Buettner, G. R. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00480-4 · Cited by 4,587 · see citing works
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716153 · Cited by 3,047 · see citing works
Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.012 · Cited by 2,662 · see citing works
Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681 · see citing works
Saito, G., Swanson, J. A., & Lee, K.-D. (2003) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00179-5 · Cited by 1,407 · see citing works
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357 · see citing works
Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo
Jayaraman, M., Ansell, S. M., Mui, B. L., Tam, Y. K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J. K., et al. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201203263 · Cited by 1,267 · see citing works
Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms
Akinc, A., Querbes, W., De, S., Qin, J., Frank-Kamenetsky, M., Jayaprakash, K. N., Jayaraman, M., Rajeev, K. G., Cantley, W. L., Dorkin, J. R., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.85 · Cited by 1,261 · see citing works
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.012 · Cited by 1,127 · see citing works
Finn, J. D., Smith, A. R., Patel, M. C., Shaw, L., Youniss, M. R., van Heteren, J., Dirstine, T., Ciullo, C., Lescarbeau, R., Seitzer, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.014 · Cited by 878 · see citing works
Sabnis, S., Kumarasinghe, E. S., Salerno, T., Mihai, C., Ketova, T., Senn, J. J., Lynn, A., Bulychev, A., McFadyen, I., Chan, J., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.03.010 · Cited by 820 · see citing works
Kauffman, K. J., Dorkin, J. R., Yang, J. H., Heartlein, M. W., DeRosa, F., Mir, F. F., Fenton, O. S., & Anderson, D. G. (2015) · Nano Letters · doi:10.1021/acs.nanolett.5b02497 · Cited by 785 · see citing works
Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
Kormann, M. S. D., Hasenpusch, G., Aneja, M. K., Nica, G., Flemmer, A. W., Herber-Jonat, S., Huppmann, M., Mays, L. E., Illenyi, M., Schams, A., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1733 · Cited by 733 · see citing works
Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy
Oberli, M. A., Reichmuth, A. M., Dorkin, J. R., Mitchell, M. J., Fenton, O. S., Jaklenec, A., Anderson, D. G., Langer, R., & Blankschtein, D. (2017) · Nano Letters · doi:10.1021/acs.nanolett.6b03329 · Cited by 719 · see citing works
Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown
Wittrup, A., Ai, A., Liu, X., Hamar, P., Trifonova, R., Charisse, K., Manoharan, M., Kirchhausen, T., & Lieberman, J. (2015) · Nature Biotechnology · doi:10.1038/nbt.3298 · Cited by 693 · see citing works
Maier, M. A., Jayaraman, M., Matsuda, S., Liu, J., Barros, S., Querbes, W., Tam, Y. K., Ansell, S. M., Kumar, V., Qin, J., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.124 · Cited by 625 · see citing works
Yanez Arteta, M., Kjellman, T., Bartesaghi, S., Wallin, S., Wu, X., Kvist, A. J., Dabkowska, A., Székely, N., Radulescu, A., Bergenholtz, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720542115 · Cited by 534 · see citing works
Semple, S. C., Chonn, A., & Cullis, P. R. (1998) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00128-2 · Cited by 403 · see citing works
The design and synthesis of polymers for eukaryotic membrane disruption
Murthy, N., Robichaud, J. R., Tirrell, D. A., Stayton, P. S., & Hoffman, A. S. (1999) · Journal of Controlled Release · doi:10.1016/s0168-3659(99)00114-5 · Cited by 403 · see citing works
Liu, J., Chang, J., Jiang, Y., Meng, X., Sun, T., Mao, L., Xu, Q., & Wang, M. (2019) · Advanced Materials · doi:10.1002/adma.201902575 · Cited by 373 · see citing works
Sago, C. D., Lokugamage, M. P., Paunovska, K., Vanover, D. A., Monaco, C. M., Shah, N. N., Gamboa Castro, M., Anderson, S. E., Rudoltz, T. G., Lando, G. N., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811276115 · Cited by 313 · see citing works
Hajj, K. A., Ball, R. L., Deluty, S. B., Singh, S. R., Strelkova, D., Knapp, C. M., & Whitehead, K. A. (2019) · Small · doi:10.1002/smll.201805097 · Cited by 312 · see citing works
Systemic delivery of factor IX messenger RNA for protein replacement therapy
Ramaswamy, S., Tonnu, N., Tachikawa, K., Limphong, P., Vega, J. B., Karmali, P. P., Chivukula, P., & Verma, I. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1619653114 · Cited by 301 · see citing works
Fenton, O. S., Kauffman, K. J., Kaczmarek, J. C., McClellan, R. L., Jhunjhunwala, S., Tibbitt, M. W., Zeng, M. D., Appel, E. A., Dorkin, J. R., Mir, F. F., et al. (2017) · Advanced Materials · doi:10.1002/adma.201606944 · Cited by 289 · see citing works
