Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown
Open accessAbstract
A central hurdle in developing small interfering RNAs (siRNAs) as therapeutics is the inefficiency of their delivery across the plasma and endosomal membranes to the cytosol, where they interact with the RNA interference machinery. With the aim of improving endosomal release, a poorly understood and inefficient process, we studied the uptake and cytosolic release of siRNAs, formulated in lipoplexes or lipid nanoparticles, by live-cell imaging and correlated it with knockdown of a target GFP reporter. siRNA release occurred invariably from maturing endosomes within ~5-15 min of endocytosis. Cytosolic galectins immediately recognized the damaged endosome and targeted it for autophagy. However, inhibiting autophagy did not enhance cytosolic siRNA release. Gene knockdown occurred within a few hours of release and required <2,000 copies of cytosolic siRNAs. The ability to detect cytosolic release of siRNAs and understand how it is regulated will facilitate the development of rational strategies for improving the cytosolic delivery of candidate drugs.
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∼2000 cytoplasmic siRNAs are estimated to achieve maximal silencing, whereas ∼50 000 are required for an ASO.
“∼2000 cytoplasmic siRNAs are estimated to achieve maximal silencing, whereas ∼50 000 are required for an ASO [54, 55].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [54]
Only a small amount of lipid nanoparticles may be able to escape from the endosome.
“Indeed, only a small amount of lipid nanoparticles may be able to escape from the endosome137–139.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [139]
Following cellular internalization, lipid nanoparticles are usually trapped in endosomal compartments.
“Following cellular internalization, lipid nanoparticles are usually trapped in endosomal compartments137–139.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [139]
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Cites
Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure.
Felgner, P. L., Gadek, T. R., Holm, M., Roman, R., Chan, H. W., Wenz, M., Northrop, J. P., RINGOLD, G. M., & Danielsen, M. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.21.7413 · Cited by 4,954 · see citing works
Huotari, J., & Helenius, A. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.286 · Cited by 2,279 · see citing works
Kimura, S., Noda, T., & Yoshimori, T. (2007) · Autophagy · doi:10.4161/auto.4451 · Cited by 2,278 · see citing works
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822 · see citing works
Self-citationDelivery materials for siRNA therapeutics
Kanasty, R., Dorkin, J. R., Vegas, A., & Anderson, D. (2013) · Nature Materials · doi:10.1038/nmat3765 · Cited by 1,800 · see citing works
Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681 · see citing works
Lentivirus-delivered stable gene silencing by RNAi in primary cells.
Stewart, S. A., Dykxhoorn, D. M., Palliser, D., Mizuno, H., Yu, E. Y., An, D., Sabatini, D., Chen, I. S. Y., Hahn, W., Sharp, P., et al. (2003) · RNA: A publication of the RNA Society · doi:10.1261/rna.2192803 · Cited by 1,619 · see citing works
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357 · see citing works
Self-citationMaximizing 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 International Edition · doi:10.1002/anie.201203263 · Cited by 1,267 · see citing works
Self-citationTargeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms
Akinc, A., Querbes, W., De, S., Qin, J., Frank-Kamenetsky, M., Jayaprakash, K. N., Jayaraman, M., Rajeev, K. G., Cantley, W. L., Dorkin, J. R., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.85 · Cited by 1,261 · see citing works
Self-citationGalectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion
Thurston, T. L. M., Wandel, M. P., von Muhlinen, N., Foeglein, Á., & Randow, F. (2012) · Nature · doi:10.1038/nature10744 · Cited by 1,034 · see citing works
Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras
McNamara, J. O., Andrechek, E. R., Wang, Y., Viles, K. D., Rempel, R. E., Gilboa, E., Sullenger, B. A., & Giangrande, P. H. (2006) · Nature Biotechnology · doi:10.1038/nbt1223 · Cited by 1,005 · see citing works
Safety and efficacy of RNAi therapy for transthyretin amyloidosis
Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P. N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1208760 · Cited by 971 · see citing works
Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
Sahay, G., Querbes, W., Alabi, C., Eltoukhy, A., Sarkar, S., Zurenko, C., Karagiannis, E., Love, K., Chen, D., Zoncu, R., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2614 · Cited by 948 · see citing works
Generation of Destabilized Green Fluorescent Protein as a Transcription Reporter
Li, X., Zhao, X., Fang, Y., Jiang, X., Duong, T., Fan, C., Huang, C.-C., & Kain, S. R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.52.34970 · Cited by 846 · see citing works
Identification of the Switch in Early-to-Late Endosome Transition
Poteryaev, D., Datta, S., Ackema, K., Zerial, M., & Spang, A. (2010) · Cell · doi:10.1016/j.cell.2010.03.011 · Cited by 752 · see citing works
EEA1, an Early Endosome-Associated Protein.
