Biosensors and Nanotheranostics
Bionanotechnology, Drug Delivery, Therapeutics | online ISSN 3064-7789
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Volume 4 Number 1 2025
REVIEWS (Open Access)
Next-generation RNA medicine: antisense, siRNA, mRNA, and CRISPR systems with organ-targeted delivery
Rifat Bin Amin1*, Samima Nasrin Setu2
Biosensors and Nanotheranostics 4 (1) 1-8 https://doi.org/10.25163/biosensors.4110687
Submitted: 24 September 2025 Revised: 16 November 2025 Accepted: 26 November 2025 Published: 28 November 2025
Abstract
Over the past decade, RNA-based therapeutics have evolved from experimental molecular tools into a transformative pillar of modern medicine. This review synthesizes current evidence across inhibitory RNAs, translatable RNA platforms, precision-guided genome editing systems, and advanced delivery technologies to evaluate the clinical and technological trajectory of RNA medicine. The findings reveal a field undergoing rapid maturation, marked by landmark regulatory approvals such as antisense oligonucleotides for neurodegenerative diseases, small interfering RNA therapies for chronic metabolic disorders, mRNA-based vaccines and protein-replacement strategies, and CRISPR–Cas9 gene-editing interventions with curative potential. Despite these advances, intracellular delivery remains the principal bottleneck. Lipid nanoparticles continue to serve as the clinical gold standard; however, hepatic tropism and limited endosomal escape efficiency restrict broader tissue applications. Emerging strategies—including Selective Organ Targeting (SORT), biomimetic extracellular vesicles, stimuli-responsive nanoplatforms, and conjugation-based targeting—are reshaping extrahepatic delivery, particularly in the central nervous system and ocular tissues. Concurrently, artificial intelligence–driven optimization of RNA sequence design and nanoparticle formulation is accelerating therapeutic development and enabling the prospect of personalized “N-of-1” genomic medicine. Collectively, the evidence confirms that RNA therapeutics have moved beyond proof-of-concept into an era of programmable medicine. While challenges related to delivery efficiency, long-term safety, scalability, and global accessibility remain, the integration of molecular engineering, nanotechnology, and computational biology positions RNA platforms at the forefront of precision healthcare. The RNA renaissance is not a transient innovation—it represents a durable shift toward treating disease at its genetic foundation.
Keywords: RNA therapeutics; lipid nanoparticles; CRISPR-Cas9; precision medicine; gene silencing
References
Adams, D., et al. (2018). Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. The New England Journal of Medicine, 379(1), 11–21. https://doi.org/10.1056/NEJMoa1716153
Adams, D., et al. (2023). Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: A randomized clinical trial. Amyloid, 30(1), 1–9. https://doi.org/10.1080/13506129.2022.2091985
Al-Hamdani, M. M., Dheyaa Noori, S., & Kassem, A. B. (2023). Advancements in nanoparticle-based RNA therapeutics and RNA delivery systems. Bulletin of Pharmaceutical Sciences, 46(2), 785–801. https://doi.org/10.21608/bfsa.2023.327759
Bakris, G. L., et al. (2024). RNA interference with zilebesiran for mild to moderate hypertension: The KARDIA-1 randomized clinical trial. JAMA, 331(9), 740–749. https://doi.org/10.1001/jama.2024.0728
Balwani, M., Sardh, E., Ventura, P., Peiró, P. A., Rees, D. C., Stölzel, U., Bissell, D. M., Bonkovsky, H. L., Windyga, J., Anderson, K. E., … & ENVISION Study Group. (2020). Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. The New England Journal of Medicine, 382(24), 2289–2301. https://doi.org/10.1056/NEJMoa1913147
Banskota, S., et al. (2022). Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell, 185, 250–265. https://doi.org/10.1016/j.cell.2021.12.021
Chakraborty, C., Bhattacharya, M., Das, A., Agoramoorthy, G., & Lee, S.-S. (2026). CRISPR-Cas9-mediated therapeutics: Current clinical trials and therapy approval landscape to treat human diseases. Molecular Therapy – Nucleic Acids. https://doi.org/10.1016/j.omtn.2026.102859
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, 313–320. https://doi.org/10.1038/s41565-020-0669-6
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., et al. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science, 339, 819–823. https://doi.org/10.1126/science.1231143
