Nanoparticle-Mediated Delivery of MicroRNA: A Transformative Approach for Therapeutic Intervention
DOI:
https://doi.org/10.33687/ricosbiol.04.02.108Keywords:
MicroRNA delivery, nanomedicine, lipid nanoparticles (LNPs), polymeric nanoparticles, gene therapy, targeted delivery, non-viral vectors, Theranostics, clinical translationAbstract
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a pivotal role in post-transcriptional gene regulation. Their dysregulation is implicated in a myriad of diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions, making them attractive therapeutic targets or agents. However, the clinical translation of miRNA-based therapies faces significant hurdles, primarily due to poor stability, off-target effects, and inefficient cellular delivery. Nanoparticles (NPs) have emerged as a powerful platform to overcome these barriers. This review comprehensively examines the current landscape of nanocarriers—including lipid-based, polymeric, inorganic, and hybrid nanoparticles—for the safe and effective delivery of miRNA. We discuss the rational design of NPs for enhanced targeting, cellular uptake, and endosomal escape. Furthermore, we highlight recent preclinical and clinical advances in miRNA-nanoparticle therapeutics for oncology, cardiovascular diseases, and other pathologies. Finally, we address the ongoing challenges, biocompatibility concerns, regulatory landscape, and future perspectives in this rapidly evolving field, emphasizing innovations from the last five years.
Downloads
References
Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology, 29(4), 341–345. https://doi.org/10.1038/nbt.1807
Bartel, D. P. (2018). Metazoan microRNAs. Cell, 173(1), 20–51. https://doi.org/10.1016/j.cell.2018.03.006
Bobo, D., Robinson, K. J., Islam, J., Thurecht, K. J., & Corrie, S. R. (2020). Nanoparticle-based medicines: A review of FDA-approved materials and clinical trials to date. Pharmaceutical Research, 37(10), 199. https://doi.org/10.1007/s11095-020-02923-8
Calin, G. A., Sevignani, C., Dumitru, C. D., Hyslop, T., Noch, E., Yendamuri, S., ... & Croce, C. M. (2004). Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences, 101(9), 2999–3004. https://doi.org/10.1073/pnas.0307323101
Cheng, Q., Wei, T., Farbiak, L., Johnson, L. T., Dilliard, S. A., & Siegwart, D. J. (2020). Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nature Nanotechnology, 15(4), 313–320. https://doi.org/10.1038/s41565-020-0669-6
Cheng, Z., Xu, C., Liu, Y., et al. (2021). A bioreducible lipid nanoparticle for potent miRNA-34a delivery and synergistic anti-tumor therapy. Journal of Controlled Release, 336, 1–13. https://doi.org/10.1016/j.jconrel.2021.06.014
Conde, J., Oliva, N., & Artzi, N. (2020). Implantable hydrogel embedded double-stranded RNA-loaded nanoparticles for the treatment of colorectal cancer. Nature Materials, 19(10), 1102–1109. https://doi.org/10.1038/s41563-020-0716-6
Cui, G. H., Wu, J., Mou, F. F., et al. (2021). Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. The FASEB Journal, 35(2), e21310. https://doi.org/10.1096/fj.202001513R
Duan, Y., & Wang, J. (2020). Introduction of nucleic acid nanostructures for miRNA therapeutics and diagnostics. Theranostics, 10(14), 6530–6548. https://doi.org/10.7150/thno.45653
Gan, L., Wang, J., Zhao, Y., et al. (2022). A pH-responsive mesoporous silica nanoparticle-based drug delivery system for targeted breast cancer therapy. Biomaterials, 284, 121498. https://doi.org/10.1016/j.biomaterials.2022.121498
Hinkel, R., Ramanujam, D., Kaczmarek, V., et al. (2019). AntimiR-92a prevents endothelial dysfunction and improves cardiac function in large animals. European Heart Journal, 40(29), 2420–2428. https://doi.org/10.1093/eurheartj/ehz137
Hong, D. S., Kang, Y. K., Borad, M., et al. (2020). Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. British Journal of Cancer, 122(11), 1630–1637. https://doi.org/10.1038/s41416-020-0802-1
Hu, C. M. J., Zhang, L., Aryal, S., et al. (2021). Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proceedings of the National Academy of Sciences, 108(27), 10980–10985. https://doi.org/10.1073/pnas.1106634108
Huang, X., Kong, N., Zhang, X., Cao, Y., Langer, R., & Tao, W. (2024). The landscape of mRNA nanomedicine. Nature Medicine, 30(1), 13–24. https://doi.org/10.1038/s41591-023-02735-4
Jin, Y., Ma, L., & Zhang, W. (2022). Engineered exosomes: A promising tool for cancer diagnosis and therapy. Advanced Drug Delivery Reviews, 185, 114296. https://doi.org/10.1016/j.addr.2022.114296