Mu, F., Callaghan, J. M., Steele‐Mortimer, O., Stenmark, H., Parton, R. G., Campbell, P. L., McCluskey, J., Yeo, J.-P., Tock, E. P. C., & Toh, B. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.22.13503 · Cited by 714 · see citing works
Maier, M. A., Jayaraman, M., Matsuda, S., Liu, J., Barros, S., Querbes, W., Tam, Y. K., Ansell, S. M., Kumar, V., Qin, J., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.124 · Cited by 625 · see citing works
Self-citationFormation and Intracellular Trafficking of Lipoplexes and Polyplexes
Elouahabi, A., & Ruysschaert, J. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2004.12.006 · Cited by 464 · see citing works
Choudhury, A., Dominguez, M., Puri, V., Sharma, D. K., Narita, K., Wheatley, C. L., Marks, D. L., & Pagano, R. E. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15420 · Cited by 407 · see citing works
Rehman, Z. U., Hoekstra, D., & Zuhorn, I. S. (2013) · ACS Nano · doi:10.1021/nn3049494 · Cited by 398 · see citing works
Galectin-3, a marker for vacuole lysis by invasive pathogens
Paz, I., Sachse, M., Dupont, N., Mounier, J., Cederfur, C., Enninga, J., Leffler, H., Poirier, F., Prévost, M., Lafont, F., et al. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01415.x · Cited by 384 · see citing works
Choudhury, A., Dominguez, M., Puri, V., Sharma, D., Narita, K., Wheatley, C. L., Marks, D. L., & Pagano, R. E. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215420 · Cited by 380 · see citing works
Internalization and Trafficking of Cell Surface Proteoglycans and Proteoglycan‐Binding Ligands
Payne, C. K., Jones, S. A., Chen, C., & Zhuang, X. (2007) · Traffic · doi:10.1111/j.1600-0854.2007.00540.x · Cited by 270 · see citing works
The rough endoplasmatic reticulum is a central nucleation site of siRNA‐mediated RNA silencing
Stalder, L., Heusermann, W., Sokol, L., Trojer, D., Wirz, J., Hean, J., Fritzsche, A., Aeschimann, F., Pfanzagl, V., Basselet, P., et al. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.52 · Cited by 229 · see citing works
Sharma, D., Choudhury, A., Singh, R. D., Wheatley, C. L., Marks, D. L., & Pagano, R. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210457200 · Cited by 218 · see citing works
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 · see citing works
Autophagy Induced by Calcium Phosphate Precipitates Targets Damaged Endosomes
Chen, X., Khambu, B., Zhang, H., Gao, W., Li, M., Chen, X., Yoshimori, T., & Yin, X. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.531855 · Cited by 81 · see citing works
Roberts, R. L., Al-Jamal, W. T., Whelband, M., Thomas, P., Jefferson, M. A., den Bossche, J. V., Powell, P. P., Kostarelos, K., & Wileman, T. E. (2013) · Autophagy · doi:10.4161/auto.23877 · Cited by 62 · see citing works
Nechaev, S., Gao, C., Moreira, D., Swiderski, P. M., Jozwiak, A. A., Kowolik, C. M., Zhou, J., Armstrong, B., Raubitschek, A. A., Rossi, J. J., et al. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.06.007 · Cited by 58 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [14]Mu FT EEA1 is a conserved α-helical peripheral membrane protein flanked by cysteine “fingers” and contains a calmodulin-binding IQ motif J. Biol. Chem 1995 270 13503 13511 7768953
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Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076 · see citing works
Cheng, Q., Wei, T., Farbiak, L., Johnson, L. T., Dilliard, S. A., & Siegwart, D. J. (2020) · Nature Nanotechnology · doi:10.1038/s41565-020-0669-6 · Cited by 2,383 · see citing works
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O’Brien, K., Breyne, K., Ughetto, S., Laurent, L. C., & Breakefield, X. O. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0251-y · Cited by 1,811 · see citing works
