The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
Rational design of cationic lipids for siRNA delivery
Abstract
We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“There are limited published data on the in vivo delivery of self-amplifying RNA using nonviral delivery strategies (3,14,18), and none has taken advantage of the recently developed, clinically suitable delivery systems for siRNA (19,20).”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [19]
In the citing paper
“Recently, there has been an exponential growth in the development of clinically suitable nonviral delivery systems for siRNA (19,20); we have taken advantage of these innovations to develop the LNP/RNA formulation and have now embarked on a more extensive evaluation of other nonviral delivery systems.”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [19]
In the citing paper
“They can also increase the transport efficiency of siRNA by lowering toxicity and enhancing biological dispersion.319”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [319]
In the citing paper
“considerable effort has been made to reduce the siRNA payload by developing different lipid formulations for delivery, which has so far led to a tenfold or even 100-fold reduction in the dose of siRNA administered to different models77,78.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [77]
In the citing paper
“Semple et al. reported that DLin-KC2-DMA containing stable nucleic acid lipid particles (SNALPs) exhibited in vivo activity at siRNA doses of 0.01 mg/kg in the mouse model and was capable of silencing the TTR gene in nonhuman primates with ED50 around 0.3 mg/kg.[63]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [63]
Citations
Cites
Knocking down barriers: advances in siRNA delivery
Whitehead, K. A., Langer, R., & Anderson, D. G. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2742 · Cited by 3,115
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357
Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA
Judge, A. D., Sood, V., Shaw, J. R., Fang, D., McClintock, K., & MacLachlan, I. (2005) · Nature Biotechnology · doi:10.1038/nbt1081 · Cited by 1,260
Self-citationPotent and persistent in vivo anti-HBV activity of chemically modified siRNAs
Morrissey, D. V., Lockridge, J. A., Shaw, L., Blanchard, K. S., Jensen, K., Breen, W., Hartsough, K. C., Machemer, L., Radka, S. F., Jadhav, V., et al. (2005) · Nature Biotechnology · doi:10.1038/nbt1122 · Cited by 1,175
Self-citationA combinatorial library of lipid-like materials for delivery of RNAi therapeutics
Akinc, A., Zumbuehl, A., Goldberg, M., Leshchiner, E. S., Busini, V., Hossain, N., Bacallado, S. A., Nguyen, D. N., Fuller, J., Alvarez, R., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1402 · Cited by 1,150
Self-citationMechanism of DNA Release from Cationic Liposome/DNA Complexes Used in Cell Transfection,
Xu, Y., & Szoka, F. C. (1996) · Biochemistry · doi:10.1021/bi9602019 · Cited by 1,136
Frank-Kamenetsky, M. D., Grefhorst, A., Anderson, N. N., Racie, T., Bramlage, B., Akinc, A., Butler, D., Charissé, K., Dorkin, J. R., Fan, Y., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805434105 · Cited by 644
Self-citationMechanism of oligonucleotide release from cationic liposomes.
Zelphati, O., & Szoka, F. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.21.11493 · Cited by 634
On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids
Hafez, I., Maurer, N., & Cullis, P. R. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301506 · Cited by 601
Self-citationCationic lipid saturation influences intracellular delivery of encapsulated nucleic acids
Heyes, J., Palmer, L., Bremner, K., & MacLachlan, I. (2005) · Journal of Controlled Release · doi:10.1016/j.jconrel.2005.06.014 · Cited by 572
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–300 of 1,003
Pulmonary delivery of therapeutic siRNA
Lam, J. K. W., Liang, W., & Chan, H. (2011) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2011.02.006 · Cited by 223
Formulation and Delivery Technologies for mRNA Vaccines
Zeng, C., Zhang, C., Walker, P. G., & Dong, Y. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_217 · Cited by 227
Zhang, X., Goel, V., & Robbie, G. J. (2019) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.1553 · Cited by 220
Exploiting Endocytosis for NanomedicinesPreprint
Akinc, A., & Battaglia, G. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016980 · Cited by 215
“These LNPs all contain ionizable lipids that are positively charged under acidic conditions and are uncharged under neutral physiological conditions (Zimmermann et al. 2006; Semple et al. 2010).”
