Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Open accessAbstract
The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic Kras G12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
siRNAs located on either side of the EV membrane can induce gene knockdown, indicating both routes are possible.
“the ability of siRNAs located on either side of the EV membrane to induce gene knockdown indicates both routes are possible15,16.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [15]
The Results describe electroporating siRNA into exosomes, and the Extended Data (Figure 4) report targeting of KRASG12D expression by siRNA-loaded exosomes. The Methods also describe mixing siRNA with exosomes as a control, but the passages do not establish that siRNA on the outside of the EV membrane induced knockdown. The claim that both locations are effective is therefore not supported in full. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOur findings have potential for rapid translation into clinic for combination trials with iExosomes or small molecular inhibitors targeting oncogenic KRAS.
“we are confident that our findings have the potential for rapid translation into the clinic for combination trials with iExosomes46 (NCT03608631) or small molecular inhibitors targeting oncogenic KRAS.”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [46]
Exosomes expressing CD47 demonstrated enhanced circulation and accumulation in pancreatic tumors, effectively reducing KrasG12D mRNA levels and inhibiting tumor growth in mouse models.
“Exosomes expressing CD47 demonstrated enhanced circulation and accumulation in pancreatic tumors, effectively reducing KrasG12D mRNA levels and inhibiting tumor growth in mouse models [96].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [96]
Exosomes engineered to deliver siRNAs that downregulate mutant KRAS, known as iExosomes, are under clinical investigation for KRASG12D-mutant PDAC.
“Exosomes are natural nanoparticles and have been engineered to deliver specific siRNAs to downregulate production of mutant KRAS (known as iExosomes) and are under clinical investigation for the treatment of KRASG12D-mutant PDAC203,204 (NCT03608631; Supplementary Table 1).”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [204]
Silencing mutant KRAS down-regulates activity of multiple Ras effector pathways including MAPK and PI3K.
“Silencing mutant KRAS down-regulates the activity of multiple Ras effector pathways including the MAPK and PI3K pathways (67, 68).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [68]
Acute silencing of KRAS via RNAi or CRISPR in KRAS mutant pancreatic cancer cells results in cell cycle arrest, apoptosis, and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models.
“In KRAS mutant pancreatic cancer cells, acute silencing of KRAS via RNAi or CRISPR results in cell cycle arrest, apoptosis and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models (66–68).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [68]
Only a few cellular sources can release exosomes sufficiently for clinical applications.
“Moreover, only a few cellular sources can release exosomes sufficiently for clinical applications [93].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [93]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids
Théry, C., Amigorena, S., Raposo, G., & Clayton, A. (2006) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0322s30 · Cited by 5,766 · see citing works
Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. A. (2011) · Nature Biotechnology · doi:10.1038/nbt.1807 · Cited by 4,930 · see citing works
Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., et al. (2009) · Science · doi:10.1126/science.1171362 · Cited by 3,170 · see citing works
Glypican-1 identifies cancer exosomes and detects early pancreatic cancer
Melo, S. A., Luecke, L. B., Kahlert, C., Fernandez, A. F., Gammon, S. T., Kaye, J., LeBleu, V. S., Mittendorf, E. A., Weitz, J., Rahbari, N., et al. (2015) · Nature · doi:10.1038/nature14581 · Cited by 2,880 · see citing works
Self-citationÖzdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.005 · Cited by 2,681 · see citing works
Self-citationA coding-independent function of gene and pseudogene mRNAs regulates tumour biology
Poliseno, L., Salmena, L., Zhang, J., Carver, B. S., Haveman, W. J., & Pandolfi, P. P. (2010) · Nature · doi:10.1038/nature09144 · Cited by 2,313 · see citing works
Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.01.007 · Cited by 2,195 · see citing works
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Initiative, A. P. C. G., Biankin, A. V., Waddell, N., Kassahn, K. S., Gingras, M.-C., Muthuswamy, L. B., Johns, A. L., Miller, D. K., Wilson, P. J., Patch, A.-M., et al. (2012) · Nature · doi:10.1038/nature11547 · Cited by 2,058 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Zheng, X., Carstens, J. L., Kim, J., Scheible, M., Kaye, J. A., Sugimoto, H., Wu, C.-C., LeBleu, V. S., & Kalluri, R. (2015) · Nature · doi:10.1038/nature16064 · Cited by 2,018 · see citing works
Self-citationBiogenesis and secretion of exosomes
Kowal, J., Tkach, M., & Théry, C. (2014) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.05.004 · Cited by 1,781 · see citing works
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., et al. (2013) · Nature · doi:10.1038/nature12138 · Cited by 1,683 · see citing works
Willingham, S. B., Volkmer, J.-P., Gentles, A. J., Sahoo, D., Dalerba, P. D., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R. K., Cohen, J. D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121623109 · Cited by 1,667 · see citing works
CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis
Jaiswal, S., Jamieson, C. H. M., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., Traver, D. J., van Rooijen, N., & Weissman, I. L. (2009) · Cell · doi:10.1016/j.cell.2009.05.046 · Cited by 1,578 · see citing works
Extracellular vesicles for drug delivery.
