Treatment of neurological disorders by introducing mRNA in vivo using polyplex nanomicelles
Open accessAbstract
Sensory nerve disorders are difficult to cure completely considering poor nerve regeneration capacity and difficulties in accurately targeting neural tissues. Administering mRNA is a promising approach for treating neurological disorders because mRNA can provide proteins and peptides in their native forms for mature non-dividing neural cells, without the need of entering their nuclei. However, direct mRNA administration into neural tissues in vivo has been challenging due to too unstable manner of mRNA and its strong immunogenicity. Thus, using a suitable carrier is essential for effective mRNA administration. For this purpose, we established a novel carrier based on the self-assembly of polyethylene glycol (PEG)-polyamino acid block copolymer, i.e. polyplex nanomicelles. To investigate the feasibility and efficacy of mRNA administration for the treatment of sensory nerve disorders, we used a mouse model of experimentally induced olfactory dysfunction. Intranasal administration of mRNA-loaded nanomicelles provided an efficient and sustained protein expression for nearly two days in nasal tissues, particularly in the lamina propria which contains olfactory nerve fibers, with effectively regulating the immunogenicity of mRNA. Consequently, once-daily intranasal administration of brain-derived neurotrophic factor (BDNF)-expressing mRNA using polyplex nanomicelles remarkably enhanced the neurological recovery of olfactory function along with repairing the olfactory epithelium to a nearly normal architecture. To the best of our knowledge, this is the first study to show the therapeutic potential of introducing exogenous mRNA for the treatment of neurological disorders. These results indicate the feasibility and safety of using mRNA, and provide a novel strategy of mRNA-based therapy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Intranasal administration of polyplex nanomicelles delivering mRNA encoding neutrophilic factor promoted recovery of olfactory function in mice with olfactory dysfunction.
“Intranasal administration of the nanomicelles promoted the recovery of their olfactory function.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [156]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 1× · see citing works
“Although little is known about the mechanisms underlying translation control in individual cells, a few studies have reported that the half-lives of mRNA in the cytoplasm were generally in the range of hours [35-37], indicating the very transient manner of protein expression from a single mRNA molecule.”
BackgroundSpecies-specific recognition of single-stranded RNA via toll-like receptor 7 and 8
Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., & Bauer, S. (2004) · Science · doi:10.1126/science.1093620 · Cited by 3,947 · see citing works
Fritsch, B., Reis, J., Martinowich, K., Schambra, H. M., Ji, Y., Cohen, L. G., & Lu, B. (2010) · Neuron · doi:10.1016/j.neuron.2010.03.035 · Cited by 1,420 · see citing works
P bodies and the control of mRNA translation and degradation
Parker, R., & Sheth, U. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.02.011 · Cited by 1,335 · see citing works
mRNA is an endogenous ligand for toll-like receptor 3
Karikó, K., Ni, H., Capodici, J., Lamphier, M., & Weissman, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310175200 · Cited by 1,062 · 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
Zangi, L., Lui, K. O., von Gise, A., Ma, Q., Ebina, W., Ptaszek, L. M., Später, D., Xu, H., Tabebordbar, M., Gorbatov, R., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2682 · Cited by 646 · see citing works
Kawamoto, T. (2003) · Archivum histologicum japonicum · doi:10.1679/aohc.66.123 · Cited by 620 · see citing works
Poduslo, J. F., & Curran, G. L. (1996) · Molecular Brain Research · doi:10.1016/0169-328x(95)00250-v · Cited by 614 · see citing works
Intranasal delivery: Physicochemical and therapeutic aspects