BackgroundSelf-citationA Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes
Ramishetti, S., Hazan‐Halevy, I., Palakuri, R., Chatterjee, S., Naidu, G. S., Dammes, N., Freilich, I., Shmuel, L. K., Danino, D., & Peer, D. (2020) · Advanced Materials · doi:10.1002/adma.201906128 · Cited by 220
Non-viral COVID-19 vaccine delivery systems
Park, K. S., Sun, X., Aikins, M. E., & Moon, J. J. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.008 · Cited by 216
RNA interference in the era of nucleic acid therapeutics
Jadhav, V., Vaishnaw, A. K., Fitzgerald, K. J., & Maier, M. A. (2024) · Nature Biotechnology · doi:10.1038/s41587-023-02105-y · Cited by 232
“Consequently, we and others in the field focused our efforts on identifying new lipids and formulations to improve nucleic acid delivery 30 .”
Self-citationArtificial intelligence-driven rational design of ionizable lipids for mRNA delivery
Wang, W., Chen, K., Jiang, T. S., Wu, Y., Wu, Z., Ying, H., Yu, H., Lu, J., Lin, J., & Ouyang, D. (2024) · Nature Communications · doi:10.1038/s41467-024-55072-6 · Cited by 235
“The weight of mice was monitored on Days 1, 2, 3, 4, 7, 9, 11, 13, and 14 after administration (Fig.9aand b).”
Buyens, K., Smedt, S. C. D., Braeckmans, K., Demeester, J., Peeters, L., van Grunsven, L. A., du Jeu, X. D. M., Sawant, R. R., Torchilin, V. P., Farkasova, K., et al. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.10.009 · Cited by 207
Lipid-based mRNA vaccine delivery systems
Midoux, P., & Pichon, C. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.986104 · Cited by 213
“DLinDMA is an ionizable cationic lipid containing two double bonds per linoleyl hydrocarbon chain [45].”
BackgroundGujrati, M. D., Malamas, A. S., Shin, T., Jin, E., Sun, Y., & Lu, Z. (2014) · Molecular Pharmaceutics · doi:10.1021/mp400787s · Cited by 216
Sager, H. B., Dutta, P., Dahlman, J. E., Hulsmans, M., Courties, G., Sun, Y., Heidt, T., Vinegoni, C., Borodovsky, A., Fitzgerald, K. J., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf1435 · Cited by 209
Engineering liposomal nanoparticles for targeted gene therapy
Zylberberg, C., Gaskill, K., Pasley, S., & Matosevic, S. (2017) · Gene Therapy · doi:10.1038/gt.2017.41 · Cited by 207
Schmidt, P. J., Toudjarska, I., Sendamarai, A. K., Racie, T., Milstein, S., Bettencourt, B. R., Hettinger, J., Bumcrot, D., & Fleming, M. D. (2013) · Blood · doi:10.1182/blood-2012-09-453977 · Cited by 204
Enzyme-triggered nanomedicine: Drug release strategies in cancer therapy (Invited Review)
Andresen, T. L., Thompson, D. H., & Kaasgaard, T. (2010) · Molecular Membrane Biology · doi:10.3109/09687688.2010.515950 · Cited by 202
“When this is said, there are many reports of highly efficient advanced drug delivery systems (Drummond et al. 2000,Needham&Dewhirst 2001, Andresen et al. 2005a, Cheong et al. 2006, Hatakeyama et al. 2007b, Semple et al. 2010) and a few have gone through clinical trials.”
BackgroundViger-Gravel, J., Schantz, A., Pinon, A. C., Rossini, A. J., Schantz, S., & Emsley, L. (2018) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.7b10795 · Cited by 202
“Four samples were studied here: native empty LNP (1); LNP containing 50% phosphorothioated siRNA strand (2) or at 100% phosphorothioated (3) and LNP containing mRNA (4).”
BackgroundInfluentialZheng, C., Zheng, M., Gong, P., Deng, J., Yi, H., Zhang, P., Zhang, Y., Liu, P., Ma, Y., & Cai, L. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.01.053 · Cited by 204
“A variety of siRNA-based therapeutics have been developed, showing great promise in disease treatments [5,6].”