Therapeutic siRNA: state of the art
Hu, B., Zhong, L., Weng, Y., Peng, L., Huang, Y., Zhao, Y., & Liang, X.-J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0207-x · Cited by 1,586 · see citing works
The current state and future directions of RNAi-based therapeutics
Setten, R. L., Rossi, J. J., & Han, S.-P. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0017-4 · Cited by 1,443 · see citing works
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Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349 · see citing works
Overcoming cellular barriers for RNA therapeutics
Dowdy, S. F. (2017) · Nature Biotechnology · doi:10.1038/nbt.3802 · Cited by 1,139 · see citing works
Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses
Mitter, N., Worrall, E. A., Robinson, K. E., Li, P., Jain, R. G., Taochy, C., Fletcher, S. J., Carroll, B. S., Lu, G. Q., & Xu, Z. P. (2017) · Nature Plants · doi:10.1038/nplants.2016.207 · Cited by 1,080 · see citing works
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
Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine
Donahue, N. D., Acar, H., & Wilhelm, S. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.04.008 · Cited by 962 · see citing works
mRNA vaccine for cancer immunotherapy
Miao, L., Zhang, Y., & Huang, L. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01335-5 · Cited by 947 · see citing works
Finn, J. D., Smith, A. R., Patel, M. C., Shaw, L., Youniss, M. R., van Heteren, J., Dirstine, T., Ciullo, C., Lescarbeau, R., Seitzer, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.014 · Cited by 878 · 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
Knocking down disease: a progress report on siRNA therapeutics
Wittrup, A., & Lieberman, J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3978 · Cited by 810 · see citing works
Self-citationTools for translation: non-viral materials for therapeutic mRNA delivery
Hajj, K. A., & Whitehead, K. A. (2017) · Nature Reviews Materials · doi:10.1038/natrevmats.2017.56 · Cited by 799 · see citing works
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Stewart, M. P., Langer, R., & Jensen, K. F. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00678 · Cited by 748 · see citing works
Dilliard, S. A., & Siegwart, D. J. (2023) · Nature Reviews Materials · doi:10.1038/s41578-022-00529-7 · Cited by 707 · see citing works
Liu, S., Cheng, Q., Wei, T., Yu, X., Johnson, L. T., Farbiak, L., & Siegwart, D. J. (2021) · Nature Materials · doi:10.1038/s41563-020-00886-0 · Cited by 653 · see citing works
Johannes, L., Jacob, R., & Leffler, H. (2018) · Journal of Cell Science · doi:10.1242/jcs.208884 · Cited by 631 · see citing works
Therapeutic Targeting of Long Non-Coding RNAs in Cancer
Arun, G., Diermeier, S. D., & Spector, D. L. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.01.001 · Cited by 612 · see citing works
Endosomal escape: A bottleneck for LNP-mediated therapeutics
Chatterjee, S., Kon, E., Sharma, P., & Peer, D. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307800120 · Cited by 607 · see citing works
Advances in COVID-19 mRNA vaccine development
Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D., & Li, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00950-y · Cited by 601 · see citing works
Self-citationLipid nanoparticles for nucleic acid delivery: Current perspectives
Samaridou, E., Heyes, J. A., & Lutwyche, P. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.002 · Cited by 593 · see citing works
Endocytosis of Extracellular Vesicles and Release of Their Cargo from Endosomes
