Extrahepatic targeting of lipid nanoparticles in vivo with intracellular targeting for future nanomedicines
Open accessAbstract
A new era of nanomedicines that involve nucleic acids/gene therapy has been opened after two decades in 21st century and new types of more efficient drug delivery systems (DDS) are highly expected and will include extrahepatic delivery. In this review, we summarize the possibility and expectations for the extrahepatic delivery of small interfering RNA/messenger RNA/plasmid DNA/genome editing to the spleen, lung, tumor, lymph nodes as well as the liver based on our studies as well as reported information. Passive targeting and active targeting are discussed in in vivo delivery and the importance of controlled intracellular trafficking for successful therapeutic results are also discussed. In addition, mitochondrial delivery as a novel strategy for nucleic acids/gene therapy is introduced to expand the therapeutic dimension of nucleic acids/gene therapy in the liver as well as the heart, kidney and brain.
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The highly modular nature of LNPs allows them to be optimized for organ- and cell type-specific delivery following systemic administration.
“Furthermore, the highly modular nature of LNPs allows them to be optimized for organ- and cell type-specific delivery following systemic administration.23–25”
From Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing (2024) · cites this paper as [25]
Cites
MicroRNA therapeutics: towards a new era for the management of cancer and other diseases
Rupaimoole, R., & Slack, F. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.246 · Cited by 4,741 · see citing works
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
mRNA-based therapeutics--developing a new class of drugs
Sahin, U., Karikó, K., & Türeci, Ö. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4278 · Cited by 2,474 · see citing works
The Effect of Nanoparticle Size on <i>In Vivo</i> Pharmacokinetics and Cellular Interaction
Hoshyar, N., Gray, S., Han, H., & Bao, G. (2016) · Nanomedicine · doi:10.2217/nnm.16.5 · Cited by 1,990 · see citing works
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822 · see citing works
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
Gillmore, J. D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M. L., Seitzer, J., O’Connell, D., Walsh, K. R., Wood, K., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2107454 · Cited by 1,766 · 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
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
An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma
Sahin, U., Oehm, P., Derhovanessian, E., Jabulowsky, R. A., Vormehr, M., Gold, M., Maurus, D., Schwarck-Kokarakis, D., Kuhn, A. N., Omokoko, T., et al. (2020) · Nature · doi:10.1038/s41586-020-2537-9 · Cited by 1,052 · 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
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
From Sewer to Saviour—Targeting the Lymphatic System to Promote Drug Exposure and Activity
Trevaskis, N. L., Kaminskas, L. M., & Porter, C. J. H. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4608 · Cited by 654 · see citing works
Liu, S., Cheng, Q., Wei, T., Yu, X., Johnson, L. T., Farbiak, L., & Siegwart, D. J. (2021) · Nature Materials · doi:10.1038/s41563-020-00886-0 · Cited by 653 · see citing works
Sebastiani, F., Yanez Arteta, M., Lerche, M., Porcar, L., Lang, C., Bragg, R. A., Elmore, C. S., Krishnamurthy, V. R., Russell, R. A., Darwish, T., et al. (2021) · ACS Nano · doi:10.1021/acsnano.0c10064 · Cited by 409 · see citing works
Selective targeting of bioactive compounds to mitochondria
Murphy, M. P. (1997) · Trends in Biotechnology · doi:10.1016/s0167-7799(97)01068-8 · Cited by 366 · see citing works
PNPASE Regulates RNA Import into Mitochondria
Wang, G., Chen, H.-W., Oktay, Y., Zhang, J., Allen, E. L., Smith, G. M., Fan, K. C., Hong, J. S., French, S. W., McCaffery, J. M., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.035 · Cited by 366 · 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
Delivery of CRISPR-Cas tools for in vivo genome editing therapy: Trends and challenges
Taha, E. A., Lee, J., & Hotta, A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.01.013 · Cited by 259 · see citing works
Abrams, M. T., Koser, M. L., Seitzer, J., Williams, S. C., DiPietro, M. A., Wang, W., Shaw, A. W., Mao, X., Jadhav, V., Davide, J. P., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2009.208 · Cited by 209 · 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
Loughrey, D., & Dahlman, J. E. (2022) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00601 · Cited by 173 · see citing works
Van der Jeught, K., De Koker, S., Bialkowski, L., Heirman, C., Tjok Joe, P., Perche, F., Maenhout, S., Bevers, S., Broos, K., Deswarte, K., et al. (2018) · ACS Nano · doi:10.1021/acsnano.8b00966 · Cited by 139 · see citing works
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Han, E. L., Padilla, M. S., Palanki, R., Kim, D., Mrksich, K., Li, J. J., Tang, S., Yoon, I.-C., & Mitchell, M. J. (2024) · Nano Letters · doi:10.1021/acs.nanolett.3c03509 · Cited by 72 · see citing works
Wang, K., Yang, R., Li, J., Wang, H., Wan, L., & He, J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1591438 · Cited by 27 · see citing works
- Authors
- Nakamura, T., Sato, Y., Yamada, Y., Abd Elwakil, M. M., Kimura, S., Younis, M. A., & Harashima, H.
- Affiliations
- Hokkaido University (JP)
- Corresponding author
- Harashima, Hideyoshi
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 188
- Pages
- 114417
- ISSN
- 0169-409X (ISSN-L)
- OpenAlex
- W4283802443
- Cited by
- 121
- References
- 22
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 47 · 2023: 26 · 2022: 7
- FWCI
- 2.71
- 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, 310 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
- Advanced Drug Delivery Reviews (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (JP17H05052, JP18K19888, JP18K19889, JP19H01170, JP20H03373, JP20H04523, JP21F21105)
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Science and Technology Agency
- Università degli Studi del Piemonte Orientale Amedeo Avogadro (21ak0101172h001)
- Fusion Oriented REsearch for disruptive Science and Technology (JPMJFR203X)
- Japan Agency for Medical Research and Development
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- lipid nanoparticles, nucleic acid delivery, gene therapy, siRNA, mRNA, plasmid DNA, genome editing, intracellular trafficking, passive targeting, active targeting, mitochondrial delivery, spleen, lung, tumors, lymph nodes, liver, heart, kidney, brain
- MeSH terms
- Humans, Liposomes, Nucleic Acids, Drug Delivery Systems, Nanomedicine, Nanoparticles
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