Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer, Cornelia; Dirin, Mehrdad; Winkler, Anna-Maria; Baumann, Volker; Winkler, Johannes

doi:10.1016/j.jconrel.2015.02.003

Cited by 284RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvanced Drug Delivery Systems

Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics

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Lorenzer, Cornelia, Dirin, Mehrdad, Winkler, Anna-Maria, Baumann, Volker, Winkler, Johannes·2015·Journal of Controlled Release

DOI 10.1016/j.jconrel.2015.02.003

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Abstract

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 for functional siRNA delivery into the brain mainly rely on protein or peptide ligands targeting receptors such as transferrin, insulin and LDL receptors, which are highly expressed on the blood brain barrier.
“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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Intravenous RNA Interference Gene Therapy Targeting the Human Epidermal Growth Factor Receptor Prolongs Survival in Intracranial Brain Cancer
Zhang, Y., Zhang, Y., Bryant, J., Charles, A. C., Boado, R. J., & Pardridge, W. M. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0740 · Cited by 330 · see citing works
Rabies virus receptors
Lafon, M. (2005) · Journal of NeuroVirology · doi:10.1080/13550280590900427 · Cited by 328 · see citing works
Efficient In Vivo Delivery of siRNA to the Liver by Conjugation of α-Tocopherol
Nishina, K., Unno, T., Uno, Y., Kubodera, T., Kanouchi, T., Mizusawa, H., & Yokota, T. (2008) · Molecular Therapy · doi:10.1038/mt.2008.14 · Cited by 312 · cited 1× · see citing works
“Several ligands have been used to further increase hepatic accumulation and uptake, including lipids [181], steroids [182], tocopherol [183], and carbohydrates [184] (Figure 2).”
Method
Biological Barriers to Therapy with Antisense and siRNA Oligonucleotides
Juliano, R. L., Bauman, J. A., Kang, H. M., & Ming, X. (2009) · Molecular Pharmaceutics · doi:10.1021/mp900093r · Cited by 306 · see citing works
Discovering the first microRNA-targeted drug
Lindow, M., & Kauppinen, S. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201208082 · Cited by 304 · cited 1× · see citing works
“Depending on their mechanism of action, therapeutic oligonucleotides are categorized into several classes: Antisense [6,7], aptamers [8], splice correcting oligonucleotide [9,10], siRNA [1], miRNA mimics and antagonists [11], immunomodulating agents [12] and decoys [13] are themost important ones.”
Background
Mutant KRAS is a druggable target for pancreatic cancer
Zorde Khvalevsky, E., Gabai, R., Rachmut, I. H., Horwitz, E., Brunschwig, Z., Orbach, A., Shemi, A., Golan, T., Domb, A. J., Yavin, E., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314307110 · Cited by 295 · cited 1× · see citing works
“adenocarcinoma Silenseed Phase I/II [66]”
Quantum-dot based nanoparticles for targeted silencing of HER2/neu gene via RNA interference
Tan, W. B., Jiang, S., & Zhang, Y. (2006) · Biomaterials · doi:10.1016/j.biomaterials.2006.11.018 · Cited by 294 · cited 2× · see citing works
“For siRNA delivery, frequently targeted receptors include Her2 [132], the epidermal growth factor receptor EGFR [133], and the epithelial cell adhesion molecule EpCAM [134].”
Background
Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression
Aleku, M., Schulz, P. M., Keil, O., Santel, A., Schaeper, U., Dieckhoff, B., Janke, O., Endruschat, J., Durieux, B., Röder, N., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-2428 · Cited by 293 · see citing works
Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection
Wooddell, C. I., Rozema, D. B., Hoßbach, M., John, M., Hamilton, H., Chu, Q., Hegge, J., Klein, J. J., Wakefield, D. H., Oropeza, C. E., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.31 · Cited by 291 · see citing works
Action and Reaction: The Biological Response to siRNA and Its Delivery Vehicles
Kanasty, R. L., Whitehead, K. A., Vegas, A. J., & Anderson, D. G. (2012) · Molecular Therapy · doi:10.1038/mt.2011.294 · Cited by 281 · cited 1× · see citing works
“In organs, the compounds need to extravasate from the blood vessels to the interstitium, overcoming the endothelial barrier [71].”
Background
Brain-targeting gene delivery and cellular internalization mechanisms for modified rabies virus glycoprotein RVG29 nanoparticles
Liu, Y., Huang, R., Han, L., Ke, W., Shao, K., Ye, L., Lou, J., & Jiang, C. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.02.051 · Cited by 281 · cited 5× · see citing works
“When attached to highly charged, spherical PAMAM dendrimers, RVG greatly increased brain accumulation compared to untargeted PAMAM [117].”
BackgroundMethodInfluential
RNAi and small interfering RNAs in human disease therapeutic applications
Lares, M. R., Rossi, J. J., & Ouellet, D. L. (2010) · Trends in biotechnology · doi:10.1016/j.tibtech.2010.07.009 · Cited by 277 · cited 1× · see citing works
“The concept of RNA interference remains to be hugely promising for therapeutic purposes [1–5].”
Background
Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1
Peer, D., Zhu, P., Carman, C. V., Lieberman, J., & Shimaoka, M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608491104 · Cited by 276 · cited 4× · see citing works
“75NTR are possible targets − Peptide/siRNA complexes [113] − Polyethyleneimine complexes [115] − Liposomes [116] − PAMAM nanoparticles [117] − Targeted exosomes [114] − Protamine-antibody/siRNA complexes [126] − Liposomes [127] − Polythyleneimine complexes [135–137] − PEG–siRNA conjugate [138] − Self-assembled nanopar…”
BackgroundMethodInfluential
Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier
Couch, J. A., Yu, Y. J., Zhang, Y., Tarrant, J. M., Fuji, R. N., Meilandt, W. J., Solanoy, H. O., Tong, R. K., Hoyte, K., Luk, W., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005338 · Cited by 270 · cited 2× · see citing works
“A ligandwith lower affinity was transported into the brain to a higher extent, obviously by avoiding lysosomal degradation [109].”
Background
First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder
Leachman, S. A., Hickerson, R. P., Schwartz, M. E., Bullough, E. E., Hutcherson, S. L., Boucher, K. M., Hansen, C. D., Eliason, M. J., Srivatsa, G. S., Kornbrust, D. J., et al. (2009) · Molecular Therapy · doi:10.1038/mt.2009.273 · Cited by 263 · cited 1× · see citing works
“completed [61]”
Lipid-Based Nanoparticles for siRNA Delivery in Cancer Therapy: Paradigms and Challenges
Gomes-da-Silva, L. C., Fonseca, N. A., Moura, V., de Lima, M. C. P., Simões, S., & Moreira, J. N. (2012) · Accounts of Chemical Research · doi:10.1021/ar300048p · Cited by 254 · see citing works
Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates
Straarup, E. M., Fisker, N., Hedtjärn, M., Lindholm, M., Rosenbohm, C., Aarup, V., Hansen, H. F., Ørum, H., Hansen, J. B., & Koch, T. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq457 · Cited by 248 · cited 1× · see citing works
“Modifications on the ribose (2′-methyl, methoxyethyl and other alkyl chains, as well as locked nucleic acids (LNA)) [23,24] aptly increase enzymatic stability, but are only efficacious in combination with at least a partial phosphorothioate backbone, which is necessary for protein binding and thus a certain amount of…”
Background
Clathrin-independent endocytosis: mechanisms and function
Sandvig, K., Pust, S., Skotland, T., & van Deurs, B. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2011.03.007 · Cited by 240 · see citing works
PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation
Ezzat, K., Andaloussi, S. E., Zaghloul, E. M., Lehto, T., Lindberg, S., Moreno, P. M. D., Viola, J. R., Magdy, T., Abdo, R., Guterstam, P., et al. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr072 · Cited by 236 · see citing works
A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA
Hwang, D. W., Son, S., Jang, J., Youn, H., Lee, S., Lee, D., Lee, Y., Jeong, J. M., Kim, W. J., & Lee, D. S. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.03.047 · Cited by 235 · see citing works
Randomized, Placebo-Controlled Trial of Mipomersen in Patients with Severe Hypercholesterolemia Receiving Maximally Tolerated Lipid-Lowering Therapy
McGowan, M. P., Tardif, J., Češka, R., Burgess, L. J., Soran, H., Gouni‐Berthold, I., Wagener, G., & Chasan-Taber, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049006 · Cited by 222 · see citing works
Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA
Singh, S. P., Narang, A. S., & Mahato, R. I. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0608-1 · Cited by 221 · see citing works
Cell-penetrating Peptides as Versatile Vehicles for Oligonucleotide Delivery
Margus, H., Padari, K., & Pooga, M. (2012) · Molecular Therapy · doi:10.1038/mt.2011.284 · Cited by 215 · cited 1× · see citing works
“Many excellent and detailed reviews have been written on this topic [70,88,164–170].”