Joshi, B. S., de Beer, M. A., Giepmans, B. N. G., & Zuhorn, I. S. (2020) · ACS Nano · doi:10.1021/acsnano.9b10033 · Cited by 585 · see citing works
Understanding Cell Penetration of Cyclic Peptides
Dougherty, P. G., Sahni, A., & Pei, D. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.9b00008 · Cited by 581 · see citing works
Miller, J. B., Zhang, S., Kos, P., Xiong, H., Zhou, K., Perelman, S. S., Zhu, H., & Siegwart, D. J. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201610209 · Cited by 540 · see citing works
Yanez Arteta, M., Kjellman, T., Bartesaghi, S., Wallin, S., Wu, X., Kvist, A. J., Dabkowska, A., Székely, N., Radulescu, A., Bergenholtz, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720542115 · Cited by 534 · see citing works
Therapeutic in vivo delivery of gene editing agents
Raguram, A., Banskota, S., & Liu, D. R. (2022) · Cell · doi:10.1016/j.cell.2022.03.045 · Cited by 532 · see citing works
Kim, J., Eygeris, Y., Gupta, M., & Sahay, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.014 · Cited by 514 · see citing works
Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Maugeri, M., Nawaz, M., Papadimitriou, A., Angerfors, A., Camponeschi, A., Na, M., Hölttä, M., Skantze, P., Johansson, S., Sundqvist, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12275-6 · Cited by 428 · see citing works
Carriers Break Barriers in Drug Delivery: Endocytosis and Endosomal Escape of Gene Delivery Vectors
Degors, I. M. S., Wang, C., Rehman, Z. U., & Zuhorn, I. S. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00177 · Cited by 426 · see citing works
Therapeutic siRNA: State-of-the-Art and Future Perspectives
Friedrich, M., & Aigner, A. M. (2022) · BioDrugs · doi:10.1007/s40259-022-00549-3 · Cited by 413 · 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
The great escape: how cationic polyplexes overcome the endosomal barrier
Buś, T., Traeger, A., & Schubert, U. S. (2018) · Journal of Materials Chemistry B · doi:10.1039/c8tb00967h · Cited by 411 · see citing works
Overcoming Endosomal Entrapment in Drug Delivery
Pei, D., & Buyanova, M. Y. (2018) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.8b00778 · Cited by 405 · see citing works
Brief update on endocytosis of nanomedicines
Patel, S., Kim, J., Herrera‐Barrera, M., Mukherjee, A., Kabanov, A. V., & Sahay, G. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.08.004 · Cited by 402 · see citing works
Materials for non-viral intracellular delivery of messenger RNA therapeutics
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Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures
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Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems
Guan, S., & Rosenecker, J. (2017) · Gene Therapy · doi:10.1038/gt.2017.5 · Cited by 389 · see citing works
Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles
Schlich, M., Palomba, R., Costabile, G., Mizrahy, S., Pannuzzo, M., Peer, D., & Decuzzi, P. (2021) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10213 · Cited by 387 · see citing works
Nonviral cancer gene therapy: Delivery cascade and vector nanoproperty integration
Zhou, Z., Liu, X., Zhu, D., Wang, Y., Zhang, Z., Zhou, X., Qiu, N., Chen, X., & Shen, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.07.021 · Cited by 380 · see citing works
Self-citationCurrent Multistage Drug Delivery Systems Based on the Tumor Microenvironment
Chen, B., Dai, W., He, B., Zhang, H., Wang, X., Wang, Y., & Zhang, Q. (2017) · Theranostics · doi:10.7150/thno.16684 · Cited by 347 · see citing works
Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver
Miao, L., Lin, J., Huang, Y., Li, L., Delcassian, D., Ge, Y., Shi, Y., & Anderson, D. G. (2020) · Nature Communications · doi:10.1038/s41467-020-16248-y · Cited by 343 · see citing works
Three decades of messenger RNA vaccine development
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2019) · Nano Today · doi:10.1016/j.nantod.2019.100766 · Cited by 342 · see citing works
Evers, M. J. W., Kulkarni, J. A., van der Meel, R., Cullis, P. R., Vader, P., & Schiffelers, R. M. (2018) · Small Methods · doi:10.1002/smtd.201700375 · Cited by 332 · see citing works
Sago, C. D., Lokugamage, M. P., Paunovska, K., Vanover, D. A., Monaco, C. M., Shah, N. N., Gamboa Castro, M., Anderson, S. E., Rudoltz, T. G., Lando, G. N., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811276115 · Cited by 313 · see citing works
Hajj, K. A., Ball, R. L., Deluty, S. B., Singh, S. R., Strelkova, D., Knapp, C. M., & Whitehead, K. A. (2019) · Small · doi:10.1002/smll.201805097 · Cited by 312 · see citing works
Emerging non-viral vectors for gene delivery
Wang, C., Pan, C., Yong, H., Wang, F., Bo, T., Zhao, Y., Ma, B., He, W., & Li, M. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-02044-5 · Cited by 309 · see citing works
Suzuki, Y., & Ishihara, H. (2021) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2021.100424 · Cited by 304 · see citing works
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Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates
Brown, C. R., Gupta, S., Qin, J., Racie, T., He, G., Lentini, S., Malone, R., Yu, M., Matsuda, S., Shulga-Morskaya, S., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa670 · Cited by 285 · see citing works
Self-citationJung, H. N., Lee, S.-Y., Lee, S., Youn, H., & Im, H.-J. (2022) · Theranostics · doi:10.7150/thno.77259 · Cited by 282 · see citing works
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Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA
Patel, S., Ashwanikumar, N., Robinson, E., DuRoss, A., Sun, C., Murphy-Benenato, K. E., Mihai, C., Almarsson, Ö., & Sahay, G. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b02664 · Cited by 251 · see citing works
Gandek, T. B., van der Koog, L., & Nagelkerke, A. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202300319 · Cited by 242 · see citing works
Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale
Paramasivam, P., Franke, C., Stöter, M., Höijer, A., Bartesaghi, S., Sabirsh, A., Lindfors, L., Arteta, M. Y., Dahlén, A., Bak, A., et al. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202110137 · Cited by 228 · see citing works
Álvarez‐Benedicto, E., Farbiak, L., Ramírez, M. M., Wang, X., Johnson, L. T., Mian, O. T., Guerrero, E. D., & Siegwart, D. J. (2021) · Biomaterials Science · doi:10.1039/d1bm01454d · Cited by 227 · see citing works
Jeong, M., Lee, Y., Park, J., Jung, H., & Lee, H. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114990 · Cited by 227 · see citing works
Cheng, Q., Wei, T., Jia, Y., Farbiak, L., Zhou, K., Zhang, S., Wei, Y., Zhu, H., & Siegwart, D. J. (2018) · Advanced Materials · doi:10.1002/adma.201805308 · Cited by 221 · see citing works
Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles
Vermeulen, L. M. P., Brans, T., Samal, S. K., Dubruel, P., Demeester, J., Smedt, S. C. D., Remaut, K., & Braeckmans, K. (2018) · ACS Nano · doi:10.1021/acsnano.7b07583 · Cited by 216 · see citing works
Dong, Y., Yu, T., Ding, L., Laurini, E., Huang, Y., Zhang, M., Weng, Y., Lin, S., Chen, P., Marson, D., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b10021 · Cited by 213 · see citing works
Self-citationImaging small molecule-induced endosomal escape of siRNA
Rietz, H. D., Hedlund, H., Wilhelmson, S., Nordenfelt, P., & Wittrup, A. (2020) · Nature Communications · doi:10.1038/s41467-020-15300-1 · Cited by 203 · see citing works