Dalabehera, M., Ghosh, A., Mohanty, S., Chellappan, D. K., Chaudhari, S., Ale, Y., & Lim, H. G. (2025). mRNA delivery systems 2.0: Engineering extrahepatic targeting. Materials Today Bio, 35, 102584. https://doi.org/10.1016/j.mtbio.2025.102584
Du, J., Wu, Q., Liu, C., Wang, N., & Gong, C. (2025). CRISPR/Cas systems: Delivery and application in gene therapy. Precision Medicine and Engineering, 2, 100048. https://doi.org/10.1016/j.pme.2025.100048
Everett, W. H., & Bucelli, R. C. (2024). Tofersen for SOD1 ALS. Neurodegenerative Disease Management, 14(5), 149–160. https://doi.org/10.1080/17582024.2024.2402216
Finkel, R. S., et al. (2017). Nusinersen versus sham control in infantile-onset spinal muscular atrophy. The New England Journal of Medicine, 377, 1723–1732. https://doi.org/10.1056/NEJMoa1702752
Fontanellas, A., Berraondo, P., Urigo, F., Jericó, D., Martini, P. G. V., Pastor, F., & Avila, M. A. (2025). RNA-based therapeutics: Fundamental aspects and developments in genetic liver metabolic diseases. Gut, 74, 1514–1527. https://doi.org/10.1136/gutjnl-2023-331742
Frangoul, H., Altshuler, D., Cappellini, M. D., et al. (2021). CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassemia. The New England Journal of Medicine, 384, 252–260. https://doi.org/10.1056/NEJMoa2031054
Gillmore, J. D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M. L., Seitzer, J., O’Connell, D., Walsh, K. R., Wood, K., … & Lebwohl, D. (2021). CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. The New England Journal of Medicine, 385(6), 493–502. https://doi.org/10.1056/NEJMoa2107454
Gu, L., et al. (2026). Recent advances in nanoparticle-based RNA therapeutics and RNA delivery systems for Alzheimer's disease. International Journal of Pharmaceutics: X, 11, 100503. https://doi.org/10.1016/j.ijpx.2026.100503
Guo, T., Dong, F., Yin, J., Wang, X., Min, P., Zhang, J., et al. (2025). A novel ultrasound-responsive cluster bomb system for efficient siRNA delivery in brain. Ultrasonics Sonochemistry, 120, 107446. https://doi.org/10.1016/j.ultsonch.2025.107446
Ho, N. T., et al. (2025). Safety profile of self-amplifying mRNA SARS-CoV-2 vaccine ARCT-154 in adults: A pooled phase 1/2/3 randomized clinical study. Expert Review of Vaccines, 24(1), 299–312. https://doi.org/10.1080/14760584.2025.2487542
Huang, Y., Li, L., Do, C. W., Luo, Q., Zheng, Z., & Xiong, W. (2026). Lipid nanoparticle-mediated CRISPR/Cas9 delivery enables efficient trabecular meshwork gene editing in mice. Journal of Controlled Release, 389, 114499. https://doi.org/10.1016/j.jconrel.2025.114499
Jones, C. H., Androsavich, J. R., So, N., et al. (2024). Breaking the mold with RNA—a “RNAissance” of life science. NPJ Genomic Medicine, 9(1), 2. https://doi.org/10.1038/s41525-023-00387-4
Khan, M., Musazzi, U. M., Manellari, S., Mouawad, N., Damiano, G., Raucci, A., & Vinci, M. C. (2025). Messenger RNA (mRNA)-based therapeutics in transforming cardiovascular care: Progress, regulatory challenges and future perspectives. Pharmacological Research, 218, 107847. https://doi.org/10.1016/j.phrs.2025.107847
Lamb, Y. N. (2021). Inclisiran: First approval. Drugs, 81(3), 389–395. https://doi.org/10.1007/s40265-021-01473-6
Maeder, M. L., Stefanidakis, M., Wilson, C. J., et al. (2019). Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nature Medicine, 25, 229–233. https://doi.org/10.1038/s41591-018-0327-9
Marschhofer, M., Chen, S., Molbay, M., et al. (2026). Shaping the future from the small scale: Dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases. Journal of Controlled Release, 391, 114607. https://doi.org/10.1016/j.jconrel.2026.114607
McColgan, P., Tabrizi, S. J., Handley, E., Zeitler, B., Sah, D. W., & Tominersen Trial Investigators. (2023). Tominersen in adults with manifest Huntington’s disease. The New England Journal of Medicine, 389(23), 2203–2205. https://doi.org/10.1056/NEJMc2300400
Mendell, J. R., Goemans, N., Lowes, L. P., Alfano, L. N., Berry, K., Shao, J., … & Kaye, E. M. (2016). Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Annals of Neurology, 79(2), 257–271. https://doi.org/10.1002/ana.24555
Musa, D. A., Raji, M. O., Sikiru, A. B., Aremu, H. K., & Aigboeghian, E. A. (2024). Promising RNA-based therapies for viral infections, genetic disorders, and cancer. Academia Molecular Biology and Genomics, 1. https://doi.org/10.20935/AcadMolBioGen7329