Background
Pulmonary delivery of therapeutic siRNA
Lam, J., Liang, W., & Chan, H. (2011) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2011.02.006 · Cited by 214 · cited 2× · see citing works
“), and inorganic carriers (calcium phosphate, mesoporous silica particles) have been employed [74].”
Background
CLINICAL TRIALS AND TRANSLATIONAL MEDICINE COMMENTARY: Drug Delivery Trends in Clinical Trials and Translational Medicine: Challenges and Opportunities in the Delivery of Nucleic Acid-Based Therapeutics
Xu, L., & Anchordoquy, T. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22243 · Cited by 209 · cited 1× · see citing works
“Many excellent and detailed reviews have been written on this topic [70,88,164–170].”
Background
Exploring Chemical Modifications for siRNA Therapeutics: A Structural and Functional Outlook
Shukla, S., Sumaria, C. S., & Pradeepkumar, P. I. (2009) · ChemMedChem · doi:10.1002/cmdc.200900444 · Cited by 208 · cited 2× · see citing works
“Both sequence-specific and sequence-unspecific off-target effects are well-documented [19,52–54].”
Background
Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges
Zhou, J., Shum, K., Burnett, J., & Rossi, J. J. (2013) · Pharmaceuticals · doi:10.3390/ph6010085 · Cited by 206 · cited 1× · see citing works
“Many excellent and detailed reviews have been written on this topic [70,88,164–170].”
Background
Tumor angiogenic vasculature targeting with PAMAM dendrimer–RGD conjugates
Shukla, R., Thomas, T. P., Peters, J. L., Kotlyar, A., Myc, A., & Baker, J. R. (2005) · Chemical Communications · doi:10.1039/b507350b · Cited by 205 · cited 1× · see citing works
“RGD peptides were also attached to the surface of PAMAM dendrimers [129,130].”
Background
Polyethylenimines for siRNA and miRNA delivery in vivo
Höbel, S., & Aigner, A. M. (2013) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1228 · Cited by 201 · see citing works
Unexpected origins of the enhanced pairing affinity of 2′-fluoro-modified RNA
Pallan, P. S., Greene, E. M., Jicman, P. A., Pandey, R. K., Manoharan, M., Rozners, E., & Egli, M. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq1270 · Cited by 199 · cited 1× · see citing works
“Rapid renal filtration and elimination are not avoided [33–36].”
Background
Polymers in Small-Interfering RNA Delivery
Singha, K., Namgung, R., & Kim, W. J. (2011) · Nucleic Acid Therapeutics · doi:10.1089/nat.2011.0293 · Cited by 198 · cited 1× · see citing works
“Many excellent and detailed reviews have been written on this topic [70,88,164–170].”
Background
Lipid nanoparticle delivery systems for siRNA-based therapeutics
Wan, C. P. L., Allen, T. M., & Cullis, P. R. (2013) · Drug Delivery and Translational Research · doi:10.1007/s13346-013-0161-z · Cited by 194 · cited 1× · see citing works
“Liver cancer Tekmira Pharmaceuticals Phase I/II [67]”
Unique Gene‐Silencing and Structural Properties of 2′‐Fluoro‐Modified siRNAs
Manoharan, M., Akinc, A., Pandey, R. K., Qin, J., Hadwiger, P., John, M., Mills, K., Charissé, K., Maier, M. A., Nechev, L. V., et al. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201006519 · Cited by 194 · cited 2× · see citing works
“Rapid renal filtration and elimination are not avoided [33–36].”
Background
Cellular Uptake and Intracellular Trafficking of Antisense and siRNA Oligonucleotides
Juliano, R. L., Ming, X., & Nakagawa, O. (2011) · Bioconjugate Chemistry · doi:10.1021/bc200377d · Cited by 193 · cited 1× · see citing works
“There are several pathways of endocytosis, the clathrin-coated pit pathway, the caveolar-dependent uptake, clathrin- and caveolinindependent pathways, and macropinocytosis [90–93].”
Background
Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial
Visser, M. E., Wagener, G., Baker, B. F., Geary, R. S., Donovan, J. M., Beuers, U. H., Nederveen, A. J., Verheij, J., Trip, M. D., Basart, D. C. G., et al. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehs023 · Cited by 191 · see citing works
Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2 + Breast Cancer Growth and Metastasis
Yao, Y., Sun, T., Huang, S., Dou, S., Lin, L., Chen, J.-N., Ruan, J.-B., Mao, C., Yu, F., Zeng, M., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003601 · Cited by 189 · see citing works
Comparison of five different targeting ligands to enhance accumulation of liposomes into the brain
van Rooy, I., Mastrobattista, E., Storm, G., Hennink, W. E., & Schiffelers, R. M. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.11.014 · Cited by 188 · see citing works
Solid-Phase Synthesis of Oligonucleotide Conjugates Useful for Delivery and Targeting of Potential Nucleic Acid Therapeutics
Lönnberg, H. (2009) · Bioconjugate Chemistry · doi:10.1021/bc800406a · Cited by 188 · cited 1× · see citing works
“Because of differing synthesis procedures and requirements for protecting groups, the latter approach is more complicated, especially when the peptide exceeds the length of a few amino acids [185].”
Background
CD44 is the Principal Mediator of Hyaluronic-Acid-Induced Melanoma Cell Proliferation
Assmann, V., Fieber, C., Herrlich, P., Hofmann‐Apitius, M., Termeer, C., Ahrens, T., & Simon, J. C. (2001) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2001.00236.x · Cited by 186 · cited 2× · see citing works
“Thismacromolecule is a ligand for CD44,which is overexpressed inmany tumors [140].”
Background
The asialoglycoprotein receptor clears glycoconjugates terminating with sialic acidα2,6GalNAc
Park, E. I., Mi, Y., Unverzagt, C., Gabius, H., & Baenziger, J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508537102 · Cited by 170 · see citing works
Antibody-drug conjugates
Beck, A., & Reichert, J. M. (2013) · mAbs · doi:10.4161/mabs.27436 · Cited by 156 · see citing works
Antisense Drug Discovery and Development
Yamamoto, T., Nakatani, M., Narukawa, K., & Obika, S. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.11.2 · Cited by 155 · cited 1× · see citing works
“Depending on their mechanism of action, therapeutic oligonucleotides are categorized into several classes: Antisense [6,7], aptamers [8], splice correcting oligonucleotide [9,10], siRNA [1], miRNA mimics and antagonists [11], immunomodulating agents [12] and decoys [13] are themost important ones.”
Background
Oligonucleotide Conjugates for Therapeutic Applications
Winkler, J. (2013) · Therapeutic Delivery · doi:10.4155/tde.13.47 · Cited by 149 · cited 2× · see citing works
“Smallmolecule ligands can be conjugatedwith relative ease to either the 3′ or the 5′-end of the sense or antisense strand of the siRNA via appropriate linkers that are incorporated during automated oligonucleotide synthesis [37].”
Background
PAMAM-RGD Conjugates Enhance siRNA Delivery Through a Multicellular Spheroid Model of Malignant Glioma
Waite, C. L., & Roth, C. M. (2009) · Bioconjugate Chemistry · doi:10.1021/bc900228m · Cited by 148 · cited 2× · see citing works
“RGD peptides were also attached to the surface of PAMAM dendrimers [129,130].”
Background
Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor
Khorev, O., Stokmaier, D., Schwardt, O., Cutting, B., & Ernst, B. (2008) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.03.017 · Cited by 147 · see citing works
Small interfering RNAs containing full 2′- O -methylribonucleotide-modified sense strands display Argonaute2/eIF2C2-dependent activity
Kraynack, B. A., & Baker, B. F. (2005) · RNA · doi:10.1261/rna.2150806 · Cited by 141 · see citing works
Extravasation of macromolecules
Takakura, Y., Mahato, R. I., & Hashida, M. (1998) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(98)00006-4 · Cited by 134 · cited 1× · see citing works
“The endothelial barrier determines distribution into organs [81].”
Background
Supramolecular assemblies in functional siRNA delivery: Where do we stand?
Aliabadi, H. M., Landry, B. K., Sun, C., Tang, T., & Uludağ, H. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.11.079 · Cited by 133 · see citing works
Prolongation of Life in Rats with Malignant Glioma by Intranasal siRNA/Drug Codelivery to the Brain with Cell-Penetrating Peptide-Modified Micelles
Kanazawa, T., Morisaki, K., Suzuki, S., & Takashima, Y. (2014) · Molecular Pharmaceutics · doi:10.1021/mp400644e · Cited by 133 · cited 1× · see citing works
“Besides intravenous injections, application routes to the blood stream include subcutaneous injection, delivery through the skin, lung [74], or nasal mucosa [75].”
Background
siRNA Delivery to the lung: What's new?