Vader, P., Mol, E. A., Pasterkamp, G., & Schiffelers, R. M. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.02.006 · Cited by 1,237 · see citing works
Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.007 · Cited by 1,158 · see citing works
MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease
Kordelas, L., Rebmann, V., Ludwig, A., Radtke, S., Ruesing, J., Doeppner, T. R., Epple, M., Horn, P., Beelen, D. W., & Giebel, B. (2014) · Leukemia · doi:10.1038/leu.2014.41 · Cited by 1,086 · see citing works
Integrin-associated protein (CD47) and its ligands
Brown, E. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01906-1 · Cited by 880 · see citing works
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Collins, M. A., Bednar, F., Zhang, Y., Brisset, J.-C., Galbán, S., Galbán, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & Pasca di Magliano, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59227 · Cited by 770 · see citing works
Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain
Ma, J., Ye, K., & Patel, D. J. (2004) · Nature · doi:10.1038/nature02519 · Cited by 727 · see citing works
Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G., & Bar-Sagi, D. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.024 · Cited by 721 · see citing works
Johnsen, K. B., Gudbergsson, J. M., Skov, M. N., Pilgaard, L., Moos, T., & Duroux, M. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.04.005 · Cited by 704 · see citing works
The CD47–SIRPα pathway in cancer immune evasion and potential therapeutic implications
Chao, M. P., Weissman, I. L., & Majeti, R. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.01.010 · Cited by 648 · see citing works
Exosome-mediated delivery of siRNA in vitro and in vivo
Andaloussi, S. E., Lee, Y., Lakhal‐Littleton, S., Li, J., Seow, Y., Gardiner, C., Alvarez‐Erviti, L., Sargent, I. L., & Wood, M. J. A. (2012) · Nature Protocols · doi:10.1038/nprot.2012.131 · Cited by 602 · see citing works
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
Oncogenic KRAS signalling in pancreatic cancer
Eser, S., Schnieke, A., Schneider, G., & Saur, D. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.215 · Cited by 504 · see citing works
Extracellular vesicles as drug delivery systems: Lessons from the liposome field
van der Meel, R., Fens, M. H. A. M., Vader, P., van Solinge, W. W., Eniola‐Adefeso, O., & Schiffelers, R. M. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.07.049 · Cited by 486 · see citing works
Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis
Melo, S. A., Sugimoto, H., O'Connell, J. T., Kato, N., Villanueva, A., Vidal, A., Qiu, L., Vitkin, E., Perelman, L., Melo, C., et al. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.09.005 · Cited by 453 · see citing works
Self-citationClayton, A., Harris, C. L., Court, J., Mason, M. D., & Morgan, B. P. (2003) · European Journal of Immunology · doi:10.1002/immu.200310028 · Cited by 347 · see citing works
Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras
Friedlander, S., Chu, G. C., Snyder, E. L., Girnius, N., Dibelius, G., Crowley, D. G., Vasile, E., DePinho, R. A., & Jacks, T. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.027 · Cited by 338 · see citing works
Golan, T., Khvalevsky, E. Z., Hubert, A., Gabai, R. M., Hen, N., Segal, A., Domb, A., Harari, G., David, E. B., Raskin, S., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4183 · Cited by 336 · see citing works
Therapeutic Strategies for Targeting Ras Proteins
Gysin, S., Salt, M. B., Young, A. E., & McCormick, F. (2011) · Genes & Cancer · doi:10.1177/1947601911412376 · Cited by 321 · see citing works
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 · see citing works
Cationic liposomes for gene delivery
Simões, S., Filipe, A. D. S., Faneca, H., et al. (2005) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2.2.237 · Cited by 286 · see citing works
Nakase, I., Kobayashi, N. B., Takatani‐Nakase, T., & Yoshida, T. (2015) · Scientific Reports · doi:10.1038/srep10300 · Cited by 271 · see citing works
Du, Q. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki312 · Cited by 264 · see citing works
Ijichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Bierie, B., Tada, M., Mohri, D., Miyabayashi, K., Asaoka, Y., Maeda, S., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42754 · Cited by 256 · see citing works