Costantino, H. R., Illum, L., Brandt, G., Johnson, P. H., & Quay, S. C. (2007) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.03.025 · Cited by 598 · see citing works
Sharova, L. V., Sharov, A. A., Nedorezov, T., Piao, Y., Shaik, N., & Ko, M. S. H. (2009) · DNA Research · doi:10.1093/dnares/dsn030 · Cited by 591 · see citing works
Simple Behavioral Assessment of Mouse Olfaction
Yang, M., & Crawley, J. N. (2009) · Current Protocols in Neuroscience · doi:10.1002/0471142301.ns0824s48 · Cited by 573 · see citing works
The role of neuronal growth factors in neurodegenerative disorders of the human brain
Connor, B. J., & Dragunow, M. (1998) · Brain Research Reviews · doi:10.1016/s0165-0173(98)00004-6 · Cited by 534 · see citing works
Kleim, J. A., Chan, S., Pringle, E., Schallert, K., Procaccio, V., Jimenez, R., & Cramer, S. C. (2006) · Nature Neuroscience · doi:10.1038/nn1699 · Cited by 529 · see citing works
Miyata, K., Nishiyama, N., & Kataoka, K. (2011) · Chemical Society Reviews · doi:10.1039/c1cs15258k · Cited by 451 · see citing works
Self-citationProtective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats
Arancibia, S., Silhol, M., Mouliere, F. C., Meffre, J., Höllinger, I., Maurice, T., & Tapia‐Arancibia, L. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.05.012 · Cited by 318 · see citing works
Lindholm, D., Dechant, G., Heisenberg, C., & Thoenen, H. (1993) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1993.tb00213.x · Cited by 282 · see citing works
Karikó, K., Muramatsu, H., Keller, J. M., & Weissman, D. (2012) · Molecular Therapy · doi:10.1038/mt.2012.7 · Cited by 282 · see citing works
Cell dynamics in the adult mouse olfactory epithelium: a quantitative autoradiographic study
Mackay‐Sim, A., & Kittel, P. W. (1991) · Journal of Neuroscience · doi:10.1523/jneurosci.11-04-00979.1991 · Cited by 271 · see citing works
Howell, T. H., Fiorellini, J. P., Jones, A. A., et al. (1997) · PubMed · Cited by 269 · see citing works
Nuclear targeting peptide scaffolds for lipofection of nondividing mammalian cells
Subramanian, A., Ranganathan, P. N., & Diamond, S. L. (1999) · Nature Biotechnology · doi:10.1038/12860 · Cited by 233 · see citing works
mRNA as gene therapeutic: How to control protein expression
Tavernier, G., Andries, O., Demeester, J., Sanders, N. N., De Smedt, S. C., & Rejman, J. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.10.020 · Cited by 232 · see citing works
The olfactory marker protein in the olfactory system of the mouse during development
Graziadei, G. A. M., Stanley, R. S., & Graziadei, P. P. C. (1980) · Neuroscience · doi:10.1016/0306-4522(80)90197-9 · Cited by 222 · see citing works
Itaka, K., Ishii, T., Hasegawa, Y., & Kataoka, K. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2009.11.072 · Cited by 211 · see citing works
Self-citationKanayama, N., Fukushima, S., Nishiyama, N., Itaka, K., Jang, W., Miyata, K., Yamasaki, Y., Chung, U., & Kataoka, K. (2006) · ChemMedChem · doi:10.1002/cmdc.200600008 · Cited by 203 · see citing works
Self-citationBDNF Prevents and Reverses Adult Rat Motor Neuron Degeneration and Induces Axonal Outgrowth
Kishino, A., Ishige, Y., Tatsuno, T., Nakayama, C., & Noguchi, H. (1997) · Experimental Neurology · doi:10.1006/exnr.1996.6367 · Cited by 193 · see citing works
Current prospects for mRNA gene delivery
Yamamoto, A., Kormann, M., Rosenecker, J., & Rudolph, C. (2008) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2008.09.016 · Cited by 193 · see citing works
Harding, J. W., Graziadei, P. P. C., Graziadei, G. A. M., et al. (1977) · Brain Research · doi:10.1016/0006-8993(77)90703-x · Cited by 188 · see citing works
Increasing Epithelial Junction Permeability Enhances Gene Transfer to Airway Epithelia In Vivo
Wang, G., Zabner, J., Deering, C., Launspach, J. L., Shao, J., Bodner, M., Jolly, D. J., Davidson, B. L., & McCray, P. B. (2000) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.22.2.3938 · Cited by 143 · see citing works
Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats
Dufès, C., Olivier, J., Gaillard, F. P., Gaillard, A., Couet, W. R., & Jm, M. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(03)00039-5 · Cited by 134 · see citing works