Merkel, O. M., Rubinstein, I., & Kissel, T. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.05.018 · Cited by 132 · see citing works
Safety profile of RNAi nanomedicines
Barros, S. A., & Gollob, J. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.06.007 · Cited by 126 · cited 1× · see citing works
“Furthermore, comprehensive drug safety assessments will have implications for the whole class of siRNA therapeutics [49,50].”
Background
The Chemistry and Biology of Oligonucleotide Conjugates
Juliano, R. L., Ming, X., & Nakagawa, O. (2012) · Accounts of Chemical Research · doi:10.1021/ar2002123 · Cited by 125 · cited 1× · see citing works
“Several ligands have been used to further increase hepatic accumulation and uptake, including lipids [181], steroids [182], tocopherol [183], and carbohydrates [184] (Figure 2).”
Method
Multivalent Cyclic RGD Conjugates for Targeted Delivery of Small Interfering RNA
Alam, M. R., Ming, X., Fisher, M. H., Lackey, J. G., Rajeev, K. G., Manoharan, M., & Juliano, R. L. (2011) · Bioconjugate Chemistry · doi:10.1021/bc200235q · Cited by 124 · cited 1× · see citing works
“The cyclic RGD peptide has been attached to siRNA for specific targeting of αvβ3 integrin-positive cells [131].”
Background
RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system
Sakurai, Y., Hatakeyama, H., Sato, Y., Hyodo, M., Akita, H., Ohga, N., Hida, K., & Harashima, H. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.10.003 · Cited by 124 · cited 1× · see citing works
“The increased expression ofαVβ3 integrin on tumor endothelial cells was exploited for delivery of siRNA through a cationic lipid systemwith cyclic RGD grafted onto its surface [128].”
Background
Gene silencing following siRNA delivery to skin via coated steel microneedles: In vitro and in vivo proof-of-concept
Chong, R. H. E., González-González, E., Lara, M. F., Speaker, T. J., Contag, C. H., Kaspar, R. L., Coulman, S. A., Hargest, R., & Birchall, J. C. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.12.030 · Cited by 122 · cited 1× · see citing works
“Therapeutic siRNAs can be coated onto those stainless steel needles, or injected with microneedle devices [76,77].”
Background
Brothers in Arms
Bhindi, R., Fahmy, R. G., Lowe, H. C., Chesterman, C. N., Dass, C. R., Cairns, M. J., Saravolac, E. G., Sun, L., & Khachigian, L. M. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070120 · Cited by 119 · see citing works
Targeted Intracellular Delivery of Antisense Oligonucleotides via Conjugation with Small-Molecule Ligands
Nakagawa, O., Ming, X., Huang, L., & Juliano, R. L. (2010) · Journal of the American Chemical Society · doi:10.1021/ja102635c · Cited by 119 · see citing works
Bevasiranib for the Treatment of Wet, Age-Related Macular Degeneration
Garba, A. O., & Mousa, S. A. (2010) · Ophthalmology and Eye Diseases · doi:10.4137/oed.s4878 · Cited by 118 · see citing works
Designed Ankyrin Repeat Proteins (DARPins)
Tamaskovic, R., Simon, M., Stefan, N., Schwill, M., & Plückthun, A. (2012) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-396962-0.00005-7 · Cited by 117 · cited 1× · see citing works
“Oligonucleotides can be site-specifically attached to protein binders such as affibodies [161], anticalins [162], or DARPins [154,163].”
Background
Defined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing
Dohmen, C., Fröhlich, T., Lächelt, U., Röhl, I., Vornlocher, H., Hadwiger, P., & Wagner, E. (2012) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2011.10 · Cited by 117 · see citing works
Liver as a target for oligonucleotide therapeutics
Sehgal, A., Vaishnaw, A. K., & Fitzgerald, K. J. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.05.045 · Cited by 115 · cited 1× · see citing works
“It is no surprise that all these clinically evaluated siRNA and miRNA drugs, as well asmany antisense agents, are tested for the antagonization of liver targets [48].”
Background
Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer
Landen, C. N., Merritt, W. M., Mangala, L. S., Sanguino, A. M., Bucana, C. D., Lü, C., Lin, Y. G., Han, L. Y., Kamat, A. A., Schmandt, R. E., et al. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.12.3468 · Cited by 115 · cited 1× · see citing works
“Center Phase I [60]”
Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides
Dirin, M., & Winkler, J. (2013) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2013.774366 · Cited by 115 · cited 4× · see citing works
“Standard single and double stranded oligonucleotides (and their metabolites) fail to reach this limit, but increasing the molecular size by either attachment of ligands such as polyethylene glycol (PEG), incorporation into larger particles or significant binding to plasma proteins efficiently saves siRNA from eliminat…”
BackgroundInfluential
Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells
Dufès, C., Al Robaian, M., & Somani, S. (2013) · Therapeutic Delivery · doi:10.4155/tde.13.21 · Cited by 110 · cited 2× · see citing works
“Transferrin receptor targeted delivery has shown some success for protein and drug uptake into the brain [102,106] but in other cases, trapping in the brain microvasculature has been reported [107,108].”
Background
Lipid Envelope-Type Nanoparticle Incorporating a Multifunctional Peptide for Systemic siRNA Delivery to the Pulmonary Endothelium
Kusumoto, K., Akita, H., Ishitsuka, T., Matsumoto, Y., Nomoto, T., Furukawa, R., El‐Sayed, A., Hatakeyama, H., Kajimoto, K., Yamada, Y., et al. (2013) · ACS Nano · doi:10.1021/nn401317t · Cited by 108 · cited 2× · see citing works
“Based on disease areas with unmet medical need, functional siRNA delivery into tumors [100], the brain [101], and endothelium [99] is especially attractive.”
Background
Anticalins
Gebauer, M., & Skerra, A. (2012) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-396962-0.00007-0 · Cited by 105 · see citing works
Novel protein scaffolds as emerging therapeutic proteins: from discovery to clinical proof-of-concept
Wurch, T., Pierré, A., & Depil, S. (2012) · Trends in biotechnology · doi:10.1016/j.tibtech.2012.07.006 · Cited by 102 · cited 1× · see citing works
“Instead of antibody fragments, alternative protein binder scaffolds offer easier production, higher stability, andmore facile derivatization [153].”
Background
Co-Injection of a Targeted, Reversibly Masked Endosomolytic Polymer Dramatically Improves the Efficacy of Cholesterol-Conjugated Small Interfering RNAs In Vivo
Wong, S. C., Klein, J. J., Hamilton, H., Chu, Q., Frey, C. L., Trubetskoy, V. S., Hegge, J., Wakefield, D. H., Rozema, D. B., & Lewis, D. L. (2012) · Nucleic Acid Therapeutics · doi:10.1089/nat.2012.0389 · Cited by 101 · see citing works
Optimized siRNA-PEG Conjugates for Extended Blood Circulation and Reduced Urine Excretion in Mice
Iversen, F., Yang, C., Dagnæs‐Hansen, F., Schaffert, D., Kjems, J., & Gao, S. (2013) · Theranostics · doi:10.7150/thno.5743 · Cited by 98 · cited 1× · see citing works
“This can be avoided by increasing the molecular size, for example by PEGylation [178–180].”
Background
A Locked Nucleic Acid Oligonucleotide Targeting MicroRNA 122 Is Well-Tolerated in Cynomolgus Monkeys
Hildebrandt-Eriksen, E. S., Aarup, V., Persson, R., Hansen, H. F., Munk, M. E., & Ørum, H. (2012) · Nucleic Acid Therapeutics · doi:10.1089/nat.2011.0332 · Cited by 97 · cited 1× · see citing works
“Modifications on the ribose (2′-methyl, methoxyethyl and other alkyl chains, as well as locked nucleic acids (LNA)) [23,24] aptly increase enzymatic stability, but are only efficacious in combination with at least a partial phosphorothioate backbone, which is necessary for protein binding and thus a certain amount of…”
Background
Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC
Fehring, V., Schaeper, U., Ahrens, K., Santel, A., Keil, O., Eisermann, M., Giese, K., & Kaufmann, J. (2014) · Molecular Therapy · doi:10.1038/mt.2013.291 · Cited by 97 · cited 1× · see citing works
“2 Lung indications Silence Therapeutics Phase I [63]”
Background
Off‐Target Effects Related to the Phosphorothioate Modification of Nucleic Acids
Winkler, J., Stessl, M., Amartey, J., & Noe, C. R. (2010) · ChemMedChem · doi:10.1002/cmdc.201000156 · Cited by 96 · cited 2× · see citing works
“Both sequence-specific and sequence-unspecific off-target effects are well-documented [19,52–54].”
Background
EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins
Winkler, J., Martin-Killias, P., Plückthun, A., & Zangemeister‐Wittke, U. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0402 · Cited by 93 · see citing works
Epithelial cell adhesion molecule-targeted drug delivery for cancer therapy
Simon, M., Stefan, N., Plückthun, A., & Zangemeister‐Wittke, U. (2013) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2013.759938 · Cited by 91 · cited 1× · see citing works
“For siRNA delivery, frequently targeted receptors include Her2 [132], the epidermal growth factor receptor EGFR [133], and the epithelial cell adhesion molecule EpCAM [134].”