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
Small RNA combination therapy for lung cancer
Xue, W., Dahlman, J. E., Tammela, T., Khan, O. F., Sood, S., Dave, A., Cai, W., Chirino, L. M., Yang, G. R., Bronson, R. T., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412686111 · Cited by 243 · see citing works
Genetically engineered mouse models of pancreatic adenocarcinoma
Guerra, C. E., & Barbacid, M. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.02.002 · Cited by 179 · see citing works
KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment
Zeitouni, D., Pylayeva‐Gupta, Y., Der, C. J., & Bryant, K. L. (2016) · Cancers · doi:10.3390/cancers8040045 · Cited by 179 · see citing works
Metastatic pancreatic cancer is dependent on oncogenic Kras in mice
Collins, M. A., Brisset, J.-C., Zhang, Y., Bednar, F., Pierre, J., Heist, K. A., Galbán, C. J., Galbán, S., & di Magliano, M. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049707 · Cited by 178 · see citing works
A rapid, automated surface protein profiling of single circulating exosomes in human blood
Kibria, G., Ramos, E. K., Lee, K. E., Bedoyan, S., Huang, S., Samaeekia, R., Athman, J. J., Harding, C. V., Lötvall, J. O., Harris, L. N., et al. (2016) · Scientific Reports · doi:10.1038/srep36502 · Cited by 169 · see citing works
Kaur, S., SINGH, S. P., ELKAHLOUN, A. G., Wu, W., Abu-Asab, M. S., & Roberts, D. D. (2014) · Matrix Biology · doi:10.1016/j.matbio.2014.05.007 · Cited by 130 · see citing works
Development of siRNA Payloads to Target <i>KRAS</i> -Mutant Cancer
Yuan, T. L., Fellmann, C., Lee, C.-S., Ritchie, C. D., Thapar, V., Lee, L. C., Hsu, D. J., Grace, D., Carver, J. O., Zuber, J., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0900 · Cited by 113 · see citing works
Improving Prospects for Targeting RAS
Singh, H., Longo, D. L., & Chabner, B. A. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.62.1052 · Cited by 105 · see citing works
Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
Pecot, C. V., Wu, S. Y., Bellister, S. A., Filant, J., Rupaimoole, R., Hisamatsu, T., Bhattacharya, R., Maharaj, A., Azam, S. H., Rodriguez‐Aguayo, C., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0074 · Cited by 96 · see citing works
Réjiba, S., Wack, S., Aprahamian, M., & Hajri, A. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00506.x · Cited by 89 · see citing works
Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas
Hidalgo, M. M., & Hoff, D. D. V. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1327 · Cited by 79 · see citing works
Rachagani, S., Senapati, S., Chakraborty, S., Ponnusamy, M. P., Sushil Kumar, K., Smith, L., Jain, M., & Batra, S. K. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.31 · Cited by 77 · see citing works
Chang, D. K.-F., Grimmond, S. M., & Biankin, A. V. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.12.001 · Cited by 62 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The biology <b>,</b> function <b>,</b> and biomedical applications of exosomes
Kalluri, R., & LeBleu, V. S. (2020) · Science · doi:10.1126/science.aau6977 · Cited by 10,770 · see citing works
Self-citationShedding light on the cell biology of extracellular vesicles
van Niel, G., D'Angelo, G., & Raposo, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.125 · Cited by 8,369 · see citing works
RNA delivery by extracellular vesicles in mammalian cells and its applications
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
Challenges and directions in studying cell–cell communication by extracellular vesicles
van Niel, G., Carter, D. R. F., Clayton, A., Lambert, D. W., Raposo, G., & Vader, P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00460-3 · Cited by 1,229 · see citing works
Exosomes: key players in cancer and potential therapeutic strategy
Dai, J., Su, Y., Zhong, S., Cong, L., Liu, B., Yang, J., Tao, Y., He, Z., Chen, C., & Jiang, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00261-0 · Cited by 1,186 · see citing works
Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy
Tian, T., Zhang, H.-X., He, C.-P., Fan, S., Zhu, Y.-L., Qi, C., Huang, N.-P., Xiao, Z.-D., Lu, Z.-H., Tannous, B. A., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2017.10.012 · Cited by 1,154 · see citing works
KRAS Mutation: From Undruggable to Druggable in Cancer