BackgroundLigand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis
Han, X., Gong, N., Xue, L., Billingsley, M. M., El-Mayta, R. D., Shepherd, S. J., Alameh, M., Weissman, D., & Mitchell, M. J. (2023) · Nature Communications · doi:10.1038/s41467-022-35637-z · Cited by 206
Non-Viral Nucleic Acid Delivery: Key Challenges and Future Directions
Elsabahy, M., Nazarali, A. J., & Földvári, M. (2011) · Current Drug Delivery · doi:10.2174/156720111795256174 · Cited by 201
“siRNA) [83,84].”
Next-Generation Lipids in RNA Interference Therapeutics
Rietwyk, S., & Peer, D. (2017) · ACS Nano · doi:10.1021/acsnano.7b04734 · Cited by 199
Sedic, M., Senn, J. J., Lynn, A., Laska, M., Smith, M., Platz, S. J., Bolen, J., Hoge, S., Bulychev, A., Jacquinet, E., et al. (2018) · Veterinary Pathology · doi:10.1177/0300985817738095 · Cited by 195
“However, the application of lipid-based nanoparticle delivery systems, initially developed for the in vivo delivery of siRNA, has enabled systemic administration of modified mRNA.(22)”
BackgroundLipid 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 198
“Two particularly potent ionizable cationic lipids were identified, 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) [89] and heptatriaconta-6,9,28,31-tetraen19-yl 4-(dimethylamino)butanoate (DLinMC3-DMA) [88] (for lipid structures, see Fig.”
BackgroundSelf-citationRational Design of a Polymer with Robust Efficacy for Intracellular Protein and Peptide Delivery
Chang, H., Lv, J., Gao, X., Wang, X. M., Wang, H., Chen, H., Xu, H., Li, L., & Cheng, Y. (2017) · Nano Letters · doi:10.1021/acs.nanolett.6b04955 · Cited by 194
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 202
Mitsutake, S., Zama, K., Yokota, H., Yoshida, T., Tanaka, M., Mitsui, M., Ikawa, M., Okabe, M., Tanaka, Y., Yamashita, T., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.255646 · Cited by 190
Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery
Alabi, C. A., Love, K. T., Sahay, G., Yin, H., Luly, K. M., Langer, R., & Anderson, D. G. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306529110 · Cited by 188
Gene therapy for neurodegenerative disorders: advances, insights and prospects
Chen, W., Hu, Y., & Ju, D. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.015 · Cited by 198
Xue, L., Gong, N., Shepherd, S. J., Xiong, X., Liao, X., Han, X., Zhao, G., Song, C., Huang, X., Zhang, H., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c02706 · Cited by 191
Self-citationLipid nanoparticle-mediated drug delivery to the brain
Khare, P., Edgecomb, S. X., Hamadani, C. M., Tanner, E. E. L., & S Manickam, D. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114861 · Cited by 187
How cationic lipids transfer nucleic acids into cells and across cellular membranes: Recent advances
Rehman, Z. U., Zuhorn, I. S., & Hoekstra, D. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.12.014 · Cited by 194
Nanotechnology for modern medicine: next step towards clinical translation
Sindhwani, S., & Chan, W. C. W. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13254 · Cited by 200
Bost, J., Barriga, H. M. G., Holme, M. N., Gallud, A., Maugeri, M., Gupta, D., Lehto, T., Valadi, H., Esbjörner, E. K., Stevens, M. M., et al. (2021) · ACS Nano · doi:10.1021/acsnano.1c05099 · Cited by 189
Omid Veiseh, A., Kievit, F. M., Fang, C., Mu, N., Jana, S., Leung, M. C., Mok, H., Ellenbogen, R. G., Park, J. O., & Zhang, M. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.07.016 · Cited by 183
“Short interfering RNA (siRNA) is double stranded, non-coding RNA, which binds to complementary mRNA to direct gene silencing through argonaute, an endonuclease within the RNA-induced silencing complex (RISC) [1,2].”
Delivery of oligonucleotides with lipid nanoparticles
Wang, Y., Miao, L., Satterlee, A., & Huang, L. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.02.007 · Cited by 184
“Generally, two important factors are considered in the rational design of ionizable lipids: (1) the pKa value of the head group which determines the pH condition at which the lipid gets protonated or deprotonated; and (2) the lipid capacity to induce the hexagonal HII phase structure when the ionized lipid interacts w…”
BackgroundZhou, K., Nguyen, L. H., Miller, J. B., Yan, Y., Kós, P., Xiong, H., Li, L., Hao, J., Minnig, J. T., Zhu, H., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520756113 · Cited by 185
“We evaluated dendrimers for their ability to silence Factor VII (FVII) in hepatocytes because this blood-clotting factor can be readily quantified from a small serum sample (3, 4).”
