Osteoclast-targeted delivery of anti-miRNA oligonucleotides by red blood cell extracellular vesicles
Abstract
Osteoporosis (OP) affects millions worldwide but currently cannot be cured. Suppressing the level of miR-214 in osteoclasts by the anti-miRNA oligonucleotide (AMO) anti-miR-214 reverses bone absorption and provides a potential treatment. Here we report a peptide-guided delivery strategy using red blood cell extracellular vesicles (RBCEVs) as the vehicle to realize osteoclast-targeted delivery of anti-miR-214. A bi-functional peptide, TBP-CP05, which binds to both the CD63 on RBCEVs and receptors on osteoclasts, acts as the guide. TBP-CP05 binds with RBCEVs through CP05, displays the TRAP-binding peptide (TBP) on the surface of EVs, and endows RBCEVs with osteoclast-targeting capability both in vitro and in vivo. Intravenous injection of the osteoclast-targeting RBCEVs (OT-RBCEVs) led to the enrichment of EVs in the bone skeleton, significant inhibition of the osteoclast activity, elevated osteoblast activity, and improved bone density in osteoporotic mice. Altogether, this work demonstrates efficient guidance of drug-loaded EVs to the targeted cells in vivo using bi-functional fusion peptides, and showcases that targeted delivery of anti-miR-214 by OT-RBCEVs may be a viable method for OP treatment. SIGNIFICANCE STATEMENT. Surface functionalization of EVs endows these nanovesicles cell-specific targeting property which guides the drug cargos to specific tissues and cells with higher accuracy, longer retention, and minimal off-target effects. Methods to functionalize EVs with minimal procedures are highly desired for clinical applications. Here we present a facile method using a bifunctional fusion peptide to guide RBCEVs to osteoclasts. A simple incubation of the bifunctional peptide and RBCEVs results in osteoclast-targeting RBCEVs (OT-RBCEVs) that effectively deliver anti-miR-214 to osteoclasts in vivo in a mouse model of osteoporosis, bringing a potential therapy to osteoporotic patients. This is, to our knowledge, the first report on peptide functionalization of RBCEVs and osteoclast-targeted delivery using RBCEVs.
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Two main approaches can be used to enhance targeting ability of exosomes: direct chemical modification or indirect genetic engineering.
“Two main approaches can be used to enhance the targeting ability of exosomes for specific applications: direct modification of exosomes by chemical means or, indirect manipulation of the donor cells through genetic engineering techniques [89, 103, 118–120]”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [120]
Cites
Revised Estimates for the Number of Human and Bacteria Cells in the Body
Sender, R., Fuchs, S., & Milo, R. (2016) · PLOS Biology · doi:10.1371/journal.pbio.1002533 · Cited by 5,425 · see citing works
Compston, J. E., McClung, M. R., & Leslie, W. D. (2019) · The Lancet · doi:10.1016/s0140-6736(18)32112-3 · Cited by 2,449 · see citing works
Mechanism of Eukaryotic Homologous Recombination
Filippo, J. S., Sung, P., & Klein, H. L. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.061306.125255 · Cited by 1,686 · see citing works
Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation.
Glass, D. A., Bialek, P., Ahn, J. D., Starbuck, M., Patel, M. S., Clevers, H., Taketo, M. M., Long, F., McMahon, A. P., Lang, R. A., et al. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.02.017 · Cited by 1,558 · see citing works
Engineering exosomes for targeted drug delivery
Liang, Y., Duan, L., Lu, J., & Xia, J. (2021) · Theranostics · doi:10.7150/thno.52570 · Cited by 1,547 · see citing works
Self-citationKauffman, K. J., Dorkin, J. R., Yang, J. H., Heartlein, M. W., DeRosa, F., Mir, F. F., Fenton, O. S., & Anderson, D. G. (2015) · Nano Letters · doi:10.1021/acs.nanolett.5b02497 · Cited by 785 · 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
Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation
Li, D., Liu, J., Guo, B., Liang, C., Dang, L., Lu, C., He, X., Cheung, H. Y.-S., Xu, L., Lu, C., et al. (2016) · Nature Communications · doi:10.1038/ncomms10872 · Cited by 588 · see citing works
Self-citationmiR-214 targets ATF4 to inhibit bone formation
Wang, X., Guo, B., Li, Q., Peng, J., Yang, Z., Wang, Y., Li, D., Hou, Z., Lv, K., Kan, G., et al. (2012) · Nature Medicine · doi:10.1038/nm.3026 · Cited by 561 · see citing works
Osteoporosis: A Review of Treatment Options.