mRNA transfection of cervical carcinoma and mesenchymal stem cells mediated by cationic carriers
Rejman, J., Tavernier, G., Bavarsad, N., Demeester, J., & Smedt, S. C. D. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.07.124 · Cited by 133 · see citing works
In Vivo Messenger RNA Introduction into the Central Nervous System Using Polyplex Nanomicelle
Uchida, S., Itaka, K., Uchida, H., Hayakawa, K., Ogata, T., Ishii, T., Fukushima, S., Osada, K., & Kataoka, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056220 · Cited by 131 · see citing works
Self-citationGenome-wide technology for determining RNA stability in mammalian cells
Tani, H., & Akimitsu, N. (2012) · RNA Biology · doi:10.4161/rna.22036 · Cited by 120 · see citing works
Zhao, M., Zhao, Z., Koh, J., Jin, T., & Franceschi, R. T. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20411 · Cited by 117 · see citing works
Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies
Shao-yun, Y., Zhao, Y. H., Feng-lan, W., et al. (2004) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2004.05.007 · Cited by 116 · see citing works
Genter, M. B., Deamer-Melia, N. J., Blake, B. L., Wesley, D. S., & Levi, P. E. (1995) · Toxicologic Pathology · doi:10.1177/019262339502300404 · Cited by 113 · see citing works
Giehl, K. M., Röhrig, S., Bonatz, H., Gutjahr, M., Leiner, B., Bartke, I., Yan, Q., Reichardt, L. F., Backus, C., Welcher, A. A., et al. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-10-03492.2001 · Cited by 94 · see citing works
Neuroprotective effects of brain-derived neurotrophic factor in seizures during development
Tandon, P., Yang, Y., Das, K. P., Holmes, G. L., & Stafstrom, C. E. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00609-5 · Cited by 77 · see citing works
Suzukawa, K., Kondo, K., Kanaya, K., et al. (2011) · The Journal of Comparative Neurology · doi:10.1002/cne.22611 · Cited by 69 · see citing works
Self-citationProgress and Prospects of Polyplex Nanomicelles for Plasmid DNA Delivery
Itaka, K., & Kataoka, K. (2011) · Current Gene Therapy · doi:10.2174/156652311798192879 · Cited by 58 · see citing works
Self-citationSoderquist, R. G., Milligan, E. D., Sloane, E. M., Harrison, J. A., Douvas, K. K., Potter, J. M., Hughes, T., Chavez, R. A., Johnson, K. W., Watkins, L. R., et al. (2008) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.32254 · Cited by 56 · see citing works
Buckland, M. E., & Cunningham, A. M. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00270-x · Cited by 53 · see citing works
Hammond, E. N. L., Tetzlaff, W., Mestres, P., & Giehl, K. M. (1999) · Neuroreport · doi:10.1097/00001756-199908200-00043 · Cited by 42 · see citing works
Yasuno, H., Fukazawa, K., Fukuoka, T., et al. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02966-8 · Cited by 35 · see citing works
Tong, L., & Perez‐Polo, R. J. (1998) · Journal of Neural Transmission · doi:10.1007/s007020050101 · Cited by 35 · see citing works
Neurotrophin expression in the adult olfactory epithelium
Feron, F. P., Bianco, J. I., Ferguson, I. M., & Mackay‐Sim, A. (2008) · Brain Research · doi:10.1016/j.brainres.2007.12.003 · Cited by 33 · see citing works
Huang, F., Yin, Z., Wu, D., et al. (2012) · Neuroreport · doi:10.1097/wnr.0b013e32835c93c5 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
mRNA vaccines for infectious diseases: principles, delivery and clinical translation
Chaudhary, N., Weissman, D., & Whitehead, K. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00283-5 · Cited by 1,555 · see citing works
Block copolymer micelles in nanomedicine applications
Cabral, H., Miyata, K., Osada, K., & Kataoka, K. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00199 · Cited by 1,309 · see citing works
Self-citationDelivering 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
Tools for translation: non-viral materials for therapeutic mRNA delivery
Hajj, K. A., & Whitehead, K. A. (2017) · Nature Reviews Materials · doi:10.1038/natrevmats.2017.56 · Cited by 799 · see citing works