Background
Technology evaluation: fomivirsen, Isis Pharmaceuticals Inc/CIBA vision.
Orr, R. M. (2001) · PubMed · Cited by 88 · see citing works
Toxicological and Pharmacokinetic Properties of QPI-1007, a Chemically Modified Synthetic siRNA Targeting Caspase 2 mRNA, Following Intravitreal Injection
Solano, E. C. R., Kornbrust, D. J., Beaudry, A. A., Foy, J. W.-D., Schneider, D. J., & Thompson, J. D. (2014) · Nucleic Acid Therapeutics · doi:10.1089/nat.2014.0489 · Cited by 87 · see citing works
Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides
White, P. J., Anastasopoulos, F., Pouton, C. W., & Boyd, B. J. (2009) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399409001021 · Cited by 87 · cited 1× · see citing works
“Generally, particles above around 200 nm are rapidly cleared by phagocytic cells mainly found in the liver and spleen [80].”
Background
Blood–brain Barrier Transport of Non-viral Gene and RNAi Therapeutics
Boado, R. J. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9321-5 · Cited by 85 · cited 2× · see citing works
“Other targets that have been used for BBB-targeting of siRNA include the insulin receptor [104], and the LDL receptor [105].”
BackgroundMethod
Uptake, Efficacy, and Systemic Distribution of Naked, Inhaled Short Interfering RNA (siRNA) and Locked Nucleic Acid (LNA) Antisense
Moschos, S. A., Frick, M., Taylor, B., Turnpenny, P., Graves, H., Spink, K. G., Brady, K., Lamb, D., Collins, D., Rockel, T. D., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2011.206 · Cited by 84 · see citing works
A Myristoylated Cell-Penetrating Peptide Bearing a Transferrin Receptor-Targeting Sequence for Neuro-Targeted siRNA Delivery
Youn, P., Chen, Y., & Furgeson, D. Y. (2014) · Molecular Pharmaceutics · doi:10.1021/mp400446v · Cited by 82 · cited 2× · see citing works
“− Liposomes [110] − Peptide/siRNA complexes [112]”
Background
Click-Modified Anandamide siRNA Enables Delivery and Gene Silencing in Neuronal and Immune Cells
Willibald, J., Harder, J., Sparrer, K. M. J., Conzelmann, K., & Carell, T. (2012) · Journal of the American Chemical Society · doi:10.1021/ja303251f · Cited by 82 · cited 2× · see citing works
“75NTR are possible targets − Peptide/siRNA complexes [113] − Polyethyleneimine complexes [115] − Liposomes [116] − PAMAM nanoparticles [117] − Targeted exosomes [114] − Protamine-antibody/siRNA complexes [126] − Liposomes [127] − Polythyleneimine complexes [135–137] − PEG–siRNA conjugate [138] − Self-assembled nanopar…”
Background
Therapeutic Applications of Synthetic CpG Oligodeoxynucleotides as TLR9 Agonists for Immune Modulation
Jurk, M., & Vollmer, J. (2007) · BioDrugs · doi:10.2165/00063030-200721060-00006 · Cited by 81 · cited 1× · see citing works
“Depending on their mechanism of action, therapeutic oligonucleotides are categorized into several classes: Antisense [6,7], aptamers [8], splice correcting oligonucleotide [9,10], siRNA [1], miRNA mimics and antagonists [11], immunomodulating agents [12] and decoys [13] are themost important ones.”
Background
Receptors, endocytosis, and trafficking: the biological basis of targeted delivery of antisense and siRNA oligonucleotides
Juliano, R. L., Carver, K. A., Cao, C., & Ming, X. (2012) · Journal of drug targeting · doi:10.3109/1061186x.2012.740674 · Cited by 79 · see citing works
Novel Hydrophobically Modified Asymmetric RNAi Compounds (sd-rxRNA) Demonstrate Robust Efficacy in the Eye
Byrne, M., Tzekov, R. T., Wang, Y., Rodgers, A., Cardia, J. P., Ford, G., Holton, K., Pandarinathan, L., Lapierre, J., Stanney, W., et al. (2013) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2013.0148 · Cited by 78 · cited 1× · see citing works
“surgery RXi Pharmaceuticals Phase II [57]”
Nano-enabled delivery systems across the blood–brain barrier
Hwang, S. R., & Kim, K. (2013) · Archives of Pharmacal Research · doi:10.1007/s12272-013-0272-6 · Cited by 75 · cited 1× · see citing works
“For therapeutic purposes, only highly lipophilic molecules with a molecular weight under 400 Da or those with an active transport system can access the brain [87].”
Background
Engineered Proteinticles for Targeted Delivery of siRNA to Cancer Cells
Lee, E. J., Lee, S. J., Kang, Y.-S., Ryu, J. H., Kwon, K. C., Jo, E., Yhee, J. Y., Kwon, I. C., Kim, K., & Lee, J. (2015) · Advanced Functional Materials · doi:10.1002/adfm.201403680 · Cited by 75 · cited 2× · see citing works
“A fusion protein with an oligonucleotide complexing domain, a cell-penetrating peptide, and a targeting peptidewas recently developed for tumor-specific delivery of siRNA [156].”
Background
Efficient targeted pDNA/siRNA delivery with folate–low-molecular-weight polyethyleneimine–modified pullulan as non-viral carrier
Wang, J., Dou, B., & Bao, Y. (2013) · Materials Science and Engineering C · doi:10.1016/j.msec.2013.08.035 · Cited by 72 · see citing works
New links between vesicle coats and Rab-mediated vesicle targeting
Angers, C. G., & Merz, A. J. (2010) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2010.07.003 · Cited by 72 · cited 1× · see citing works
“The Rab family, especially Rab5, is a key regulatory component for this process and, together with other coating proteins, decisive for selection of the targeted cell compartment [95].”
Background
The emerging role of new protein scaffold-based agents for treatment of cancer.
Weidle, U. H., Auer, J., Brinkmann, U., Georges, G. J., & Tiefenthaler, G. (2013) · PubMed · Cited by 72 · see citing works
Efficient In Vivo Delivery of siRNA Into Brain Capillary Endothelial Cells Along With Endogenous Lipoprotein
Kuwahara, H., Nishina, K., Yoshida, K., Nishina, T., Yamamoto, M., Saito, Y., Piao, W., Yoshida, M., Mizusawa, H., & Yokota, T. (2011) · Molecular Therapy · doi:10.1038/mt.2011.186 · Cited by 71 · cited 1× · see citing works
“Other targets that have been used for BBB-targeting of siRNA include the insulin receptor [104], and the LDL receptor [105].”
Background
In Vivo Labeling of Brain Capillary Endothelial Cells after Intravenous Injection of Monoclonal Antibodies Targeting the Transferrin Receptor
Paris‐Robidas, S., Émond, V., Tremblay, C., Soulet, D., & Calon, F. (2011) · Molecular Pharmacology · doi:10.1124/mol.111.071027 · Cited by 69 · cited 1× · see citing works
“Transferrin receptor targeted delivery has shown some success for protein and drug uptake into the brain [102,106] but in other cases, trapping in the brain microvasculature has been reported [107,108].”
Background
Bioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting
Yoon, H. Y., Kim, H. R., Saravanakumar, G., Heo, R., Chae, S. Y., Um, W., Kim, K., Kwon, I. C., Lee, J. Y., Lee, D. S., et al. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.09.008 · Cited by 68 · see citing works
Mad2 Checkpoint Gene Silencing Using Epidermal Growth Factor Receptor-Targeted Chitosan Nanoparticles in Non-Small Cell Lung Cancer Model
Nascimento, A. V., Singh, A., Bousbaa, H., Ferreira, D., Sarmento, B. F. C. C., & Amiji, M. M. (2014) · Molecular Pharmaceutics · doi:10.1021/mp5002894 · Cited by 68 · cited 2× · see citing works
“For siRNA delivery, frequently targeted receptors include Her2 [132], the epidermal growth factor receptor EGFR [133], and the epithelial cell adhesion molecule EpCAM [134].”
Background
Cyclodextrin-Containing Polymers: Versatile Platforms of Drug Delivery Materials
Heidel, J. D., & Schluep, T. (2012) · Journal of Drug Delivery · doi:10.1155/2012/262731 · Cited by 65 · cited 1× · see citing works
“completed [59]”
The Therapeutic Potential of LNA-modified siRNAs: Reduction of Off-target Effects by Chemical Modification of the siRNA Sequence
Fluiter, K., Mook, O. R. F., & Baas, F. (2008) · Methods in molecular biology · doi:10.1007/978-1-60327-547-7_9 · Cited by 62 · cited 1× · see citing works
“Rapid renal filtration and elimination are not avoided [33–36].”