BackgroundMethodEmerging Roles for MicroRNAs in Diabetic Microvascular Disease: Novel Targets for Therapy
Zhang, Y., Sun, X., Icli, B., & Feinberg, M. W. (2017) · Endocrine Reviews · doi:10.1210/er.2016-1122 · Cited by 191
Brito, L. A., Kommareddy, S., Maione, D., Uematsu, Y., Giovani, C., Scorza, F. B., Otten, G. R., Yu, D. L., Mandl, C. W., Mason, P. W., et al. (2014) · Advances in genetics · doi:10.1016/bs.adgen.2014.10.005 · Cited by 181
Kozielski, K., Tzeng, S. Y., Mendoza, B. A. H. D., & Green, J. J. (2014) · ACS Nano · doi:10.1021/nn500704t · Cited by 181
Basha, G., Novobrantseva, T. I., Rosin, N. L., Tam, Y. Y. C., Hafez, I. M., Wong, M., Sugo, T., Ruda, V. M., Qin, J., Klebanov, B., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2011.190 · Cited by 182
Self-citationLipid Nanoparticles for Gene Delivery
Zhao, Y. D., & Huang, L. (2014) · Advances in genetics · doi:10.1016/b978-0-12-800148-6.00002-x · Cited by 185
“4, have been successfully developed to formulate stable nucleic acid lipid particles (SNALPs) (Heyes, Palmer, Bremner, & MacLachlan, 2005; Jayaraman et al., 2012; Semple et al., 2010), which are 100-fold and 1000-fold more potent in silencing hepatic genes in comparison to the previously used lipids (Heyes et al.”
BackgroundResultEffect of Chemical Modifications on Aptamer Stability in Serum
Kratschmer, C., & Levy, M. (2017) · Nucleic Acid Therapeutics · doi:10.1089/nat.2017.0680 · Cited by 181
“Oligonucleotides were recovered by methanol chloroform extraction [19].”
MethodLiposome-based delivery of biological drugs
Magar, K. T., Boafo, G. F., Li, X., Chen, Z., & He, W. (2021) · Chinese Chemical Letters · doi:10.1016/j.cclet.2021.08.020 · Cited by 189
Sato, Y., Hashiba, K., Sasaki, K., Maeki, M., Tokeshi, M., & Harashima, H. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.01.001 · Cited by 183
Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines
Deering, R. P., Kommareddy, S., Ulmer, J. B., Brito, L. A., & Geall, A. J. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.901308 · Cited by 180
“, siRNA) into the cytoplasm of cells [45-47].”
BackgroundMembrane‐destabilizing ionizable lipid empowered imaging‐guided siRNA delivery and cancer treatment
Guo, S., Li, K., Hu, B., Li, C., Zhang, M., Hussain, A., Wang, X., Cheng, Q., Yang, F., Ge, K., et al. (2021) · Exploration · doi:10.1002/exp.20210008 · Cited by 176
Cationic lipid nanoparticles for therapeutic delivery of siRNA and miRNA to murine liver tumor
Hsu, S., Yu, B., Wang, X., Lu, Y., Schmidt, C. R., Lee, R. J., Lee, L. J., Jacob, S. T., & Ghoshal, K. (2013) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2013.05.007 · Cited by 185
Recent Advances in Lipid Nanoparticles for Delivery of mRNA
Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F. H., Zhang, Z., Li, Y., & Huang, W. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122682 · Cited by 190
“Increasing the molar ratio of ionizable lipids to 40 mol% could enhance hepatic accumulation and gene-silencing activity [99], and a molar ratio of lipid composition of 50:10:38.”
BackgroundDrug delivery systems for CRISPR-based genome editors
Madigan, V. J., Zhang, F., & Dahlman, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00762-x · Cited by 193
“This ApoE–LDLR ‘endogenous targeting’ has resulted in efficient hepatocyte delivery in NHPs 162,171,173 and humans 16,174 .”