Tu, K. N., Lie, J. D., Wan, C. K. V., Cameron, M., Austel, A. G., Nguyen, J. K., Van, K., & Hyun, D. (2018) · PubMed Central · Cited by 534 · see citing works
Surface Functionalization of Exosomes Using Click Chemistry
Smyth, T., Petrova, K., Payton, N. M., Persaud, I., Redzic, J. S., Graner, M. W., Smith-Jones, P., & Anchordoquy, T. J. (2014) · Bioconjugate Chemistry · doi:10.1021/bc500291r · Cited by 532 · see citing works
Advances in the regulation of osteoclasts and osteoclast functions
Boyce, B. F. (2013) · Journal of Dental Research · doi:10.1177/0022034513500306 · Cited by 457 · 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
Liang, Y., Xu, X., Li, X., Xiong, J., Li, B., Duan, L., Wang, D., & Xia, J. (2020) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.0c10458 · Cited by 391 · see citing works
Self-citationXu, X., Liang, Y., Li, X., Ouyang, K., Wang, M., Cao, T., Li, W., Liu, J., Xiong, J., Li, B., et al. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2020.120539 · Cited by 377 · see citing works
Self-citationThe Regulation of Bone Metabolism and Disorders by Wnt Signaling
Maeda, K., Kobayashi, Y., Koide, M., Uehara, S., Okamoto, M., Ishihara, A., Kayama, T., Saito, M., & Marumo, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225525 · Cited by 353 · see citing works
Ryu, J., Kim, H. J., Chang, E., Huang, H., Banno, Y., & Hong‐Hee, K. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601430 · Cited by 318 · see citing works
Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity
Sun, W., Zhao, C., Li, Y., Wang, L., Nie, G., Peng, J., Wang, A., Zhang, P., Tian, W., Li, Q., et al. (2016) · Cell Discovery · doi:10.1038/celldisc.2016.15 · Cited by 308 · see citing works
Self-citationSnapShot: Extracellular Vesicles
Cocozza, F., Grisard, E., Jaular, L. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.054 · Cited by 308 · see citing works
Cdk2 suppresses cellular senescence induced by the c-myc oncogene
Campaner, S., Doni, M., Hydbring, P., Verrecchia, A., Bianchi, L., Sardella, D., Schleker, T., Perna, D., Tronnersjö, S., Murga, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb2004 · Cited by 251 · see citing works
Pham, T. C., Jayasinghe, M. K., Pham, T. T., Yang, Y., Wei, L., Usman, W. M., Chen, H., Pirisinu, M., Gong, J., Kim, S., et al. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12057 · Cited by 250 · see citing works
Danesh, A., Inglis, H. C., Jackman, R. P., et al. (2013) · Blood · doi:10.1182/blood-2013-10-530469 · Cited by 249 · 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
Self-citationmiR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway
Zhao, C., Sun, W., Zhang, P., Ling, S., Li, Y., Dingsheng, Z., Peng, J., Wang, A., Li, Q., Song, J., et al. (2015) · RNA Biology · doi:10.1080/15476286.2015.1017205 · Cited by 234 · see citing works
Self-citationOsteoclast precursors, RANKL/RANK, and immunology
Xing, L., Schwarz, E. M., & Boyce, B. F. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00336.x · Cited by 234 · see citing works
Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development
Li, H., Xiao, Z., Quarles, L. D., & Li, W. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867327666200330142432 · Cited by 226 · see citing works
Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes
Shi, J., Kundrat, L., Pishesha, N., Bilate, A. M. B., Theile, C. S., Maruyama, T., Dougan, S. K., Ploegh, H. L., & Lodish, H. F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409861111 · Cited by 212 · see citing works
Ye, Z., Zhang, T., He, W., Jin, H., Liu, C., Yang, Z., & Ren, J. (2018) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b18135 · Cited by 206 · see citing works
Molecular Mechanisms in Coupling of Bone Formation to Resorption
Martin, T. J., Gooi, J. H., & Sims, N. A. (2009) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v19.i1.40 · Cited by 167 · see citing works