Andries, O., Mc Cafferty, S., De Smedt, S. C., Weiss, R., Sanders, N. N., & Kitada, T. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.051 · Cited by 701 · see citing works
Hwang, D., Ramsey, J. D., & Kabanov, A. V. (2020) · Advanced drug delivery reviews · doi:10.1016/j.addr.2020.09.009 · Cited by 699 · see citing works
Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems
Guan, S., & Rosenecker, J. (2017) · Gene Therapy · doi:10.1038/gt.2017.5 · Cited by 389 · see citing works
Ball, R., Bajaj, P., & Whitehead, K. (2016) · International Journal of Nanomedicine · doi:10.2147/ijn.s123062 · Cited by 333 · see citing works
Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia
An, D., Schneller, J. L., Frassetto, A., Liang, S., Zhu, X., Park, J.-S., Theisen, M., Hong, S.-J., Zhou, J., Rajendran, R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.11.081 · Cited by 263 · see citing works
Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
DeRosa, F., Guild, B., Karve, S., Smith, L., Love, K., Dorkin, J. R., Kauffman, K. J., Zhang, J., Yahalom, B., Anderson, D. G., et al. (2016) · Gene Therapy · doi:10.1038/gt.2016.46 · Cited by 159 · see citing works
Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency
Prieve, M. G., Harvie, P., Monahan, S. D., Roy, D., Li, A. G., Blevins, T. L., Paschal, A. E., Waldheim, M., Bell, E. C., Galperin, A., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2017.12.024 · Cited by 145 · see citing works
Nanomedicine-Based Approaches for mRNA Delivery
Uchida, S., Perche, F., Pichon, C., & Cabral, H. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00618 · Cited by 139 · see citing works
Nanoplatforms for mRNA Therapeutics
Meng, C., Chen, Z., Li, G., Welte, T., & Shen, H. (2021) · Advanced Therapeutics · doi:10.1002/adtp.202000099 · Cited by 130 · see citing works
Biomedical applications of mRNA nanomedicine
Xiong, Q., Lee, G. Y., Ding, J., Li, W., & Shi, J. (2018) · Nano Research · doi:10.1007/s12274-018-2146-1 · Cited by 125 · see citing works
Evading innate immunity in nonviral mRNA delivery: don't shoot the messenger.
Devoldere, J., Dewitte, H., De Smedt, S. C., & Remaut, K. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2015.07.009 · Cited by 112 · see citing works
Recent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases
Sahu, I., Haque, A. K. M. A., Weidensee, B., Weinmann, P., & Kormann, M. S. D. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.019 · Cited by 104 · see citing works
RNA delivery biomaterials for the treatment of genetic and rare diseases
Zhao, W., Hou, X., Vick, O. G., & Dong, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119291 · Cited by 82 · see citing works
- Authors
- Baba, M., Itaka, K., Kondo, K., Yamasoba, T., & Kataoka, K.
- Affiliations
- Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
- The University of Tokyo (JP)
- Corresponding author
- Itaka, Keiji
- Kataoka, Kazunori
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 201
- Pages
- 41-48
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2090729959
- Cited by
- 109
- References
- 47
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 3 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 10 · 2019: 11 · 2018: 8 · 2017: 4 · 2016: 13 · 2015: 7
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 411 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Journal of Controlled Release (acceptedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- JSPS (24300170)
- Japan Science and Technology Agency
- JSPS Core-to-Core Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- mRNA delivery, olfactory dysfunction, brain-derived neurotrophic factor, intranasal administration, lamina propria, neurological recovery
- MeSH terms
- Administration, Intranasal, Animals, Olfaction Disorders, Methimazole, Mice, Inbred BALB C, Micelles, Olfactory Mucosa, RNA, Messenger, Tumor Necrosis Factor-alpha, Interleukin-6, Gene Transfer Techniques, Brain-Derived Neurotrophic Factor, Nanostructures, Olfactory Marker Protein
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