Navid Talemi, M., Ramezani Farani, M., Alipour Eskandani, N., Mirzaee, D., Alipourfard, I., & Huh, Y. S. (2026). Programmable lipid nanoparticles for RNA therapeutics: Design principles and clinical translation. Materials Today Bio, 37, 102774. https://doi.org/10.1016/j.mtbio.2026.102774
Parums, D. V. (2024). Editorial: First regulatory approvals for CRISPR-Cas9 therapeutic gene editing for sickle cell disease and transfusion-dependent beta-thalassemia. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 30, e944204. https://doi.org/10.12659/MSM.944204
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022). Drug delivery systems for RNA therapeutics. Nature Reviews Genetics, 23, 265–280. https://doi.org/10.1038/s41576-021-00439-4
Pierce, E. A., Aleman, T. S., Zhu, X., & EDIT-101 Study Group. (2024). Gene editing for CEP290-associated retinal degeneration. The New England Journal of Medicine, 390(21), 1972–1984. https://doi.org/10.1056/NEJMoa2309915
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., … & C4591001 Clinical Trial Group. (2020). Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. The New England Journal of Medicine, 383(27), 2603–2615. https://doi.org/10.1056/NEJMoa2034577
Santos, R. D., Raal, F. J., Catapano, A. L., Witztum, J. L., Steinhagen-Thiessen, E., & Tsimikas, S. (2015). Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: Results of 4 phase III trials. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(3), 689–699. https://doi.org/10.1161/ATVBAHA.114.304549
Setia, A., Deshmukh, K., & Muthu, M. S. (2026). CRISPR/Cas9 system for the fine-tuning of cancer cell genetic and epigenetic regulation. International Journal of Biological Macromolecules, 345, 150582. https://doi.org/10.1016/j.ijbiomac.2026.150582
Shahid, U. (2025). Advances in RNA therapeutics: Classes, innovations and clinical applications. The Journal of Precision Medicine: Health and Disease, 3, 100016. https://doi.org/10.1016/j.premed.2025.100016
Shevelev, A., Pozdniakova, N., Generalov, E., & Tarasova, O. (2025). siRNA therapeutics for the treatment of hereditary diseases and other conditions: A review. International Journal of Molecular Sciences, 26, 8651. https://doi.org/10.3390/ijms26178651
Song, X., Wang, C., Ding, Q., Li, P., Sun, S., Wei, W., Zhang, J., Sun, R., Yin, L., Liu, S., & Pu, Y. (2025). Modulation of β-secretase and neuroinflammation by biomimetic nanodelivery system for Alzheimer’s disease therapy. Journal of Controlled Release, 378, 735–749. https://doi.org/10.1016/j.jconrel.2024.12.060
Sparmann, A., & Vogel, J. (2023). RNA-based medicine: From molecular mechanisms to therapy. The EMBO Journal, 42(17), e114760. https://doi.org/10.15252/embj.2023114760
Sun, Y., Cao, Y., Song, Y., Li, J., Hou, Y., Huang, W., Xie, G., Yang, W., & Zhang, R. (2025). Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates. Nature Biotechnology, 1–13. https://doi.org/10.1038/s41587-025-02628-6
Tani, H. (2024). Recent advances and prospects in RNA drug development. International Journal of Molecular Sciences, 25(22), 12284. https://doi.org/10.3390/ijms252212284
Torrisi, S. A., Geraci, F., Diolosà, L., et al. (2026). RNA-based drugs: Current, imminent and possible therapeutic applications. Pharmacology & Therapeutics, 277, 108958. https://doi.org/10.1016/j.pharmthera.2025.108958
Volpini, L., Monaco, F., Santarelli, L., Neuzil, J., & Tomasetti, M. (2023). Advances in RNA cancer therapeutics: New insight into exosomes as miRNA delivery. Aspects of Molecular Medicine, 1, 100005. https://doi.org/10.1016/j.amolm.2023.100005
Wang, S., Weissman, D., & Dong, Y. (2025). RNA chemistry and therapeutics. Nature Reviews Drug Discovery, 24(11), 828–851. https://doi.org/10.1038/s41573-025-01237-x
Weber, J. S., Carlino, M. S., Khattak, A., Meniawy, T. M., Ansstas, G., Taylor, M. H., … & KEYNOTE-942 Investigators. (2024). Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): A randomised, phase 2b study. The Lancet, 403(10427), 632–644. https://doi.org/10.1016/S0140-6736(23)02268-7
Yan, Y., Liu, S., Wen, J., et al. (2025). Advances in RNA-based cancer therapeutics: Pre-clinical and clinical implications. Molecular Cancer, 24, 251. https://doi.org/10.1186/s12943-025-02463-y
Zhu, Y., Zhu, L., Wang, X., & Jin, H. (2022). RNA-based therapeutics: An overview and prospectus. Cell Death & Disease, 13, 644. https://doi.org/10.1038/s41419-022-05075-2
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