Liang, Y., Iqbal, Z., Lu, J., Wang, J., Zhang, H., Chen, X., Duan, L., & Xia, J. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2022.10.008 · Cited by 162 · see citing works
Self-citationGap junctions and hemichannels in signal transmission, function and development of bone
Batra, N. R., Kar, R., & Jiang, J. X. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2011.09.018 · Cited by 157 · see citing works
Wu, K., Feng, J., Lyu, F., Xing, F., Sharma, S., Liu, Y., Wu, S.-Y., Zhao, D., Tyagi, A., Deshpande, R. P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25473-y · Cited by 152 · see citing works
MiR-214 regulate gastric cancer cell proliferation, migration and invasion by targeting PTEN
Yang, T., Yang, X., Wang, X., et al. (2013) · Cancer Cell International · doi:10.1186/1475-2867-13-68 · Cited by 151 · see citing works
Bi, H., Chen, X., Gao, S., Yu, X., Xiao, J., Zhang, B., Liu, X., & Dai, M. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00234 · Cited by 145 · see citing works
Zhao, B., & Ivashkiv, L. B. (2011) · Arthritis Research & Therapy · doi:10.1186/ar3379 · Cited by 144 · see citing works
Zhou, Y., Deng, Y., Liu, Z., Yin, M., Hou, M., Zhao, Z., Zhou, X., & Yin, L. (2021) · Science Advances · doi:10.1126/sciadv.abl6432 · Cited by 126 · see citing works
MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα
Bae, S., Lee, M. J., Mun, S. H., Γιαννοπούλου, Ε., Yong‐Gonzalez, V., Cross, J. R., Murata, K., Giguère, V., van der Meulen, M. C. H., & Park‐Min, K. (2017) · Journal of Clinical Investigation · doi:10.1172/jci89935 · Cited by 120 · see citing works
Osteoporosis Remission and New Bone Formation with Mesoporous Silica Nanoparticles
Mora‐Raimundo, P., Lozano, D., Benito, M., Mulero, F., Manzano, M., & Vallet‐Regí, M. (2021) · Advanced Science · doi:10.1002/advs.202101107 · Cited by 115 · see citing works
Mashel, T. V., Tarakanchikova, Y. V., Muslimov, A. R., Zyuzin, M. V., Timin, A. S., Lepik, K. V., & Fehse, B. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120282 · Cited by 100 · see citing works
Misiewicz-Krzemińska, I., Sarasquete, M. E., Quwaider, D., Krzemiński, P., Ticona, F. V., Paíno, T., Delgado, M., Aires, A., Ocio, E. M., García‐Sánz, R., et al. (2012) · Haematologica · doi:10.3324/haematol.2012.070011 · Cited by 85 · see citing works
Ejiri, S. (1983) · Archivum histologicum japonicum · doi:10.1679/aohc.46.533 · Cited by 82 · see citing works
MiR‐214 is an important regulator of the musculoskeletal metabolism and disease
Sun, Y., Kuek, V., Liu, Y., Tickner, J. C., Yuan, Y. J., Chen, L., Zeng, Z., Shao, M., He, W., & Xu, J. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26856 · Cited by 80 · see citing works
Li, X., Liang, Y., Lian, C., et al. (2021) · Theranostics · doi:10.7150/thno.62187 · Cited by 72 · see citing works
Self-citationGu, C., Wang, W., Tang, X., Xu, T., Zhang, Y., Guo, M., Wei, R., Wang, Y., Jurczyszyn, A. J., Janz, S., et al. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01380-0 · Cited by 70 · see citing works
Sheu, T., Schwarz, E. M., O’Keefe, R. J., et al. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.5.915 · Cited by 51 · see citing works
Bottani, M., Banfi, G., & Lombardi, G. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01044 · Cited by 49 · see citing works
Chen, K., Ng, P. Y., Chen, R., Hu, D. Z., Berry, S., Baron, R., & Gori, F. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900881116 · Cited by 45 · see citing works
Borgheti-Cardoso, L. N., Kooijmans, S. A. A., Gutiérrez-Chamorro, L., Biosca, A., Lantero, E., Ramírez, M., Avalos‐Padilla, Y., Crespo, I., Fernández, I., Fernández-Becerra, C., et al. (2020) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2020.119627 · Cited by 44 · see citing works
Wang, C., Sun, W., Ling, S., Wang, Y., Wang, X., Meng, H., Li, Y., Yuan, X., Liu, R., Liu, R., et al. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.09.030 · Cited by 43 · see citing works
Blood cell-derived extracellular vesicles: diagnostic biomarkers and smart delivery systems