Background
Mipomersen
Ricotta, D. N., & Frishman, W. H. (2012) · Cardiology in Review · doi:10.1097/crd.0b013e31823424be · Cited by 59 · cited 1× · see citing works
“Mipomersen inhibits the transcription of apolipoprotein B 100 and reduces blood levels of cholesterol, LDL-C, and apolipoprotein B [16].”
Background
Low-weight polyethylenimine cross-linked 2-hydroxypopyl-ß-cyclodextrin and folic acid as an efficient and nontoxic siRNA carrier for gene silencing and tumor inhibition by VEGF siRNA
Li, J., Ji, Mao, Z., Wang, Zhang, W., & Su, H. (2013) · International Journal of Nanomedicine · doi:10.2147/ijn.s42440 · Cited by 59 · see citing works
Knockdown of β-catenin with Dicer-Substrate siRNAs Reduces Liver Tumor Burden In vivo
Dudek, H., Wong, D. H., Arvan, R., Shah, A., Wortham, K. A., Ying, B., Diwanji, R., Zhou, W. L., Holmes, B. R., Yang, H., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.233 · Cited by 56 · see citing works
Protein-resistant, reductively dissociable polyplexes for in vivo systemic delivery and tumor-targeting of siRNA
Kim, J. S., Oh, M. H., Park, J. Y., Park, T. G., & Nam, Y. S. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2012.12.004 · Cited by 53 · see citing works
Developing microRNA Therapeutics: Approaching the Unique Complexities
Jackson, A. L., & Levin, A. A. (2012) · Nucleic Acid Therapeutics · doi:10.1089/nat.2012.0356 · Cited by 52 · cited 1× · see citing works
“The recently expanding knowledge about microRNAs (miRNA) has quickly prompted the development of miRNA-mimicking oligonucleotides for therapeutic applications [45].”
Background
Renal uptake and tolerability of a 2′-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey
Henry, S. P., Johnson, M., Zanardi, T. A., Fey, R. A., Auyeung, D. J., Lappin, P. B., & Levin, A. A. (2012) · Toxicology · doi:10.1016/j.tox.2012.06.005 · Cited by 50 · cited 1× · see citing works
“Modifications on the ribose (2′-methyl, methoxyethyl and other alkyl chains, as well as locked nucleic acids (LNA)) [23,24] aptly increase enzymatic stability, but are only efficacious in combination with at least a partial phosphorothioate backbone, which is necessary for protein binding and thus a certain amount of…”
Background
Pegaptanib sodium as maintenance therapy in neovascular age-related macular degeneration: the LEVEL study
Friberg, T. R., Tolentino, M., & for the LEVEL Study Group (2010) · British Journal of Ophthalmology · doi:10.1136/bjo.2009.174946 · Cited by 49 · cited 1× · see citing works
“Pegaptanib is an aptamer available for local therapy of age-related macular degeneration, and antagonizes the detrimental effects of the vascular endothelial growth factor (VEGF) [15].”
Background
Enhanced Extravasation, Stability and in Vivo Cardiac Gene Silencing via in Situ siRNA–Albumin Conjugation
Lau, S., Graham, B., Cao, N., Boyd, B. J., Pouton, C. W., & White, P. J. (2011) · Molecular Pharmaceutics · doi:10.1021/mp2002522 · Cited by 46 · see citing works
Oligo Safety Working Group Exaggerated Pharmacology Subcommittee Consensus Document
Kornbrust, D. J., Cavagnaro, J. A., Levin, A. A., Foy, J. W.-D., Pavco, P. A., Gamba‐Vitalo, C., & Guimond, A. (2013) · Nucleic Acid Therapeutics · doi:10.1089/nat.2012.0399 · Cited by 45 · cited 1× · see citing works
“Furthermore, comprehensive drug safety assessments will have implications for the whole class of siRNA therapeutics [49,50].”
Background
Brain-targeting gene delivery using a rabies virus glycoprotein peptide modulated hollow liposome: bio-behavioral study
Tao, Y., Han, J., & Dou, H. (2012) · Journal of Materials Chemistry · doi:10.1039/c2jm31675g · Cited by 41 · cited 4× · see citing works
“75NTR are possible targets − Peptide/siRNA complexes [113] − Polyethyleneimine complexes [115] − Liposomes [116] − PAMAM nanoparticles [117] − Targeted exosomes [114] − Protamine-antibody/siRNA complexes [126] − Liposomes [127] − Polythyleneimine complexes [135–137] − PEG–siRNA conjugate [138] − Self-assembled nanopar…”
BackgroundMethodInfluential
Study of the transcytosis of an anti-transferrin receptor antibody with a Fab′ cargo across the blood–brain barrier in mice
Manich, G., Cabezón, I., del Valle, J., Duran‐Vilaregut, J., Camins, A., Pallàs, M., Pelegrı́, C., & Vilaplana, J. (2013) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2013.05.027 · Cited by 39 · see citing works
Targeting cancer cell-specific RNA interference by siRNA delivery using a complex carrier of affibody-displaying bio-nanocapsules and liposomes
Nishimura, Y., Mieda, H., Ishii, J., Ogino, C., Fujiwara, T., & Kondo, A. (2013) · Journal of Nanobiotechnology · doi:10.1186/1477-3155-11-19 · Cited by 39 · cited 2× · see citing works
“For Her2-mediated targeting, a recent report used particles consisting of hepatitis B virus L protein, the viral surface antigen (HBsAg), a lipid bilayer, and a Her2-selective affibody [142].”
Method
Therapeutic Potential of Mipomersen in the Management of Familial Hypercholesterolaemia
Gelsinger, C., Steinhagen‐Thiessen, E., & Kassner, U. (2012) · Drugs · doi:10.2165/11635060-000000000-00000 · Cited by 35 · cited 1× · see citing works
“Biological investigations and the clinical evaluation of mipomersen and other antisense agents have recently proven that these off-target effects are indeed translated to considerable relevant side effects [20,21].”
Background
Recent advances in small interfering RNA sensing by the immune system
Sioud, M. (2010) · New Biotechnology · doi:10.1016/j.nbt.2010.02.015 · Cited by 29 · cited 2× · see citing works
“Both sequence-specific and sequence-unspecific off-target effects are well-documented [19,52–54].”
Background
Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect
Gaziova, Z., Baumann, V., Winkler, A.-M., & Winkler, J. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.02.004 · Cited by 29 · see citing works
Self-assembled proteinticle nanostructures for 3-dimensional display of antibodies
Lee, E. J., Lee, E., Kim, H. J., Lee, J.-H., Ahn, K.-Y., Park, J.-S., & Lee, J. (2014) · Nanoscale · doi:10.1039/c4nr03635b · Cited by 29 · cited 1× · see citing works
“Recombinant engineering of self-multiplexing proteins yields well-controlled particles, termed proteinticles, with a uniform size distribution [155].”
Background
A proteomic study reveals unspecific apoptosis induction and reduction of glycolytic enzymes by the phosphorothioate antisense oligonucleotide oblimersen in human melanoma cells
Stessl, M., Marchetti‐Deschmann, M., Winkler, J., Lachmann, B., Allmaier, G. M., & Noe, C. R. (2009) · Journal of Proteomics · doi:10.1016/j.jprot.2009.06.001 · Cited by 29 · cited 1× · see citing works
“On the flip side, the high non-specific protein affinity results in significant off-target effects, meaning biological outcomes that are caused by interactions other than that on the targeted gene [18,19].”
Background
Gene Silencing in Skin After Deposition of Self-Delivery siRNA With a Motorized Microneedle Array Device
Hickerson, R. P., Wey, W. C., Rimm, D. L., Speaker, T. J., Suh, S., Flores, M. A., González-González, E., Leake, D., Contag, C. H., & Kaspar, R. L. (2013) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2013.56 · Cited by 29 · cited 1× · see citing works
“Therapeutic siRNAs can be coated onto those stainless steel needles, or injected with microneedle devices [76,77].”
Background
Nanomedicines Based on Recombinant Fusion Proteins for Targeting Therapeutic siRNA Oligonucleotides
Winkler, J. (2011) · Therapeutic Delivery · doi:10.4155/tde.11.56 · Cited by 28 · cited 1× · see citing works
“Several antibody-mediated strategies made use of fusion proteins with basic peptides, such as protamine [126,147–151].”
Background
Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents
Shokrzadeh, N., Winkler, A.-M., Dirin, M., & Winkler, J. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.10.045 · Cited by 27 · cited 1× · see citing works
“This can be avoided by increasing the molecular size, for example by PEGylation [178–180].”