Huang, L., Guo, Z., Wang, F., & Fu, L. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00780-4 · Cited by 1,127 · see citing works
Advances in therapeutic applications of extracellular vesicles
Wiklander, O. P. B., Brennan, M. Á., Lötvall, J., Breakefield, X. O., & EL Andaloussi, S. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav8521 · Cited by 1,039 · see citing works
Exosomes and Ectosomes in Intercellular Communication
Meldolesi, J. (2018) · Current Biology · doi:10.1016/j.cub.2018.01.059 · Cited by 944 · see citing works
Jia, G., Han, Y., An, Y., Ding, Y., He, C., Wang, X., & Tang, Q. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.06.029 · Cited by 753 · see citing works
Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation
Yang, Z., Shi, J., Xie, J., Wang, Y., Sun, J., Liu, T., Zhao, Y., Zhao, X., Wang, X., Ma, Y., et al. (2019) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0485-1 · Cited by 744 · see citing works
Challenges and Opportunities for Pancreatic Cancer Immunotherapy
Bear, A. S., Vonderheide, R. H., & O'Hara, M. H. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.08.004 · Cited by 674 · see citing works
Kim, M. S., Haney, M. J., Zhao, Y., Yuan, D., Deygen, I., Klyachko, N. L., Kabanov, A. V., & Batrakova, E. V. (2018) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2017.09.011 · Cited by 663 · see citing works
Efficient RNA drug delivery using red blood cell extracellular vesicles
Usman, W. M., Pham, T. C., Kwok, Y. Y., Vu, L. T., Ma, V., Peng, B., Chan, Y. S., Wei, L., Chin, S. M., Azad, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04791-8 · Cited by 663 · see citing works
Tian, Y., Gong, M., Hu, Y., Liu, H., Zhang, W., Zhang, M., Hu, X., Aubert, D., Zhu, S., Wu, L., et al. (2020) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2019.1697028 · Cited by 643 · see citing works
Exosome Processing and Characterization Approaches for Research and Technology Development
Lai, J. J., Chau, Z. L., Chen, S., Hill, J. J., Korpany, K. V., Liang, N., Lin, L., Lin, Y., Liu, J. K., Liu, Y., et al. (2022) · Advanced Science · doi:10.1002/advs.202103222 · Cited by 623 · see citing works
Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT
Zhang, X., Sai, B., Wang, F., Wang, L., Wang, Y., Zheng, L., Li, G., Tang, J., & Xiang, J. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0959-5 · Cited by 560 · see citing works
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
Engineered Extracellular Vesicles for Cancer Therapy
Zhang, X., Zhang, H., Gu, J., Zhang, J., Shi, H., Qian, H., Wang, D., Xu, W., Pan, J., & Santos, H. A. (2021) · Advanced Materials · doi:10.1002/adma.202005709 · Cited by 428 · see citing works
Anchor peptide captures, targets, and loads exosomes of diverse origins for diagnostics and therapy
Gao, X., Ran, N., Dong, X., Zuo, B., Yang, R., Zhou, Q., Moulton, H. M., Seow, Y., & Yin, H. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat0195 · Cited by 426 · see citing works
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420 · 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
Exosomes in the tumor microenvironment as mediators of cancer therapy resistance
Li, I., & Nabet, B. Y. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0975-5 · Cited by 416 · see citing works
Wang, S., Zheng, Y., Yang, F., Zhu, L., Zhu, X.-Q., Wang, Z.-F., Wu, X.-L., Zhou, C.-H., Yan, J.-Y., Hu, B.-Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00659-4 · Cited by 369 · see citing works
Cheng, G., Li, W., Ha, L., Han, X., Hao, S., Wan, Y., Wang, Z., Dong, F., Zou, X., Mao, Y., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b03584 · Cited by 371 · see citing works
KRAS mutation in pancreatic cancer
Luo, J. (2021) · Seminars in Oncology · doi:10.1053/j.seminoncol.2021.02.003 · Cited by 360 · see citing works
Extracellular vesicles: A bright star of nanomedicine
Wu, P., Zhang, B., Ocansey, D. K. W., Xu, W., & Qian, H. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2020.120467 · Cited by 368 · see citing works
Borghesan, M., Fafián-Labora, J., Eleftheriadou, O., Carpintero-Fernández, P., Paez-Ribes, M., Vizcay-Barrena, G., Swisa, A., Kolodkin-Gal, D., Ximénez-Embún, P., Lowe, R., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.095 · Cited by 315 · see citing works
“, 2015), and therapeutic carriers (Kamerkar et al., 2017).”
Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336 · see citing works
Recent advances in exosome-mediated nucleic acid delivery for cancer therapy
Zhang, Y., Liu, Q., Zhang, X., Huang, H., Tang, S., Chai, Y., Xu, Z., Li, M., Chen, X., Liu, J., et al. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01472-z · Cited by 306 · see citing works
The function and clinical application of extracellular vesicles in innate immune regulation
Zhou, X., Xie, F., Wang, L., Zhang, L., Zhang, S., Fang, M., & Zhou, F. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-0391-1 · Cited by 294 · see citing works
Chen, Y., Yang, S., Tavormina, J., Tampe, D., Zeisberg, M., Wang, H., Mahadevan, K. K., Wu, C.-J., Sugimoto, H., Chang, C.-C., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.06.011 · Cited by 289 · see citing works
Self-citationCao, J., Wang, B., Tang, T., Lv, L., Ding, Z., Li, Z., Hu, R., Wei, Q., Shen, A., Fu, Y., et al. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01719-2 · Cited by 264 · see citing works
Mahadevan, K. K., McAndrews, K. M., LeBleu, V. S., Yang, S., Lyu, H., Li, B., Sockwell, A. M., Kirtley, M. L., Morse, S. J., Moreno Diaz, B. A., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.07.002 · Cited by 258 · see citing works
Self-citationIntradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy
You, Y., Tian, Y., Yang, Z., Shi, J., Kwak, K. J., Tong, Y., Estania, A. P., Cao, J., Hsu, W.-H., Liu, Y., et al. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00989-w · Cited by 258 · see citing works
Exosome-mediated delivery of gene vectors for gene therapy
Duan, L., Xu, L., Xu, X., Qin, Z., Zhou, X., Xiao, Y., Liang, Y., & Xia, J. (2021) · Nanoscale · doi:10.1039/d0nr07622h · Cited by 238 · see citing works
O’Brien, K. P., Khan, S., Gilligan, K. E., Zafar, H., Lalor, P., Glynn, C., O’Flatharta, C., Ingoldsby, H., Dockery, P., De Bhulbh, A., et al. (2018) · Oncogene · doi:10.1038/s41388-017-0116-9 · Cited by 215 · see citing works
Mehryab, F., Rabbani, S., Shahhosseini, S., Shekari, F., Fatahi, Y., Baharvand, H., & Haeri, A. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.06.036 · Cited by 216 · see citing works
McAndrews, K. M., Xiao, F., Chronopoulos, A., LeBleu, V. S., Kugeratski, F. G., & Kalluri, R. (2021) · Life Science Alliance · doi:10.26508/lsa.202000875 · Cited by 216 · see citing works
Self-citationRAS: Striking at the Core of the Oncogenic Circuitry
Gimple, R. C., & Wang, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00965 · Cited by 174 · see citing works
Exosomes as bio-inspired nanocarriers for RNA delivery: preparation and applications
Amiri, A., Bagherifar, R., Ansari Dezfouli, E., Kiaie, S. H., Jafari, R., & Ramezani, R. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03325-7 · Cited by 186 · see citing works
Wang, J., Zhu, M., & Nie, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113974 · Cited by 153 · see citing works
Emerging Role of Extracellular Vesicles in Bone Remodeling
Liu, M., Sun, Y., & Zhang, Q. (2018) · Journal of Dental Research · doi:10.1177/0022034518764411 · Cited by 142 · see citing works
Alzahrani, F. A., Khan, M. I., Kameli, N., Alsahafi, E., & Riza, Y. M. (2023) · Biomolecules · doi:10.3390/biom13050839 · Cited by 143 · see citing works
“The benefits of EV-mediated delivery include low immunogenicity, ability to penetrate biological barriers, potential ability to reach and treat hard-to-reach areas such as solid tumors, and longer half-life in the blood compared to alternative methods [97–99].”