Self-citationDirect cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes
Zhuo, Y., Luo, Z., Zhu, Z., Wang, J., Li, X., Zhang, Z., Guo, C., Wang, B., Nie, D., Gan, Y., et al. (2024) · Nature Nanotechnology · doi:10.1038/s41565-024-01785-0 · Cited by 203 · see citing works
Tapping the RNA world for therapeutics
Lieberman, J. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0054-4 · Cited by 195 · see citing works
Self-citationLipid-based nanoparticle formulations for small molecules and RNA drugs
Ickenstein, L. M., & Garidel, P. (2019) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2019.1669558 · Cited by 193 · see citing works
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 187 · see citing works
Zhou, 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 184 · see citing works
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 180 · see citing works
Wang, Y., Xie, Y., Kilchrist, K. V., Li, J., Duvall, C. L., & Oupický, D. (2020) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.9b21214 · Cited by 175 · see citing works
Liu, S., Wang, X., Yu, X., Cheng, Q., Johnson, L. T., Chatterjee, S., Zhang, D., Lee, S. M., Sun, Y., Lin, T., et al. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c09822 · Cited by 175 · see citing works
Yoon, J., Gurusamy, D., & Palli, S. R. (2017) · Insect Biochemistry and Molecular Biology · doi:10.1016/j.ibmb.2017.09.011 · Cited by 172 · see citing works
Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery
Herrera‐Barrera, M., Kim, J., Eygeris, Y., Jozić, A., & Sahay, G. (2021) · Biomaterials Science · doi:10.1039/d0bm01947j · Cited by 172 · see citing works
Leveraging 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 · see citing works
Rui, Y., Wilson, D. R., Tzeng, S. Y., Yamagata, H. M., Sudhakar, D., Conge, M., Berlinicke, C. A., Zack, D. J., Tuesca, A. D., & Green, J. J. (2022) · Science Advances · doi:10.1126/sciadv.abk2855 · Cited by 168 · see citing works
López-Bertoni, H., Kozielski, K., Rui, Y., Lal, B., Vaughan, H. J., Wilson, D. R., Mihelson, N., Eberhart, C. G., Laterra, J., & Green, J. J. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b00390 · Cited by 164 · see citing works
Reshke, R., Taylor, J. A., Savard, A., Guo, H., Rhym, L. H., Kowalski, P. S., Trung, M. T., Campbell, C. M., Little, W., Anderson, D. G., et al. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0502-4 · Cited by 163 · see citing works
Omo‐Lamai, S., Wang, Y., Patel, M. N., Milosavljevic, A., Zuschlag, D. W., Poddar, S., Wu, J., Wang, L., Dong, F., Espy, C. L., et al. (2025) · Nature Nanotechnology · doi:10.1038/s41565-025-01974-5 · Cited by 162 · see citing works
Au, J. L. ‐., Yeung, B. Z., Wientjes, M. G., Lu, Z., & Wientjes, M. G. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.12.002 · Cited by 161 · see citing works
Tanowitz, M., Hettrick, L. A., Revenko, A. S., Kinberger, G. A., Prakash, T. P., & Seth, P. P. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx960 · Cited by 161 · see citing works
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
Dowdy, S. F. (2023) · RNA · doi:10.1261/rna.079507.122 · Cited by 160 · see citing works
Delivery 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 158 · see citing works
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 156 · see citing works
Mrksich, K., Padilla, M. S., & Mitchell, M. J. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115446 · Cited by 155 · see citing works
Challenges in carrier‐mediated intracellular delivery: moving beyond endosomal barriers
Stewart, M. P., Lorenz, A. S., Dahlman, J. E., & Sahay, G. (2015) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1377 · Cited by 154 · see citing works