Khan, A. A., Huat, T. J., Al Mutery, A., et al. (2022). Significant transcriptomic changes are associated with differentiation of bone marrow-derived mesenchymal stem cells into neural progenitor-like cells in the presence of bFGF and EGF. Cells, 11(3), 433. https://doi.org/10.3390/cells11030433
Lagos-Quintana, M., Rauhut, R., Lendeckel, W., & Tuschl, T. (2001). Identification of novel genes coding for small expressed RNAs. Science, 294(5543), 853-858. https://doi.org/10.1126/science.1064921
Lau, N. C., Lim, L. P., Weinstein, E. G., & Bartel, D. P. (2001). An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science, 294(5543), 858-862. https://doi.org/10.1126/science.1065062
Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5), 843-854. https://doi.org/10.1016/0092-8674(93)90529-y
Li, Y., Duo, Y., Zhai, P., et al. (2021). Dual-targeting supramolecular nanocarrier based on capped mesoporous silica nanoparticles for cancer therapy. Advanced Functional Materials, 31(12), 2008786. https://doi.org/10.1002/adfm.202008786
O’Brien, J., Hayder, H., Zayed, Y., & Peng, C. (2018). Overview of microRNA biogenesis, mechanisms of actions, and circulation. Frontiers in Endocrinology, 9, 402. https://doi.org/10.3389/fendo.2018.00402
Pasquinelli, A. E., Reinhart, B. J., Slack, F., Martindale, M. Q., Kuroda, M. I., Maller, B., ... & Ruvkun, G. (2000). Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature, 408(6808), 86-89. https://doi.org/10.1038/35040556
Pattipeiluhu, R., Arias-Alpízar, G., Basha, G., Chan, K. Y. T., & Visser, J. C. (2022). Anionic lipid nanoparticles preferentially sequester mRNA from endogenous RNA–protein complexes and deliver functional mRNA. Nature Communications, 13, 869. https://doi.org/10.1038/s41467-022-28534-y
Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C., Rougvie, A. E., ... & Ruvkun, G. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 403(6772), 901-906. https://doi.org/10.1038/35002607
Rupaimoole, R., & Slack, F. J. (2017). MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery, 16(3), 203–222. https://doi.org/10.1038/nrd.2016.246
Wang, J., Mi, P., Lin, G., Wang, Y., & Liu, G. (2022). Imaging-guided delivery of RNAi for anticancer treatment. Advanced Drug Delivery Reviews, 179, 113907. https://doi.org/10.1016/j.addr.2021.113907
Wang, Y., Xie, Y., Kilchrist, K. V., Li, J., Duvall, C. L., & Oupický, D. (2023). Endosomolytic and tumor-penetrating mesoporous silica nanoparticles for siRNA/miRNA combination therapy. ACS Nano, 17(3), 2009–2023. https://doi.org/10.1021/acsnano.2c07234
Wei, T., Liu, J., Ma, H., et al. (2023). Reactive oxygen species (ROS)-responsive nanomedicine for RNAi-based cancer therapy. Nano Today, 48, 101726. https://doi.org/10.1016/j.nantod.2022.101726
Wightman, B., Ha, I., & Ruvkun, G. (1993). Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell, 75(5), 855-862. https://doi.org/10.1016/0092-8674(93)90530-4
Xu, Y., Fourniols, T., Labrak, Y., et al. (2023). Artificial intelligence for RNA therapeutics. Nature Reviews Drug Discovery, 22(8), 661–679. https://doi.org/10.1038/s41573-023-00733-2
Zhang, M., Zang, X., Wang, M., et al. (2021). Exosome-based nanocarriers as bio-inspired and versatile vehicles for drug delivery: recent advances and challenges. Journal of Controlled Release, 337, 266–289. https://doi.org/10.1016/j.jconrel.2021.07.027
Zhang, Y., Li, H., Sun, J., et al. (2023). Targeted lipid nanoparticle delivery of microRNA-145 for the stabilization of atherosclerotic plaques. Science Advances, 9(8), eabk0852. https://doi.org/10.1126/sciadv.abk0852
Zhou, K., Nguyen, L. H., Miller, J. B., et al. (2022). Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proceedings of the National Academy of Sciences, 119(6), e2112808119. https://doi.org/10.1073/pnas.2112808119
Zhu, Y., & Wang, Z. (2024). Endosomal escape pathways for non-viral nucleic acid delivery systems. Molecular Therapy - Nucleic Acids, 35 (1), 102127. https://doi.org/10.1016/j.omtn.2024.102127
Published
Data Availability Statement
This is a review article. All data analyzed or discussed herein were derived from the publicly available research articles cited in the reference list. No new primary data were generated for this manuscript.
Issue
Section
Categories
License
Copyright (c) 2026 Hussein Abouelhag
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/ by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