McKinlay, C. J., Vargas, J. R., Blake, T. R., Hardy, J. W., Kanada, M., Contag, C. H., Wender, P. A., & Waymouth, R. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614193114 · Cited by 288 · see citing works
Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery
Fenton, O. S., Kauffman, K. J., McClellan, R. L., Appel, E. A., Dorkin, J. R., Tibbitt, M. W., Heartlein, M. W., DeRosa, F., Langer, R., & Anderson, D. G. (2016) · Advanced Materials · doi:10.1002/adma.201505822 · Cited by 254 · see citing works
Genome Editing with mRNA Encoding ZFN, TALEN, and Cas9
Zhang, H., Zhang, Y., & Yin, H. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.01.014 · Cited by 248 · see citing works
McKinlay, C. J., Benner, N. L., Haabeth, O. A. W., Waymouth, R. M., & Wender, P. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1805358115 · Cited by 240 · see citing works
Kumar, V., Qin, J., Jiang, Y., Duncan, R. G., Brigham, B., Fishman, S., Nair, J. K., Akinc, A., Barros, S. A., & Kasperkovitz, P. V. (2014) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2014.61 · Cited by 222 · see citing works
Kaczmarek, J. C., Kauffman, K. J., Fenton, O. S., Sadtler, K., Patel, A. K., Heartlein, M. W., DeRosa, F., & Anderson, D. G. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b02917 · Cited by 218 · see citing works
Paunovska, K., Da Silva Sanchez, A. J., Sago, C. D., Gan, Z., Lokugamage, M. P., Islam, F. Z., Kalathoor, S., Krupczak, B. R., & Dahlman, J. E. (2019) · Advanced Materials · doi:10.1002/adma.201807748 · Cited by 205 · see citing works
Won, S. J., Kit, M. C. S., & Martin, B. R. (2017) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2017.1409191 · Cited by 193 · see citing works
Haabeth, O. A. W., Blake, T. R., McKinlay, C. J., Waymouth, R. M., Wender, P. A., & Levy, R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810002115 · Cited by 143 · see citing works
Kowalski, P. S., Palmiero, U. C., Huang, Y., Rudra, A., Langer, R., & Anderson, D. G. (2018) · Advanced Materials · doi:10.1002/adma.201801151 · Cited by 139 · see citing works
Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism
Mays, L. E., Ammon-Treiber, S., Mothes, B., Alkhaled, M., Rottenberger, J., Müller-Hermelink, E. S., Grimm, M., Mezger, M., Beer-Hammer, S., von Stebut, E., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65351 · Cited by 113 · see citing works
Hama, S., Akita, H., Iida, S., Mizuguchi, H., & Harashima, H. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkl1165 · Cited by 111 · see citing works
Self-citationThe molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics
Zaballa, M.-E., & van der Goot, F. G. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1488804 · Cited by 105 · see citing works
Enhanced Intracellular siRNA Delivery using Bioreducible Lipid‐Like Nanoparticles
Wang, M., Alberti, K. A., Varone, A., Pouli, D., Georgakoudi, I., & Xu, Q. (2014) · Advanced Healthcare Materials · doi:10.1002/adhm.201400039 · Cited by 101 · see citing works
Benner, N. L., McClellan, R. L., Turlington, C. R., Haabeth, O. A. W., Waymouth, R. M., & Wender, P. A. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b03154 · Cited by 98 · see citing works
Messenger RNA-based therapeutics for the treatment of apoptosis-associated diseases
Matsui, A., Uchida, S., Ishii, T., Itaka, K., & Kataoka, K. (2015) · Scientific Reports · doi:10.1038/srep15810 · Cited by 93 · see citing works
Akita, H., Ishiba, R., Hatakeyama, H., Tanaka, H., Sato, Y., Tange, K., Arai, M., Kubo, K., & Harashima, H. (2013) · Advanced Healthcare Materials · doi:10.1002/adhm.201200431 · Cited by 83 · see citing works
Self-citationStructurally Programmed Assembly of Translation Initiation Nanoplex for Superior mRNA Delivery
Li, J., Wang, W., He, Y., Li, Y., Yan, E. Z., Zhang, K., Irvine, D. J., & Hammond, P. T. (2017) · ACS Nano · doi:10.1021/acsnano.6b08447 · Cited by 82 · see citing works
Hedberg, C., Dekker, F. J., Rusch, M., Renner, S., Wetzel, S., Vartak, N., Gerding‐Reimers, C., Bon, R. S., Bastiaens, P. I. H., & Waldmann, H. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201102965 · Cited by 80 · see citing works
Combinatorial Approach to Nanoarchitectonics for Nonviral Delivery of Nucleic Acids
Molla, M. R., & Levkin, P. A. (2015) · Advanced Materials · doi:10.1002/adma.201502888 · Cited by 62 · see citing works
Real-Time Fluorescence Detection of Protein Transduction into Live Cells
Lee, Y.-J., Datta, S., & Pellois, J. (2008) · Journal of the American Chemical Society · doi:10.1021/ja7102026 · Cited by 51 · see citing works
Doi, H., Okuwaki, K., Mochizuki, Y., et al. (2017) · Chemical Physics Letters · doi:10.1016/j.cplett.2017.07.032 · Cited by 43 · see citing works