BackgroundInfluentialIn vivo delivery of RNAi with lipid-based nanoparticles
Huang, L., & Liu, Y. (2011) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071910-124709 · Cited by 174
Zhang, R., Ahmed, T., Li, L. Y., Li, J., Abbasi, A. Z., & Wu, X. Y. (2016) · Nanoscale · doi:10.1039/c6nr08486a · Cited by 180
PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery
Zhao, Y. D., Wang, W., Guo, S., Wang, Y., Miao, L., Xiong, Y., & Huang, L. (2016) · Nature Communications · doi:10.1038/ncomms11822 · Cited by 173
Reductively Responsive siRNA-Conjugated Hydrogel Nanoparticles for Gene Silencing
Dunn, S. S., Tian, S., Blake, S., Wang, J., Galloway, A. L., Murphy, A., Pohlhaus, P. D., Rolland, J. P., Napier, M. E., & DeSimone, J. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja300174v · Cited by 168
RNAi-based nanomedicines for targeted personalized therapy
Daka, A., & Peer, D. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.08.014 · Cited by 169
Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm
Wang, W., Feng, S., Ye, Z., Gao, H., Lin, J., & Ouyang, D. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.11.021 · Cited by 173
“…group, such as IL-ECFP 160, combined with two relatively large dilinoleyloxy tails (IL-ECFP 162 and 171) may behave in a “cone” shape and facilitate the formation of hexagonal H II phase when contacting with endosomal membrane, disrupting the bilayer structure and release the RNA therapeutics 29 .”
BackgroundLeveraging Physiology for Precision Drug Delivery
Sun, W., Hu, Q., Ji, W., Wright, G., & Gu, Z. (2017) · Physiological Reviews · doi:10.1152/physrev.00015.2016 · Cited by 169
“Due to the negative charge of phospholipids, positively charged nanocarriers generally show stronger interaction with plasma membranes, leading to increased internalization (378).”
BackgroundLipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain
Rungta, R. L., Choi, H. B., Lin, P. J., Ko, R. W., Ashby, D., Nair, J., Manoharan, M., Cullis, P. R., & MacVicar, B. A. (2013) · Molecular Therapy—Nucleic Acids · doi:10.1038/mtna.2013.65 · Cited by 165
Self-citationA review on cationic lipids with different linkers for gene delivery
Zhi, D., Bai, Y., Yang, J., Cui, S., Zhao, Y., Chen, H., & Zhang, S. (2017) · Advances in Colloid and Interface Science · doi:10.1016/j.cis.2017.12.006 · Cited by 164
Lipid nanoparticles for targeted siRNA delivery - going from bench to bedside
Zatsepin (2016) · International Journal of Nanomedicine · doi:10.2147/ijn.s106625 · Cited by 162
“Novel lipids selected by advanced screening 13,21,46 facilitate clinical trials, but application of similar LNPs does not guarantee the success of novel siRNA therapeutics.”
Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads
Kulkarni, J. A., Witzigmann, D., Leung, J., van der Meel, R., Zaifman, J., Darjuan, M. M., Grisch-Chan, H. M., Thöny, B., Tam, Y. Y. C., & Cullis, P. R. (2019) · Nanoscale · doi:10.1039/c9nr02004g · Cited by 161
Self-citationPaunovska, 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
Single-Step Assembly of Cationic Lipid–Polymer Hybrid Nanoparticles for Systemic Delivery of siRNA
Yang, X., Dou, S., Wang, Y., Long, H., Xiong, M., Mao, C., Yao, Y., & Wang, J. (2012) · ACS Nano · doi:10.1021/nn300500u · Cited by 161
Lipid nanoparticles for short interfering RNA delivery
Leung, A. K. K., Tam, Y. Y. C., & Cullis, P. R. (2014) · Advances in genetics · doi:10.1016/b978-0-12-800148-6.00004-3 · Cited by 158
“FUTURE PROSPECTS 5.1 Avenues for Improving LNP Delivery As mentioned above, tremendous efforts have been invested in the design of ionizable cationic lipids for maximizing the gene silencing capability of LNP-siRNA (Jayaraman et al., 2012; Semple et al., 2010).”
