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Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics
Open accessAbstract
Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.
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“Strategies that have been applied for achieving functional siRNA delivery into the brain mainly rely on employing potent protein or peptide ligands to target the receptors, such as transferrin, insulin and LDL receptors, which are highly expressed on the blood brain barrier (BBB).[102]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [102]
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“Additionally, administration routes are also listed for demonstration of early developments, and ongoing clinical trials.(21,22)”
BackgroundLipid Nanoparticles for Cell-Specific in Vivo Targeted Delivery of Nucleic Acids
Khalil, I. A., Younis, M. A., Kimura, S., & Harashima, H. (2020) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b19-00743 · Cited by 68
Cancer Vaccine Immunotherapy with RNA-Loaded Liposomes
Sayour, E. J., Méndez‐Gómez, H. R., & Mitchell, D. A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102890 · Cited by 67
“In the systemic circulation, liposomes tend to localize to reticuloendothelial organs such as the liver and spleen, and while not ideal target sites for a drug or gene therapy, these are more optimal locations for a cancer vaccine to induce APC transfection and T cell priming [65].”
BackgroundRationally Designed Polycationic Carriers for Potent Polymeric siRNA-Mediated Gene Silencing
Wu, C., Li, J., Wang, W., & Hammond, P. T. (2018) · ACS Nano · doi:10.1021/acsnano.7b08777 · Cited by 65
Application of Non-Viral Vectors in Drug Delivery and Gene Therapy
Ren, S., Wang, M., Wang, C., Wang, Y., Sun, C., Zeng, Z., Cui, H., & Zhao, X. (2021) · Polymers · doi:10.3390/polym13193307 · Cited by 69
Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells
Childs‐Disney, J. L., & Disney, M. D. (2015) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103910 · Cited by 65
Connerty, P., Moles, E., de Bock, C. E., Jayatilleke, N., Smith, J. L., Meshinchi, S., Mayoh, C., Kavallaris, M., & Lock, R. B. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13101681 · Cited by 63
“While this provides excellent efficiency of cargo delivery to hepatic diseases, it limits the application of LNP-siRNA based therapies in other tissues [45].”
BackgroundRecent Update on siRNA Therapeutics
Ebenezer, O., Oyebamiji, A. K., Olanlokun, J. O., Tuszyński, J. A., & Wong, G. K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083456 · Cited by 71
“For example, the liver and kidneys often accumulate siRNAs from systemic administration, as these organs have a high uptake capacity for nucleic acids [61,62].”
Wang, Y., Newman, M. R., & Benoit, D. S. W. (2018) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2018.02.023 · Cited by 65
“While this is not favorable for some applications, it results in highly effective siRNA uptake in the liver, leading to several ongoing clinical trials [116].”
Joshi, U., Filipczak, N., Khan, M. M., Attia, S. A., & Torchilin, V. P. (2020) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2020.119915 · Cited by 62
Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models
Elks, P. M., Renshaw, S. A., Meijer, A. H., Walmsley, S. R., & van Eeden, F. J. (2015) · Disease Models & Mechanisms · doi:10.1242/dmm.021865 · Cited by 64
“Liposomes accumulate at high levels in the liver when administered systemically, potentially as a result of the liver vasculature having many dead ends (Lorenzer et al., 2015; Nair et al., 2014).”
BackgroundKim, J.-K., Chung, K., Choi, C., Beloor, J., Ullah, I., Kim, N., Lee, K. Y., Lee, S., & Kumar, P. (2016) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2015.51 · Cited by 58
Yanagi, T., Tachikawa, K., Wilkie-Grantham, R. P., Hishiki, A., Nagai, K., Toyonaga, E., Chivukula, P., & Matsuzawa, S. (2016) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2016.40 · Cited by 56
RNA therapeutics: Identification of novel targets leading to drug discovery
Qadir, M. I., Bukhat, S., Rasul, S., Manzoor, H., & Manzoor, M. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29364 · Cited by 57
“alteration,(70) and use of nanoparticle carriers for effective delivery.(71) Additionally, siRNA sequences can be optimized and bioconjugated.”
Dendrimer–siRNA Conjugates for Targeted Intracellular Delivery in Glioblastoma Animal Models
Liyanage, W., Wu, T., Kannan, S., & Kannan, R. M. (2022) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.2c13129 · Cited by 56
Camorani, S., Tortorella, S., Agnello, L., Spanu, C., d’Argenio, A., Nilo, R., Zannetti, A., Locatelli, E., Fedele, M., Franchini, M. C., et al. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14102225 · Cited by 56
“Advances in nanocarriers’ formulations have recently enabled several clinical trials in which siRNAs have been systemically administered to cancer patients [18].”