Xu, L., Liang, Y., Xu, X. G., Xia, J., Wen, C., Zhang, P., & Duan, L. (2021) · Bioengineered · doi:10.1080/21655979.2021.1982320 · Cited by 40 · see citing works
Self-citationShafiey, S. I., Mohamed, W. R., & Abo‐Saif, A. A. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.09.046 · Cited by 39 · see citing works
Tao, S., Yu, F., Song, Y., et al. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.11.059 · Cited by 39 · see citing works
Exosome-Mediated Drug Delivery for Cell-Free Therapy of Osteoarthritis
Duan, L., Xu, X. G., Xu, L., et al. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327666201118161232 · Cited by 35 · see citing works
Self-citationWeivoda, M. M., Lee, S., & Monroe, D. G. (2020) · Bone · doi:10.1016/j.bone.2020.115757 · Cited by 34 · see citing works
Migration and differentiation of osteoclast precursors under gradient fluid shear stress
Gao, Y., Li, T., Sun, Q., Ye, C., Guo, M., Chen, Z., Chen, J., & Huo, B. (2019) · Biomechanics and Modeling in Mechanobiology · doi:10.1007/s10237-019-01171-z · Cited by 25 · see citing works
Gradient fluid shear stress regulates migration of osteoclast precursors
Gao, Y., Li, T., Sun, Q., et al. (2019) · Cell Adhesion & Migration · doi:10.1080/19336918.2019.1619433 · Cited by 22 · see citing works
Cytoplasmic PCNA is located in the actin belt and involved in osteoclast differentiation
Tang, D., Liu, X., Chen, K., Li, Z., Dai, Y., Xu, J., Zhang, H., Gao, X., & Liu, L. (2020) · Aging · doi:10.18632/aging.103434 · Cited by 22 · see citing works
Insight into the possible role of miR‐214 in primary osteoporosis via osterix
Mohamad, N., Nabih, E. S., Zakaria, Z. M., et al. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28818 · Cited by 18 · see citing works
Weivoda, M. M., Ruan, M. M., Hachfeld, C. M., et al. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3740 · Cited by 17 · see citing works
Gao, Y., Jin, H., Tan, H. Q., et al. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1a0220-666r · Cited by 16 · see citing works
A novel nano delivery system targeting different stages of osteoclasts
Zhang, B., Zhao, J., Yan, H., Zhao, Y., Tian, H., Cao, W. F., Wang, R. L., Jin, J., Chen, Y., Yang, C., et al. (2022) · Biomaterials Science · doi:10.1039/d2bm00076h · Cited by 15 · see citing works
Chen, H., Li, S., Yin, H., et al. (2021) · Bioengineered · doi:10.1080/21655979.2021.2008666 · Cited by 13 · see citing works
Lorenzo, J. A. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-72009-8_10 · Cited by 7 · see citing works
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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
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Self-citation
- Authors
- Xu, L., Xu, X., Liang, Y., Wen, C., Ouyang, K., Huang, J., Xiao, Y., Deng, X., Xia, J., & Duan, L.
- Affiliations
- Shenzhen University (CN)
- Chinese University of Hong Kong (HK)
- City University of Hong Kong (HK)
- Queensland University of Technology (AU)
- Corresponding author
- Xia, Jiang
- Duan, Li
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2023-06
- Volume
- 358
- Pages
- 259-272
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W4367601861
- Cited by
- 65
- References
- 63
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 24 · 2023: 14
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research Grants Council, University Grants Committee (R5013-19)
- Jining Medical University (2022-BS-03, 2022-BS-04)
- National Natural Science Foundation of China (81772394, 81972116, 82102607)
- China Postdoctoral Science Foundation (2020M682907, 2021M702286)
- 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
- osteoporosis, osteoclasts, antagomir, miR-214, CD63, bone resorption, bone mineral density
- MeSH terms
- Extracellular Vesicles, Antagomirs, Animals, Erythrocytes, Oligonucleotides, Osteoclasts, Osteoporosis, Peptides, MicroRNAs, Mice
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