MethodExosome for mRNA delivery: Strategies and therapeutic applications
Iqbal, Z., Rehman, K., Mahmood, A., Shabbir, M., Liang, Y., Duan, L., & Zeng, H. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02634-x · Cited by 144 · see citing works
Exosome-mediated mRNA delivery in vivo is safe and can be used to induce SARS-CoV-2 immunity
Tsai, S. J., Atai, N. A., Cacciottolo, M., Nice, J., Salehi, A., Guo, C., Sedgwick, A., Kanagavelu, S., & Gould, S. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101266 · Cited by 142 · see citing works
Exosomes in cancer: Use them or target them?
Bastos, N., Ruivo, C. F., da Silva, S., & Melo, S. A. (2018) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2017.08.009 · Cited by 140 · see citing works
Self-citationNanomedicine-Based Approaches for mRNA Delivery
Uchida, S., Perche, F., Pichon, C., & Cabral, H. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00618 · Cited by 139 · see citing works
Casella, G., Colombo, F., Finardi, A., Descamps, H., Ill-Raga, G., Spinelli, A., Podini, P., Bastoni, M., Martino, G., Muzio, L., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.06.024 · Cited by 134 · see citing works
Blasco, M. T., Navas, C., Martín-Serrano, G., Graña-Castro, O., Lechuga, C. G., Martín-Díaz, L., Djurec, M., Li, J., Morales-Cacho, L., Esteban-Burgos, L., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.03.002 · Cited by 115 · see citing works
Research progress of CTC, ctDNA, and EVs in cancer liquid biopsy
Wang, X., Wang, L., Lin, H., Zhu, Y., Huang, D., Lai, M., Xi, X., Huang, J., Zhang, W., & Zhong, T. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1303335 · Cited by 112 · see citing works
Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer
Stefanoudakis, D., Frountzas, M., Schizas, D., Michalopoulos, N. V., Drakaki, A., & Toutouzas, K. G. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46040177 · Cited by 110 · see citing works
Truong, L.-H., & Pauklin, S. (2021) · Cancers · doi:10.3390/cancers13195028 · Cited by 102 · see citing works
Dar, G. H., Mendes, C. C., Kuan, W.-L., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., Lobo, M. J., Lim, W. F., EL Andaloussi, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27056-3 · Cited by 100 · see citing works
Extracellular vesicles in cancer nanomedicine
Tarasov, V. V., Svistunov, A. A., Chubarev, V. N., Dostdar, S. A., Sokolov, A. V., Brzecka, A., Sukocheva, O., Neganova, M. E., Klochkov, S. G., Somasundaram, S. G., et al. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.017 · Cited by 97 · see citing works
Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context
Esmaeili, A., Alini, M., Baghaban Eslaminejad, M., & Hosseini, S. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02806-2 · Cited by 94 · see citing works
Current advances in non‐viral gene delivery systems: Liposomes versus extracellular vesicles
Belhadj, Z., Qie, Y., Carney, R. P., Li, Y., & Nie, G. (2023) · BMEMat · doi:10.1002/bmm2.12018 · Cited by 79 · see citing works
KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma
Gao, G., Liao, W., Ma, Q., Zhang, B., Chen, Y., & Wang, Y. (2020) · Lung Cancer · doi:10.1016/j.lungcan.2020.09.004 · Cited by 71 · see citing works
Applications of Plant-Derived Extracellular Vesicles in Medicine
Zhu, Y., Zhao, J., Ding, H., Qiu, M., Xue, L., Ge, D., Wen, G., Ren, H., Li, P., & Wang, J. (2024) · MedComm · doi:10.1002/mco2.741 · Cited by 75 · see citing works
Analysis of extracellular vesicles as emerging theranostic nanoplatforms
Xing, Y., Cheng, Z., Wang, R., Lv, C., James, T. D., & Yu, F. (2020) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2020.213506 · Cited by 67 · see citing works
Exosome-mediated delivery of siRNA molecules in cancer therapy: triumphs and challenges