Background
Time to deliver
Mash, R. J. (2006) · South African Family Practice · doi:10.1080/20786204.2006.10873431 · Cited by 26 · see citing works
Retina Expression and Cross-Species Validation of Gene Silencing by PF-655, a Small Interfering RNA Against RTP801 for the Treatment of Ocular Disease
Lee, D. U., Huang, W., Rittenhouse, K. D., & Jessen, B. A. (2012) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2011.0116 · Cited by 25 · see citing works
Conjugation with Receptor-Targeted Histidine-Rich Peptides Enhances the Pharmacological Effectiveness of Antisense Oligonucleotides
Nakagawa, O., Ming, X., Carver, K. A., & Juliano, R. L. (2013) · Bioconjugate Chemistry · doi:10.1021/bc400500h · Cited by 24 · cited 2× · see citing works
“n molecule − Nanocomplexes [154] − Chitosan nanoparticles [133] − Conjugate [146] − Proteinticle [156]”
Background
Rational design of an immunoconjugate for selective knock-down of leukemia-specific E2A–PBX1 fusion gene expression in human Pre-B leukemia
Uckun, F. M., Qazi, S., Dıbırdık, İ., & Myers, D. E. (2012) · Integrative Biology · doi:10.1039/c2ib20114c · Cited by 22 · cited 1× · see citing works
“Several antibody-mediated strategies made use of fusion proteins with basic peptides, such as protamine [126,147–151].”
Background
Is mipomersen ready for clinical implementation? A transatlantic dilemma
Sjouke, B., Balak, D., Beuers, U. H., Ratziu, V., & Stroes, E. S. G. (2013) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328362dfd9 · Cited by 20 · cited 3× · see citing works
“The tendency of mipomersen to induce an elevation of the plasma levels of liver alanine transaminase (ALT) and aspartate transaminase (AST), and hepatosteatosis have triggered controversy during the approval processes on both sides of the atlantic [5].”
Background
Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy
Scully, M. A., Pandya, S., & Moxley, R. T. (2012) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2013.746939 · Cited by 20 · cited 1× · see citing works
“The orphan disease Duchenne muscular dystrophy is caused by the expression of a non-functional dystrophin protein due to deletion of a section of its corresponding gene [26].”
Background
Real-time quantification of antibody–short interfering RNA conjugate in serum by antigen capture reverse transcription–polymerase chain reaction
Tan, M., Vernes, J.-M., Chan, J. C. Y., Cuellar, T. L., Asundi, A., Nelson, C., Yip, V., Shen, B., VANDLEN, R. L., Siebel, C. W., et al. (2012) · Analytical Biochemistry · doi:10.1016/j.ab.2012.08.018 · Cited by 19 · cited 1× · see citing works
“Genentech has recently reported the generation and development of analytical methodology for an siRNA–antibody conjugate [159], but to date no pharmacological data”
Generation and characterization of a fusion protein of single-chain fragment variable antibody against hemagglutinin antigen of avian influenza virus and truncated protamine
Zhang, T., Wang, C., Zhang, W., Gao, Y., Yang, S., Wang, T., Zhang, R.-Z., Qin, C., & Xia, X. (2010) · Vaccine · doi:10.1016/j.vaccine.2010.03.045 · Cited by 16 · cited 2× · see citing works
“Several antibody-mediated strategies made use of fusion proteins with basic peptides, such as protamine [126,147–151].”
Background
Nucleic Acid Therapeutics: Concepts for Targeted Delivery to Solid Tumors
Ogris, M. (2010) · Therapeutic Delivery · doi:10.4155/tde.10.9 · Cited by 7 · cited 1× · see citing works
“Based on disease areas with unmet medical need, functional siRNA delivery into tumors [100], the brain [101], and endothelium [99] is especially attractive.”
Background

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M. Gebauer, A. Skerra, Anticalins: small engineered binding proteins based on the lipocalin scaffoldChapter seven in: K.D. Wittrup, L.V. Gregory (Eds.), Methods Enzymol, Academic Press, 2012, pp. 157-188.

Sorted by citations

Emerging Frontiers in Drug Delivery
Tibbitt, M. W., Dahlman, J. E., & Langer, R. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.5b09974 · Cited by 982 · see citing works
The delivery of therapeutic oligonucleotides
Juliano, R. L. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw236 · Cited by 863 · see citing works
“This approach has been especially important for therapeutic use of siRNA (164) and good accounts of current clinical trials using siRNA LNPs are found in recent reviews (10,165).”
Background
Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development
Dhuri, K., Bechtold, C., Quijano, E., Pham, H. T. T., Gupta, A., Vikram, A., & Bahal, R. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9062004 · Cited by 554 · see citing works
Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting
Kim, S. M., Yang, Y., Oh, S. J., Hong, Y., Seo, M., & Jang, M. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.09.013 · Cited by 481 · see citing works
Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives
Poller, W. C., Dimmeler, S., Heymans, S. R. B., Zeller, T., Haas, J., Karakas, M., Leistner, D. M., Jakob, P., Nakagawa, S., Blankenberg, S., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx165 · Cited by 412 · see citing works
Targeted gene silencing in vivo by platelet membrane–coated metal-organic framework nanoparticles
Zhuang, J., Gong, H., Zhou, J., Zhang, Q., Gao, W., Fang, R. H., & Zhang, L. (2020) · Science Advances · doi:10.1126/sciadv.aaz6108 · Cited by 365 · see citing works
“To address this, a number of different strategies can be used to decrease nonspecific interactions while improving targeting efficiency (11).”
Background
Nucleic acid delivery for therapeutic applications
Gupta, A., Andresen, J. L., Manan, R. S., & Langer, R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113834 · Cited by 339 · see citing works
Emerging Concepts and Technologies in Vaccine Development
Brisse, M. E., Vrba, S. M., Kirk, N. M., Liang, Y., & Ly, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.583077 · Cited by 325 · see citing works
Lipid-Based DNA Therapeutics: Hallmarks of Non-Viral Gene Delivery
Buck, J., Grossen, P., Cullis, P. R., Huwyler, J., & Witzigmann, D. (2019) · ACS Nano · doi:10.1021/acsnano.8b07858 · Cited by 318 · see citing works
Gemcitabine loaded autologous exosomes for effective and safe chemotherapy of pancreatic cancer
Li, Y., Wu, J., Wang, J., Hu, X.-B., Cai, J., & Xiang, D. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.10.022 · Cited by 291 · see citing works
Safety of antisense oligonucleotide and siRNA-based therapeutics
Chi, X., Gatti, P. J., & Papoian, T. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.01.013 · Cited by 280 · see citing works
Oligonucleotide Therapies: The Past and the Present
Lundin, K. E., Gissberg, O., & Smith, C. I. E. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.070 · Cited by 268 · see citing works
Super-resolution Imaging of Proton Sponge-Triggered Rupture of Endosomes and Cytosolic Release of Small Interfering RNA
Wojnilowicz, M., Glab, A., Bertucci, A., Caruso, F., & Cavalieri, F. (2018) · ACS Nano · doi:10.1021/acsnano.8b05151 · Cited by 265 · see citing works
Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis
Zhu, C., Kim, K., Wang, X., Bartolome, A., Salomao, M., Dongiovanni, P., Meroni, M., Graham, M. J., Yates, K. P., Diehl, A. M., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat0344 · Cited by 250 · see citing works
“However, because liver-targeted Notch antagonism may be fraught with side effects including disruption of hepatic vascular integrity (62), N-acetylgalactosamine–modified siRNA (63, 64) or nanoparticle strategies (65) retain great potential to address the inappropriate Fig.”
Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach
Chalbatani, G. M., Dana, H., Gharagouzloo, E., Grijalvo, S., Eritja, R., Logsdon, C. D., Memari, F., Miri, S. R., Rad, M. R., & Marmari, V. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s200253 · Cited by 238 · see citing works
“21 Therefore, the development of this therapeutic strategy may have a high impact on modern medicine.”
Paving the Road for RNA Therapeutics
Dammes, N., & Peer, D. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.08.004 · Cited by 220 · see citing works
“Therefore, for leukocyte-implicated diseases such as chronic lymphocytic leukemia or autoimmunity, tumors with insufficient enhanced permeability and retention (EPR) effect or any other condition where specific targeting to the cell of interest is critical, a variety of delivery vehicles such as LNPs and dendrimers th…”
The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market
Titze‐de‐Almeida, R., David, C., & Titze-de-Almeida, S. S. (2017) · Pharmaceutical Research · doi:10.1007/s11095-017-2134-2 · Cited by 198 · see citing works
Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo
Ni, H., Hatit, M. Z. C., Zhao, K., Loughrey, D., Lokugamage, M. P., Peck, H. E., Cid, A. D., Muralidharan, A., Kim, Y., Santangelo, P. J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32281-5 · Cited by 192 · see citing works
Journey of siRNA: Clinical Developments and Targeted Delivery
Nikam, R. R., & Gore, K. R. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2017.0715 · Cited by 175 · see citing works
“…many siRNA drugs are still in clinical trial pipeline, which will deﬁnitely emerge out with immense and beneﬁcial results. siRNA Therapeutics: Barriers and Remedies Since the discovery of RNAi, major research has been focused on the application of siRNA as a drug against various diseases [113].”