BackgroundGlycogen-nucleic acid constructs for gene silencing in multicellular tumor spheroids
Wojnilowicz, M., Besford, Q. A., Wu, Y., Loh, X. J., Braunger, J. A., Glab, A., Cortez‐Jugo, C., Caruso, F., & Cavalieri, F. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.05.024 · Cited by 53
Rossi, J. J., & Rossi, D. J. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.01.015 · Cited by 53
“Ultimately, a combination of methods to improve siRNA pharmacokinetics in plasma, increase endosomal escape, and enhance tissue-specific delivery will be required to target a broader array of diseases using siRNA technology, depending on the context of the target cell population.(7)”
BackgroundGangopadhyay, S., Nikam, R. R., & Gore, K. R. (2021) · Nucleic Acid Therapeutics · doi:10.1089/nat.2020.0882 · Cited by 53
“Polymeric nanoparticles such as chitosan (CS), dendrimers, cyclodextrin, and nanogels have been employed for siRNA delivery [68,110–113].”
An “eat me” combinatory nano-formulation for systemic immunotherapy of solid tumors
Abdel‐Bar, H. M., Walters, A. A., Lim, Y. M., Rouatbi, N., Qin, Y., Gheidari, F., Han, S., Osman, R., Wang, J. T.-W., & Al‐Jamal, K. T. (2021) · Theranostics · doi:10.7150/thno.56936 · Cited by 52
“Furthermore, as expected, the SNALPs were also accumulated in both liver and spleen as they are a part of the mononuclear phagocytic system as previously reported [22, 56-58].”
Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics
de Vyver, T. V., Smedt, S. C. D., & Raemdonck, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114041 · Cited by 51
Zeng, S., Chen, Y., Zhou, F., Zhang, T., Fan, X., Chrzanowski, W., Gillies, M. C., & Zhu, L. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114965 · Cited by 51
Cell Subtypes Within the Liver Microenvironment Differentially Interact with Lipid Nanoparticles
Sago, C. D., Krupczak, B. R., Lokugamage, M. P., Gan, Z., & Dahlman, J. E. (2019) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-019-00573-4 · Cited by 53
Polynucleotides in cellular mimics: Coacervates and lipid vesicles
Vieregg, J., & Tang, T. ‐. D. (2016) · Current Opinion in Colloid & Interface Science · doi:10.1016/j.cocis.2016.09.004 · Cited by 49
“[70] Lorenzer C, Dirin M, Winkler A-M, Baumann V, Winkler J.”
BackgroundMethodD’souza, A. A., Nozohouri, S., Bleier, B. S., & Amiji, M. M. (2022) · Pharmaceutical Research · doi:10.1007/s11095-022-03433-5 · Cited by 49
More than a delivery system: the evolving role of lipid-based nanoparticles
Karmaker, S., Rosales, P. D., Tirumuruhan, B., Viravalli, A., & Boehnke, N. (2025) · Nanoscale · doi:10.1039/d4nr04508d · Cited by 56
Optimal delivery of RNA interference by viral vectors for cancer therapy
Wong, B., Birtch, R., Rezaei, R., Jamieson, T. R., Crupi, M. J. F., Diallo, J., & Ilkow, C. S. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.09.012 · Cited by 47
Arnold, A. E., Czupiel, P., & Shoichet, M. S. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.02.019 · Cited by 46
“Since most nano-scale formulations naturally accumulate in the liver [61,62], many strategies deliver therapeutics against diseases of the liver [62,63].”
BackgroundModifying a Commonly Expressed Endocytic Receptor Retargets Nanoparticles in Vivo
Sago, C. D., Lokugamage, M. P., Lando, G. N., Djeddar, N., Shah, N. N., Syed, C., Bryksin, A. V., & Dahlman, J. E. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b03149 · Cited by 46
Metadata
- Authors
- Lorenzer, C., Dirin, M., Winkler, A.-M., Baumann, V., & Winkler, J.
- Affiliations
- University of Vienna (AT)
- Corresponding author
- Winkler, Johannes
- ORCID
- Winkler, Johannes
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 203
- Pages
- 1-15
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2019613864
- Cited by
- 284
- References
- 188
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 17 · 2023: 17 · 2022: 22 · 2021: 25 · 2020: 23 · 2019: 35 · 2018: 34 · 2017: 33 · 2016: 37 · 2015: 18
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Controlled Release (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- FWF (I519-B11)
- Innovative Medicines Initiative Joint Undertaking (115363)
- European Union's (FP7/2007–2013)
- EFPIA companies'
- 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 › Advanced Drug Delivery Systems
- Keywords
- siRNA therapeutics, targeted delivery, gene silencing, liposomes, nanoparticle drug delivery, tumor targeting, blood-brain barrier, transcytosis, cellular uptake, pharmacokinetics, oligonucleotide therapeutics, liver-targeted drug delivery
- MeSH terms
- RNAi Therapeutics, Animals, Blood-Brain Barrier, Endothelium, Humans, Leukocytes, Liposomes, Liver, Models, Molecular, Neoplasms, Drug Delivery Systems, Gene Transfer Techniques, RNA, Small Interfering, Nanoparticles
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