Self-citationMonitoring Translation Activity of mRNA-Loaded Nanoparticles in Mice
Rosigkeit, S., Meng, M., Grunwitz, C. R., Gomes, P., Kreft, A., Hayduk, N., Heck, R., Pickert, G., Ziegler, K., Abassi, Y., et al. (2018) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b00370 · Cited by 43 · see citing works
Dom34 mediates targeting of exogenous RNA in the antiviral OAS/RNase L pathway
Nogimori, T., Nishiura, K., Kawashima, S., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1087 · Cited by 43 · see citing works
Ukawa, M., Akita, H., Hayashi, Y., Ishiba, R., Tange, K., Arai, M., Kubo, K., Higuchi, Y., Shimizu, K., Konishi, S., et al. (2014) · Advanced Healthcare Materials · doi:10.1002/adhm.201300629 · Cited by 42 · see citing works
Self-citationJiang, Z., Cui, W., Prasad, P., Touve, M. A., Gianneschi, N. C., Mager, J., & Thayumanavan, S. (2018) · Biomacromolecules · doi:10.1021/acs.biomac.8b01321 · Cited by 35 · see citing works
Kohn, F. R., Malkmus, S. A., Brownson, E. A., et al. (1998) · Drug Delivery · doi:10.3109/10717549809031390 · Cited by 31 · see citing works
Ohto, T., Konishi, M., Tanaka, H., Onomoto, K., Yoneyama, M., Nakai, Y., Tange, K., Yoshioka, H., & Akita, H. (2019) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b18-00783 · Cited by 29 · see citing works
Self-citationTanaka, H., Watanabe, A., Konishi, M., et al. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e00959 · Cited by 28 · see citing works
Self-citationOkuwaki, K., Doi, H., Fukuzawa, K., & Mochizuki, Y. (2019) · Applied Physics Express · doi:10.7567/1882-0786/ab5e0a · Cited by 26 · see citing works
Self-citationPostfunctionalization of Noncationic RNA–Polymer Complexes for RNA Delivery
Jiang, Z., Cui, W., Mager, J., & Thayumanavan, S. (2019) · Industrial & Engineering Chemistry Research · doi:10.1021/acs.iecr.9b00666 · Cited by 23 · see citing works
Tanaka, H., Oasa, S., Kinjo, M., Tange, K., Nakai, Y., Harashima, H., & Akita, H. (2016) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2016.11.020 · Cited by 16 · see citing works
Self-citationTanaka, H., Sato, Y., Harashima, H., & Akita, H. (2016) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2016.1154531 · Cited by 14 · see citing works
Self-citationA triumph of perseverance over interference
(2018) · Nature Biotechnology · doi:10.1038/nbt.4255 · Cited by 11 · see citing works
Shinsho, E., Okuwaki, K., Doi, H., et al. (2018) · Journal of Computer Chemistry Japan · doi:10.2477/jccj.2018-0012 · Cited by 9 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076 · see citing works
mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability
Schoenmaker, L., Witzigmann, D., Kulkarni, J. A., Verbeke, R., Kersten, G., Jiskoot, W., & Crommelin, D. J. A. (2021) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2021.120586 · Cited by 1,566 · see citing works
Kim, J., Eygeris, Y., Gupta, M., & Sahay, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.014 · Cited by 514 · see citing works
Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain
Ogawa, K., Kato, N., Yoshida, M., Hiu, T., Matsuo, T., Mizukami, S., Omata, D., Suzuki, R., Maruyama, K., Mukai, H., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.042 · Cited by 144 · see citing works
- Authors
- Tanaka, H., Takahashi, T., Konishi, M., Takata, N., Gomi, M., Shirane, D., Miyama, R., Hagiwara, S., Yamasaki, Y., Sakurai, Y., Ueda, K., Higashi, K., Moribe, K., Shinsho, E., Nishida, R., Fukuzawa, K., Yonemochi, E., Okuwaki, K., Mochizuki, Y., Nakai, Y., Tange, K., Yoshioka, H., Tamagawa, S., & Akita, H.
- Affiliations
- Chiba University (JP)
- Hoshi University (JP)
- Rikkyo University (JP)
- NOF Corporation (Japan) (JP)
- Corresponding author
- Tanaka, Hiroki
- Akita, Hidetaka
- ORCID
- Venue
- Advanced Functional Materials
- Publisher
- Wiley
- Published
- 2020-06-23
- Volume
- 30
- Issue
- 34
- ISSN
- 1616-301X (ISSN-L)
- 1616-3028
- OpenAlex
- W3037446636
- Cited by
- 126
- References
- 60
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 22 · 2023: 17 · 2022: 26 · 2021: 18 · 2020: 4
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Advanced Functional Materials (publishedVersion, cc-by)
- Funders
- Japan Society for the Promotion of Science (17H06558, 18K18377, 20H00657)
- Chiba University
- Japan Science and Technology Agency (JPMJCR17H1)
- Asahi Glass Foundation
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- lipid nanoparticles, mRNA delivery, siRNA delivery, disulfide bond cleavage, endosomal escape, transfection efficiency, RNA therapeutics, intracellular trafficking
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