Ubanako, P., Mirza, S., Ruff, P., & Penny, C. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1447953 · Cited by 68 · see citing works
Fuller, O. K., Whitham, M., Mathivanan, S., & Febbraio, M. A. (2020) · Cells · doi:10.3390/cells9102182 · Cited by 60 · see citing works
Kalluri, V. S., Smaglo, B. G., Mahadevan, K. K., Kirtley, M. L., McAndrews, K. M., Mendt, M., Yang, S., Maldonado, A. S., Sugimoto, H., Salvatierra, M. E., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63718-2 · Cited by 70 · see citing works
Self-citationTirella, A., Kloc-Muniak, K., Good, L., Ridden, J., Ashford, M., Puri, S., & Tirelli, N. (2019) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2019.02.032 · Cited by 60 · see citing works
The Advances and Challenges in Utilizing Exosomes for Delivering Cancer Therapeutics
Yang, M., & Wu, S. Y. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00735 · Cited by 59 · see citing works
Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides
Wang, D., Wang, Q., Wang, Y., Chen, P., Lu, X., Jia, F., Sun, Y., Sun, T., Zhang, L., Che, F., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113180119 · Cited by 43 · see citing works
Techniques for increasing the yield of stem cell-derived exosomes: What factors may be involved?
Feng, Z.-Y., Zhang, Q.-Y., Tan, J., & Xie, H.-Q. (2022) · Science China Life Sciences · doi:10.1007/s11427-021-1997-2 · Cited by 40 · see citing works
Gu, Y., Ji, Y., Jiang, H., & Qiu, G. (2020) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2020.0078 · Cited by 28 · see citing works
Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy
Tang, Y., Liu, X., Sun, M., Xiong, S., Xiao, N., Li, J., He, X., & Xie, J. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15071902 · Cited by 24 · see citing works
Chen, L., Zhang, J., Wang, X., Li, Y., Zhou, L., Lu, X., Dong, G., & Sheng, C. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.07.009 · Cited by 20 · see citing works
Exosomes: Potential Biomarkers and Functions in Head and Neck Squamous Cell Carcinoma
Li, T., Li, J., Wang, H., Zhao, J., Yan, M., He, H., & Yu, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.881794 · Cited by 18 · see citing works
He, J., Xue, W., & Li, Y. (2026) · International Journal of Nanomedicine · doi:10.2147/ijn.s560983 · Cited by 16 · see citing works
Theardy, M. S., Takeda, M., Sorokin, A., Chen, S., Yang, Z., Wang, X., Kanikarla, P., Coker, O., Nguyen, P., Wei, Y., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102253 · Cited by 6 · see citing works
- Authors
- Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Universidade do Porto (PT)
- Corresponding author
- Kalluri, Raghu
- ORCID
- Venue
- Nature
- Published
- 2017-06
- Volume
- 546
- Issue
- 7659
- Pages
- 498-503
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5538883
- OpenAlex
- W2624616322
- Cited by
- 2,639
- References
- 51
- Citations by year
- 2026: 246 · 2025: 267 · 2024: 370 · 2023: 344 · 2022: 394 · 2021: 361 · 2020: 273 · 2019: 198 · 2018: 146 · 2017: 36 · 2013: 2
- FWCI
- 72.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5u24ca126577-05)
- National Cancer Institute (U24-CA-126577, R01CA213233, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- exosomes, pancreatic cancer, KRAS G12D, siRNA delivery, CD47, macropinocytosis, phagocytosis, immune clearance, liposomes, extracellular vesicles, tumor targeting, gene silencing therapy
- MeSH terms
- Animals, Disease Models, Animal, Female, Liposomes, Monocytes, Neoplasm Metastasis, Pancreatic Neoplasms, Pinocytosis, Genetic Therapy, Survival Rate, Proto-Oncogene Proteins p21(ras), Gene Silencing, RNA, Small Interfering, Mice, CD47 Antigen, Exosomes
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