InfluentialSelf-citationHarnessing Nanoparticles for Immunomodulation and Vaccines
Gomes, A. C., Mohsen, M. O., & Bachmann, M. F. (2017) · Vaccines · doi:10.3390/vaccines5010006 · Cited by 162
“NPs in general can be assembled in vitro to encapsulate a variety of substances, which makes them a valuable tool to cargo immunomodulatory sequences such as siRNA, adjuvants such as immunostimulatory sequences (ISS) [5], and drugs such as antibiotics [5,10].”
BackgroundInfluentialDelivery of RNA Therapeutics: The Great Endosomal Escape!
Dowdy, S. F., Setten, R. L., Cui, X.-S., & Jadhav, S. G. (2022) · Nucleic Acid Therapeutics · doi:10.1089/nat.2022.0004 · Cited by 164
“Therefore, ionized cationic lipids are thought to ion-pair with endosomal anionic lipids to form a cone structure that destabilizes lipid bilayers by driving transition into an inverted hexagonal H II phase, resulting in endosomal escape of the LNP into the cytoplasm [48].”
Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
DeRosa, F., Guild, B., Karve, S., Smith, L., Love, K., Dorkin, J. R., Kauffman, K. J., Zhang, J., Yahalom, B., Anderson, D. G., et al. (2016) · Gene Therapy · doi:10.1038/gt.2016.46 · Cited by 159
Self-citationConstrained 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 157
Osteoblast-Targeting-Peptide Modified Nanoparticle for siRNA/microRNA Delivery
Sun, Y., Ye, X., Cai, M., Liu, X., Xiao, J., Zhang, C., Wang, Y., Yang, L., Liu, J., Li, S., et al. (2016) · ACS Nano · doi:10.1021/acsnano.5b07828 · Cited by 157
Chen, D., Ganesh, S., Wang, W., & Amiji, M. M. (2019) · Nanoscale · doi:10.1039/c8nr09855g · Cited by 158
Munson, M. J., O’Driscoll, G., da Silva, A. M., Lázaro‐Ibáñez, E., Gallud, A., Wilson, J. T., Collén, A., Esbjörner, E. K., & Sabirsh, A. (2021) · Communications Biology · doi:10.1038/s42003-021-01728-8 · Cited by 160
Insight Into the Prospects for RNAi Therapy of Cancer
Tian, Z., Liang, G., Cui, K., Liang, Y., Wang, Q., Lv, S., Cheng, X., & Zhang, L. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.644718 · Cited by 157
“Another approach is to use ionizable lipids with neutral charges, which cause lysosomes to break apart to release siRNA (Semple et al., 2010).”
BackgroundKumari, M., Lu, R., Li, M., Huang, J., Hsu, F., Ko, S.-H., Ke, F.-Y., Su, S.-C., Liang, K.-H., Yuan, J. P., et al. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00852-9 · Cited by 166
“A recent study also showed that head groups bearing tertiary amines serve to increase transfection efficiency by conferring the lipids with buffering capacity that expedites endo/lysosome escape and mRNA release within the cells [104, 105].”
BackgroundCuboplexes: Topologically Active siRNA Delivery
Kim, H., & Leal, C. (2015) · ACS Nano · doi:10.1021/acsnano.5b03902 · Cited by 157
Granot-Matok, Y., & Peer, D. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.08.015 · Cited by 160
Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery
Zimmermann, C. M., Baldassi, D., Chan, K. Y. T., Adams, N. B. P., Neumann, A., Porras-Gonzalez, D., Wei, X. C., Kneidinger, N., Stoleriu, M. G., Burgstaller, G., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.09.021 · Cited by 153
“[17] The major advantage of LNP technology is its adaptability to different siRNA payloads as its physicochemical properties remain similar.”
BackgroundOptimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines
Kim, B., Hosn, R. R., Remba, T. K., Yun, D. S., Li, N., Abraham, W. D., Melo, M. B., Cortés, M., Li, B., Zhang, Y., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.11.022 · Cited by 157
Enhancing immunotherapy with tumour-responsive nanomaterials
Linderman, S. W., DeRidder, L. B., Sanjurjo, L., Foote, M. B., Alonso, M. J., Kirtane, A. R., Langer, R., & Traverso, G. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01000-6 · Cited by 165
“This interaction results in disruption of the organelle membrane and release of mRNA into the cytoplasm 27 .”
Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**
Jayaraman, M., Ansell, S. M., Mui, B. L., Tam, Y. K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J. K., et al. (2012) · Angewandte Chemie · doi:10.1002/ange.201203263 · Cited by 150
Self-citationChen, S., Tam, Y. Y. C., Lin, P. J. C., Leung, A. K. K., Tam, Y. K., & Cullis, P. R. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.09.025 · Cited by 160
Self-citationSilencing of CCR2 in myocarditis
Leuschner, F., Courties, G., Dutta, P., Mortensen, L. J., Gorbatov, R., Sena, B. F., Novobrantseva, T. I., Borodovsky, A., Fitzgerald, K. J., Koteliansky, V., et al. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu225 · Cited by 152
“A spontaneous vesicle formation formulation procedure was performed using disteroylphosphatidyl choline, cholesterol, PEG-DMG, and siRNA.(14,17) The final lipid:siRNA weight ratio was 12:1.”
MethodOligonucleotide Conjugates for Therapeutic Applications
Winkler, J. (2013) · Therapeutic Delivery · doi:10.4155/tde.13.47 · Cited by 149
mRNA vaccine in cancer therapy: Current advance and future outlook
Li, Y., Wang, M., Peng, X., Yang, Y., Chen, Q., Liu, J., She, Q., Tan, J., Lou, C., Liao, Z., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1384 · Cited by 158
Self-citationMrksich, K., Padilla, M. S., & Mitchell, M. J. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115446 · Cited by 162
Philipp, J., Dabkowska, A. P., Reiser, A., Frank, K., Krzysztoń, R., Brummer, C., Nickel, B. A., Blanchet, C. E., Sudarsan, A., Ibrahim, M., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2310491120 · Cited by 158
“Furthermore, the order of expression level follows the same trend, albeit less pronounced, as for siRNA - LNP - mediated hepatic gene silencing (18, 19).”
InfluentialYeast-Derived β-Glucan in Cancer: Novel Uses of a Traditional Therapeutic
Geller, A. E., Shrestha, R., & Yan, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153618 · Cited by 154
Delivery of CRISPR/Cas9 for therapeutic genome editing
Xu, X., Wan, T., Xin, H., Li, D., Pan, H., Wu, J., & Ping, Y. (2019) · The Journal of Gene Medicine · doi:10.1002/jgm.3107 · Cited by 134
Timko, B. P., Whitehead, K. A., Gao, W., Kohane, D. S., Farokhzad, O. C., Anderson, D. G., & Langer, R. (2011) · Annual Review of Materials Research · doi:10.1146/annurev-matsci-062910-100359 · Cited by 143
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
Exploiting RIG-I-like receptor pathway for cancer immunotherapy
Jiang, Y., Zhang, H., Wang, J., Chen, J., Guo, Z., Liu, Y., & Hua, H. M. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01405-9 · Cited by 151
“These types of LNPs are cocktails of amphipathic phospholipid, ionizable amino lipid, polyethylene glycol (PEG) lipid and cholesterol [156, 157].”
BackgroundSelf-citationCharacterization of therapeutic oligonucleotides by liquid chromatography
Goyon, A., Yehl, P., & Zhang, K. (2020) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2020.113105 · Cited by 144
Park, S., Choi, Y. K., Kim, S., Lee, J., & Im, W. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c00770 · Cited by 143
Transforming Medicine: Cutting-Edge Applications of Nanoscale Materials in Drug Delivery
Tenchov, R., Hughes, K. J., Ganesan, M., Iyer, K. A., Ralhan, K., Diaz, L. M. L., Bird, R. E., Ivanov, J. M., & Zhou, Q. A. (2025) · ACS Nano · doi:10.1021/acsnano.4c09566 · Cited by 153
Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping
Zheng, Z., Li, Z., Xu, C., Guo, B., & Guo, P. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.08.021 · Cited by 143
“Delivery strategies including cationic lipids [15], cationic liposomes [16], and cationic polymers [17] that can deliver the RNAi to cells but specific targeting is still challenging.”
BackgroundLipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid
Jia, Y., Wang, X., Li, L., Li, F., Zhang, J., & Liang, X. (2023) · Advanced Materials · doi:10.1002/adma.202305300 · Cited by 147
Lipid Delivery Systems for Nucleic-Acid-Based-Drugs: From Production to Clinical Applications
Barba, A. A., Bochicchio, S., Dalmoro, A., & Lamberti, G. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11080360 · Cited by 147
“By utilizing this method Stabilized Antisense-Lipid Particles (SALPs) can be obtained [87], i.”
MethodNovel vectors and approaches for gene therapy in liver diseases
Maestro, S., Weber, N. D., Zabaleta, N., Aldabe, R., & González‐Aseguinolaza, G. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100300 · Cited by 143
“However, the major challenge when developing LNP-based gene therapies is finding effective, tissue-specific delivery strategies.(52) Traditionally, targeting is achieved by physically or chemically conjugating ligands for specific receptors onto the nanoparticle surface.”
BackgroundTransferrin Receptor-Targeted Nanocarriers: Overcoming Barriers to Treat Glioblastoma
Ramalho, M. J., Loureiro, J. A., Coelho, M. A. N., & Pereira, M. D. C. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14020279 · Cited by 138
Cationic lipids for gene delivery: many players, one goal
Ponti, F., Campolungo, M., Melchiori, C., Bono, N., & Candiani, G. (2021) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2020.105032 · Cited by 146
Lipid nanoparticles produce chimeric antigen receptor T cells with interleukin-6 knockdown in vivo
Zhou, J., Sun, L., Jia, Y., Wang, Z., Luo, T., Tan, J., Fang, X., Zhu, H., Wang, J., Yu, L., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.08.033 · Cited by 141
Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia
Swingle, K. L., Hamilton, A. G., Safford, H. C., Geisler, H. C., Thatte, A. S., Palanki, R., Murray, A. M., Han, E. L., Mukalel, A. J., Han, X., et al. (2025) · Nature · doi:10.1038/s41586-024-08291-2 · Cited by 129
Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells
Novobrantseva, T. I., Borodovsky, A., Wong, J., Klebanov, B., Zafari, M. R., Yucius, K., Querbes, W., Ge, P., Ruda, V. M., Milstein, S., et al. (2012) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2011.3 · Cited by 137
“…efficacious mRNA silencing in hepatocytes at siRNA doses of ~1 mg/kg 6,7 and more recent reports show similar efficacy at doses of ~0.01 mg/kg. 4,5 Importantly, not only has progress been made in the potency and mechanistic understanding of how these LNP mediate siRNA delivery, 8 but also in…”
InfluentialSelf-citation
Metadata
- Authors
- Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., Hafez, I. M., Dorkin, J. R., Qin, J., Lam, K., Rajeev, K. G., Wong, K. F., Jeffs, L. B., Nechev, L., Eisenhardt, M. L., Jayaraman, M., Kazem, M., Maier, M. A., Srinivasulu, M., Weinstein, M. J., Chen, Q., Alvarez, R., Barros, S. A., De, S., Klimuk, S. K., Borland, T., Kosovrasti, V., Cantley, W. L., Tam, Y. K., Manoharan, M., Ciufolini, M. A., Tracy, M. A., de Fougerolles, A., MacLachlan, I., Cullis, P. R., Madden, T. D., & Hope, M. J.
- Affiliations
- Arbutus Biopharma (Canada) (CA)
- Alnylam Pharmaceuticals (United States) (US)
- University of British Columbia (CA)
- Corresponding author
- Semple, Sean C
- Akinc, Akin
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2010-01-17
- Volume
- 28
- Issue
- 2
- Pages
- 172-176
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2083249633
- Cited by
- 1,822
- References
- 24
- Citations by year
- 2026: 124 · 2025: 165 · 2024: 175 · 2023: 145 · 2022: 145 · 2021: 119 · 2020: 90 · 2019: 102 · 2018: 83 · 2017: 85 · 2016: 95 · 2015: 85 · 2014: 105 · 2013: 103 · 2012: 98
- FWCI
- 39.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alnylam Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- siRNA delivery, lipid nanoparticles, RNAi therapeutics, ionizable cationic lipids
- MeSH terms
- Cations, Drug Carriers, Drug Compounding, Lipids, Transfection, Drug Design, RNA, Small Interfering
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