Nonviral Gene Delivery with Cationic Glycopolymers
Bruggen, C. V., Hexum, J. K., Tan, Z., Dalal, R. J., & Reineke, T. M. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.8b00665 · Cited by 162 · see citing works
Analyzing 2000 in Vivo Drug Delivery Data Points Reveals Cholesterol Structure Impacts Nanoparticle Delivery
Paunovska, K., Gil, C. J., Lokugamage, M. P., Sago, C. D., Sato, M., Lando, G. N., Gamboa Castro, M., Bryksin, A. V., & Dahlman, J. E. (2018) · ACS Nano · doi:10.1021/acsnano.8b03640 · Cited by 160 · see citing works
Constrained Nanoparticles Deliver siRNA and sgRNA to T Cells In Vivo without Targeting Ligands
Lokugamage, M. P., Sago, C. D., Gan, Z., Krupczak, B. R., & Dahlman, J. E. (2019) · Advanced Materials · doi:10.1002/adma.201902251 · Cited by 155 · see citing works
Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing
Wang, Y., Malcolm, D. W., & Benoit, D. S. W. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.06.001 · Cited by 143 · see citing works
“, macrophages and liver Kupffer cells) [53], resulting in highly effective siRNA-mediated liver disease modification and several ongoing clinical trials [54].”
siRNA Delivery with Chitosan: Influence of Chitosan Molecular Weight, Degree of Deacetylation, and Amine to Phosphate Ratio on in Vitro Silencing Efficiency, Hemocompatibility, Biodistribution, and in Vivo Efficacy
Alameh, M., Lavertu, M., Tran‐Khanh, N., Chang, C., Lesage, F., Bail, M., Darras, V., Chevrier, A., & Buschmann, M. D. (2017) · Biomacromolecules · doi:10.1021/acs.biomac.7b01297 · Cited by 142 · see citing works
Design of lipid-based nanoparticles for delivery of therapeutic nucleic acids
Mendonça, M. C. P., Kont, A., Kowalski, P. S., & O’Driscoll, C. M. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103505 · Cited by 137 · see citing works
Hydroxycholesterol substitution in ionizable lipid nanoparticles for mRNA delivery to T cells
Patel, S. K., Billingsley, M. M., Frazee, C. P., Han, X., Swingle, K. L., Qin, J., Alameh, M., Wang, K., Weissman, D., & Mitchell, M. J. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.020 · Cited by 134 · see citing works
“However, limitations of LNPs include liver accumulation which can prevent the optimal biodistribution required to achieve delivery to extrahepatic tissues [40], accelerated blood clearance due to PEGylation [41], and endosomal recycling – a process in which cells exocytose lipid-containing exogenous materials to maint…”
Background
Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent
Gish, R. G., Yuen, M., Chan, H. L., Given, B. D., Lai, C., LOCARNINI, S. A., Lau, J. Y. N., Wooddell, C. I., Schluep, T., & Lewis, D. L. (2015) · Antiviral Research · doi:10.1016/j.antiviral.2015.06.019 · Cited by 130 · see citing works
“enterally administered RNAi triggers to liver hepatocytes in humans with resultant silencing of the target gene expression are in development (Haussecker and Kay, 2015; Lorenzer et al., 2015).”
Background
Nanoparticles That Deliver RNA to Bone Marrow Identified by in Vivo Directed Evolution
Sago, C. D., Lokugamage, M. P., Islam, F. Z., Krupczak, B. R., Sato, M., & Dahlman, J. E. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b08976 · Cited by 129 · see citing works
Intracellular Trafficking and Endosomal Release of Oligonucleotides: What We Know and What We Don’t
Juliano, R. L. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0727 · Cited by 122 · see citing works
Lyophilized liposome-based parenteral drug development: Reviewing complex product design strategies and current regulatory environments
Wang, Y., & Grainger, D. W. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.03.003 · Cited by 124 · see citing works
Imaging-guided delivery of RNAi for anticancer treatment
Wang, J., Mi, P., Lin, G., Wáng, Y. X. J., Liu, G., & Chen, X. S. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.01.008 · Cited by 122 · see citing works
“Pros and cons of using various targeting ligands for siRNA therapeutics have been reviewed elsewhere [94].”
Background
Bioinspired pH- and Temperature-Responsive Injectable Adhesive Hydrogels with Polyplexes Promotes Skin Wound Healing
Le, T. M. D., Duong, H. T. T., Thambi, T., Phan, V. H. G., Jeong, J. H., & Lee, D. S. (2018) · Biomacromolecules · doi:10.1021/acs.biomac.8b00819 · Cited by 118 · see citing works
Polymeric nanoparticles for siRNA delivery: Production and applications
Cavallaro, G., Sardo, C., Craparo, E. F., Porsio, B., & Giammona, G. (2017) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2017.04.008 · Cited by 118 · see citing works
Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype
Conceição, M., Mendonça, L., Nóbrega, C., Gomes, C., Costa, P., Hirai, H., Moreira, J. N., Lima, M. C., Manjunath, N., & Pereira de Almeida, L. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2015.12.021 · Cited by 117 · see citing works
Engineered Hydrogels for Local and Sustained Delivery of RNA‐Interference Therapies
Wang, L. L., & Burdick, J. A. (2016) · Advanced Healthcare Materials · doi:10.1002/adhm.201601041 · Cited by 114 · see citing works
Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines
Park, J., Park, J., Pei, Y., Xu, J., & Yeo, Y. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.12.004 · Cited by 114 · see citing works
A basic insight into aptamer-drug conjugates (ApDCs)
Xuan, W., Peng, Y., Deng, Z., Peng, T., Kuai, H., Li, Y., He, J., Jin, C. Y., Liu, Y., Wang, R., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.08.021 · Cited by 111 · see citing works
Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections
Abramson, A., Kirtane, A. R., Shi, Y., Zhong, G., Collins, J. E., Tamang, S. M., Ishida, K., Hayward, A. M., Wainer, J., Rajesh, N. U., et al. (2022) · Matter · doi:10.1016/j.matt.2021.12.022 · Cited by 109 · see citing works
Current Challenges in Delivery and Cytosolic Translocation of Therapeutic RNAs
Johannes, L., & Lucchino, M. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2017.0716 · Cited by 108 · see citing works
“The hydrophilic and flexible PEG chains form a protecting shell around the nanoparticles, thereby preventing their interaction with opsonins and RES activation (stealth effect) [1,101,102].”
Vitamin A-decorated biocompatible micelles for chemogene therapy of liver fibrosis
Qiao, J.-B., Fan, Q.-Q., Xing, L., Cui, P., He, Y., Zhu, J., Wang, L., Pang, T., Oh, Y., Zhang, C., et al. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.05.032 · Cited by 102 · see citing works
Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo
Jyotsana, N., Sharma, A. K., Chaturvedi, A., Budida, R., Scherr, M., Kuchenbauer, F. C., Lindner, R. M., Noyan, F., Sühs, K., Stangel, M., et al. (2019) · Annals of Hematology · doi:10.1007/s00277-019-03713-y · Cited by 97 · see citing works
Navigating the intricate in-vivo journey of lipid nanoparticles tailored for the targeted delivery of RNA therapeutics: a quality-by-design approach
Haghighi, E., Abolmaali, S. S., Dehshahri, A., Shaegh, S. A. M., Azarpira, N., & Tamaddon, A. M. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02972-w · Cited by 110 · see citing works
Topical delivery of siRNA into skin using ionic liquids
Dharamdasani, V., Mandal, A., Qi, Q. M., Suzuki, I., Bentley, M. V. L. B., & Mitragotri, S. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.04.038 · Cited by 100 · see citing works
Small non-coding RNA therapeutics for cardiovascular disease
Shah, A. M., & Giacca, M. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac463 · Cited by 97 · see citing works
Structure–Property Relationships of Oligonucleotide Polyelectrolyte Complex Micelles
Lueckheide, M. J., Vieregg, J., Bologna, A. J., Leon, L., & Tirrell, M. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b03132 · Cited by 95 · see citing works
Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles
Sayour, E. J., De Leon, G., Pham, C., Grippin, A., Kemeny, H., Chua, J., Huang, J., Sampson, J. H., Sanchez-Perez, L., Flores, C., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2016.1256527 · Cited by 93 · see citing works
Micellar carriers for the delivery of multiple therapeutic agents
Thipparaboina, R., Chavan, R. B., Kumar, D. K., Modugula, S., & Shastri, N. R. (2015) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2015.07.046 · Cited by 93 · see citing works
Use of Protamine in Nanopharmaceuticals—A Review
Ruseska, I., Fresacher, K., Petschacher, C., & Zimmer, A. (2021) · Nanomaterials · doi:10.3390/nano11061508 · Cited by 90 · see citing works
RNA Therapy: Current Status and Future Potential
Kim, Y. (2020) · Chonnam Medical Journal · doi:10.4068/cmj.2020.56.2.87 · Cited by 89 · see citing works
HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells
Muralidharan, R., Mehta, M., Ahmed, R. A., Roy, S., Xu, L., Aubé, J., Chen, A., Zhao, Y. D., Herman, T. S., Ramesh, R., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-07787-4 · Cited by 85 · see citing works
High‐Contrast Fluorescence Detection of Metastatic Breast Cancer Including Bone and Liver Micrometastases via Size‐Controlled pH‐Activatable Water‐Soluble Probes
Xiong, H., Zuo, H., Yan, Y., Occhialini, G., Zhou, K., Wan, Y., & Siegwart, D. J. (2017) · Advanced Materials · doi:10.1002/adma.201700131 · Cited by 85 · see citing works
Testing thousands of nanoparticles in vivo using DNA barcodes
Lokugamage, M. P., Sago, C. D., & Dahlman, J. E. (2018) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2018.08.001 · Cited by 81 · see citing works
Vaccine development: Current trends and technologies
Poria, R., Kala, D., Nagraik, R., Walia, Y., Dhir, S., Singh, B., Kaushik, N. K., Noorani, M. S., Kaushal, A., & Gupta, S. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122331 · Cited by 83 · 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
“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] In recent years, some brain targeting siRNA delivery systems, including spherical nucleic acid (SNA), stable nucleic acid lipid particles (SNALPs) and ta…”
Background
Preparation and In Vitro/In Vivo Characterization of Polymeric Nanoparticles Containing Methotrexate to Improve Lymphatic Delivery
Jang, J.-H., Jeong, S., & Lee, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133312 · Cited by 82 · see citing works
“In addition, NPs with an appropriate size inhibit phagocytosis by the immune system, such as RES system and lead to less excretion into the kidney or liver [40].”