Lipid peroxidation causes endosomal antigen release for cross-presentation
Dingjan, I., Verboogen, D. R. J., Paardekooper, L. M., Revelo, N. H., Sittig, S. P., Visser, L. J., von Mollard, G. F., Henriet, S., Figdor, C. G., ter Beest, M., et al. (2016) · Scientific Reports · doi:10.1038/srep22064 · Cited by 153 · see citing works
Nanoparticles for cancer gene therapy: Recent advances, challenges, and strategies
Wang, K., Kievit, F. M., & Zhang, M. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.10.016 · Cited by 152 · see citing works
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 149 · see citing works
Lee, S. M., Cheng, Q., Yu, X., Liu, S., Johnson, L. T., & Siegwart, D. J. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202013927 · Cited by 140 · see citing works
Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery
Hu, M., Li, X., You, Z., Cai, R., & Chen, C. (2023) · Advanced Materials · doi:10.1002/adma.202303266 · Cited by 133 · see citing works
Global analyses of the dynamics of mammalian microRNA metabolism
Kingston, E. R., & Bartel, D. P. (2019) · Genome Research · doi:10.1101/gr.251421.119 · Cited by 133 · see citing works
Visualization of self-delivering hydrophobically modified siRNA cellular internalization
Ly, S., Navaroli, D. M., Didiot, M.-C., Cardia, J., Pandarinathan, L., Alterman, J. F., Fogarty, K., Standley, C., Lifshitz, L. M., Bellve, K. D., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkw1005 · Cited by 132 · see citing works
Escaping the endosome: assessing cellular trafficking mechanisms of non-viral vehicles
Xu, E., Saltzman, W. M., & Piotrowski-Daspit, A. S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.05.038 · Cited by 132 · see citing works
Responsive Nanocarriers as an Emerging Platform for Cascaded Delivery of Nucleic Acids to Cancer
Liu, Y., Xu, C., Iqbal, S., Yang, X., & Wang, J. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.03.004 · Cited by 130 · see citing works
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
mRNA nanomedicine: Design and recent applications
Kubiatowicz, L. J., Mohapatra, A., Krishnan, N., Fang, R. H., & Zhang, L. (2022) · Exploration · doi:10.1002/exp.20210217 · Cited by 130 · see citing works
- Authors
- Wittrup, A., Ai, A., Liu, X., Hamar, P., Trifonova, R., Charisse, K., Manoharan, M., Kirchhausen, T., & Lieberman, J.
- Affiliations
- Boston Children's Hospital (US)
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Wittrup, Anders
- Lieberman, Judy
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2015-07-20
- Volume
- 33
- Issue
- 8
- Pages
- 870-876
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC4663660
- OpenAlex
- W1844274376
- Cited by
- 693
- References
- 30
- Citations by year
- 2026: 101 · 2025: 104 · 2024: 82 · 2023: 60 · 2022: 59 · 2021: 63 · 2020: 53 · 2019: 40 · 2018: 54 · 2017: 37 · 2016: 31 · 2015: 8
- FWCI
- 18.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA139444, CA139444)
- National Institute of General Medical Sciences (GM075252, R01GM075252)
- National Institute of Allergy and Infectious Diseases (AI090671, AI057159, R01AI090671, U54AI057159)
- 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 › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- siRNA delivery, endosomal escape, lipoplexes, lipid nanoparticles, endocytosis, autophagy, galectins, gene knockdown, live-cell imaging, RNA interference, siRNA therapeutics
- MeSH terms
- HeLa Cells, Humans, Lipids, Luminescent Proteins, Endosomes, RNA Interference, RNA, Small Interfering, Nanoparticles, Gene Knockdown Techniques
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