Background
Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles
Vaidya, A., Moore, S., Chatterjee, S., Guerrero, E. D., Kim, M., Farbiak, L., Dilliard, S. A., & Siegwart, D. J. (2024) · Advanced Materials · doi:10.1002/adma.202313791 · Cited by 85 · see citing works
Variable asialoglycoprotein receptor 1 expression in liver disease: Implications for therapeutic intervention
Witzigmann, D., Quagliata, L., Schenk, S., Quintavalle, C., Terracciano, L., & Huwyler, J. (2015) · Hepatology Research · doi:10.1111/hepr.12599 · Cited by 80 · see citing works
Nanoparticle-mediated delivery of anti-PU.1 siRNA via localized intracisternal administration reduces neuroinflammation
Ralvenius, W. T., Andresen, J. L., Huston, M. M., Penney, J., Bonner, J. M., Fenton, O. S., Langer, R., & Tsai, L. (2024) · Advanced Materials · doi:10.1002/adma.202309225 · Cited by 78 · see citing works
siRNA therapeutics for breast cancer: recent efforts in targeting metastasis, drug resistance, and immune evasion
Ngamcherdtrakul, W., & Yantasee, W. (2019) · Translational research · doi:10.1016/j.trsl.2019.08.005 · Cited by 80 · see citing works
T ranslational A dvances in the F ield of P ulmonary H ypertension . Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words
Chun, H. J., Bonnet, S., & Chan, S. Y. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201604-0886pp · Cited by 78 · see citing works
Virus-inspired nucleic acid delivery system: Linking virus and viral mimicry
Ni, R., Zhou, J., Hossain, N., & Chau, Y. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.07.005 · Cited by 78 · see citing works
The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease
Titze-de-Almeida, S. S., Soto‐Sánchez, C., Fernández, E., Koprich, J. B., Brotchie, J. M., & Titze‐de‐Almeida, R. (2020) · Cells · doi:10.3390/cells9040841 · Cited by 76 · see citing works
Targeted lipid nanoparticles for RNA therapeutics and immunomodulation in leukocytes
Veiga, N., Diesendruck, Y., & Peer, D. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.04.002 · Cited by 74 · see citing works
Augmented lipid-nanoparticle-mediated in vivo genome editing in the lungs and spleen by disrupting Cas9 activity in the liver
Sago, C. D., Lokugamage, M. P., Loughrey, D., Lindsay, K. E., Hincapie, R., Krupczak, B. R., Kalathoor, S., Sato, M., Echeverri, E. S., Fitzgerald, J. P., et al. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00847-9 · Cited by 74 · see citing works
Advances in the Structural Design of Polyelectrolyte Complex Micelles
Marras, A. E., Ting, J., Stevens, K. C., & Tirrell, M. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c01258 · Cited by 72 · see citing works
Polyester-based nanoparticles for nucleic acid delivery
Zhao, J., Weng, G., Li, J., Zhu, J. R., & Zhao, J. (2018) · Materials Science and Engineering C · doi:10.1016/j.msec.2018.07.027 · Cited by 71 · see citing works
Translation of angiotensin-converting enzyme 2 upon liver-and lung-targeted delivery of optimized chemically modified mRNA
Schrom, E., Huber, M., Aneja, M., Dohmen, C., Emrich, D., Geiger, J., Hasenpusch, G., Herrmann-Janson, A., Kretzschmann, V., Mykhailyk, O., et al. (2017) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2017.04.006 · Cited by 69 · see citing works
“This makes them highly permeable for small molecules, and lipoplexes are easily taken up into the interstitium, where they are transported by ligand-based targeting or diffusion from the afferent to the efferent vessels.(56,57,59) This is visible in the histochemical stainings for luciferase protein showing a gradual…”
Background
Microvesicle-Mediated Delivery of Minicircle DNA Results in Effective Gene-Directed Enzyme Prodrug Cancer Therapy
Kanada, M., Kim, B. D., Hardy, J. W., Ronald, J. A., Bachmann, M. H., Bernard, M. P., Perez, G. I., Zarea, A. A., Ge, T. J., Withrow, A., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0299 · Cited by 69 · see citing works
“The efficiency of gene delivery by the synthetic systems, and their rapid clearance from the circulation, predominantly by macrophages in the liver and spleen, have limited their utility [5] [7].”
Background
Inorganic nanoparticle-based advanced cancer therapies: Promising combination strategies
Amaldoss, M. J. N., Yang, J., Koshy, P., Unnikrishnan, A., & Sorrell, C. C. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.103386 · Cited by 68 · see citing works
A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy
Abdelaal, A. M., Sohal, I. S., Iyer, S. G., Sudarshan, K., Kothandaraman, H., Lanman, N. A., Low, P. S., & Kasinski, A. L. (2023) · Oncogene · doi:10.1038/s41388-023-02801-8 · Cited by 67 · see citing works
“For all other in vitro studies, sample sizes were based on previous work done in the laboratory.”
Method
Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors
Yan, Y., Zhou, K., Xiong, H., Miller, J. B., Motea, E. A., Boothman, D. A., Liu, L., & Siegwart, D. J. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.12.001 · Cited by 68 · see citing works
Update on the clinical utility of an RNA interference-based treatment: focus on Patisiran
Rizk, M., & Tüzmen, Ş. (2017) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s87945 · Cited by 68 · see citing works
“Additionally, administration routes are also listed for demonstration of early developments, and ongoing clinical trials.(21,22)”
Background
Lipid 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 67 · see citing works
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 65 · see citing works
“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].”
Background
Rationally 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 · see citing works
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 65 · see citing works
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 · see citing works
Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia
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 · see citing works
“While this provides excellent efficiency of cargo delivery to hepatic diseases, it limits the application of LNP-siRNA based therapies in other tissues [45].”
Background
Recent 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 66 · see citing works
“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].”
Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review
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 62 · see citing works
“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].”
Hypoxia-sensitive micellar nanoparticles for co-delivery of siRNA and chemotherapeutics to overcome multi-drug resistance in tumor cells
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 61 · see citing works
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 59 · see citing works
“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).”
Background
Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice
Kim, 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 56 · see citing works
Lipid Nanoparticle-mediated siRNA Transfer Against PCTAIRE1/PCTK1/Cdk16 Inhibits In Vivo Cancer Growth
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 · see citing works
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 56 · see citing works
“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 55 · see citing works
Aptamer-Functionalized Nanoparticles Mediate PD-L1 siRNA Delivery for Effective Gene Silencing in Triple-Negative Breast Cancer Cells
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 54 · see citing works
“Advances in nanocarriers’ formulations have recently enabled several clinical trials in which siRNAs have been systemically administered to cancer patients [18].”
Background
Glycogen-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 · see citing works
siRNA Drugs: Here to Stay
Rossi, J. J., & Rossi, D. J. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.01.015 · Cited by 53 · see citing works
“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)”
Background
Folate Receptor-Mediated siRNA Delivery: Recent Developments and Future Directions for RNAi Therapeutics
Gangopadhyay, S., Nikam, R. R., & Gore, K. R. (2021) · Nucleic Acid Therapeutics · doi:10.1089/nat.2020.0882 · Cited by 53 · see citing works
“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 51 · see citing works
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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)
DOI: 10.1016/j.jconrel.2015.02.003
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
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
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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Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics

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