Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
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Articles
Volume 10 Number 2 2026
REVIEWS (Open Access)
Engineering Lipid Nanoparticles for Mutation-Agnostic Pulmonary Gene Therapy in Cystic Fibrosis, Beyond mRNA Vaccines
Afia Farjana Trishna 1* Md Sohel Rana 2, Most Farhana Akter 2, Anwar Hossain 3
Integrative Biomedical Research 10 (2) 1-22 https://doi.org/10.25163/biomedical.10210929
Submitted: 12 July 2026 Revised: 08 September 2026 Accepted: 14 September 2026 Published: 16 September 2026
Abstract
Cystic fibrosis (CF) is, in some sense, a disease that modern medicine has only half-solved. Small-molecule CFTR modulators have transformed outcomes for most patients, yet roughly one in ten still carries nonsense or splicing mutations for which no protein-folding corrector can help, because there is, quite literally, no protein to correct. This review works through how lipid nanoparticles (LNPs), the platform that carried mRNA vaccines into hundreds of millions of arms during the COVID-19 pandemic, are being reshaped for a very different job: reaching, and durably editing, the airway epithelium. We trace the obstacle course an inhaled LNP must survive - viscoelastic CF mucus, an apical membrane with little appetite for non-specific uptake, and a notoriously leaky endosomal escape step - and examine how five convergent design strategies (PEG and helper-lipid tuning, phytosterol substitution, selective organ targeting lipids, ligand/peptide conjugation, and dry-powder reformulation) address each obstacle. Drawing on primary human airway and organoid-level evidence, we synthesize editing efficiencies across CRISPR/Cas9, base-editing, prime-editing, and homology-directed repair platforms, and set these alongside parallel advances in ocular gene editing that illustrate how programmable nanoparticle tropism has become. We further examine extrahepatic targeting logic - route of administration, PEGylation state, and protein corona engineering - across lung endothelium versus epithelium. Finally, we map the current clinical pipeline (ARCT-032, VX-522, RCT2100, and their forerunners) against the safety and translational gaps still separating bench success from bedside cure. Altogether, the evidence points toward inhaled LNP-based gene editing converging, gradually but unmistakably, on a solution that may eventually offer a mutation-agnostic cure for CF.
Keywords: Cystic fibrosis (CFTR), Lipid nanoparticles (LNPs), Inhaled gene editing / CRISPR-Cas9, Airway epithelium delivery; mRNA-based gene therapy
References
Allaire, N. E., Griesenbach, U., Kerem, B., Lueck, J. D., Stanleigh, N., & Oren, Y. S. (2023). Gene, RNA, and ASO-based therapeutic approaches in Cystic Fibrosis. Journal of Cystic Fibrosis, 22, S39–S44. https://doi.org/10.1016/j.jcf.2022.12.016
Bhattacharya, S., et al. (2025). The vitamin D3-based ENDO platform recruits endogenous chaperones for high-precision islet β-cell gene editing. Nature Biomedical Engineering, 10(2), 211–226.
Boucher, R. C. (2019). Muco-obstructive lung diseases. New England Journal of Medicine, 380(20), 1941–1953. https://doi.org/10.1056/NEJMra1813799
Brimacombe, C. A., Kulkarni, J. A., Cheng, M. H. Y., An, K., Witzigmann, D., & Cullis, P. R. (2025). Rational design of lipid nanoparticles for enabling gene therapies. Molecular Therapy Methods & Clinical Development, 33(3), 101518. https://doi.org/10.1016/j.omtm.2025.101518
Bulcaen, M., Kortleven, P., Liu, R. B., Maule, G., Dreano, E., Kelly, M., Ensinck, M. M., Thierie, S., Smits, M., Ciciani, M., et al. (2024). Prime editing functionally corrects cystic fibrosis-causing CFTR mutations in human organoids and airway epithelial cells. Cell Reports Medicine, 5(5), 101544. https://doi.org/10.1016/j.xcrm.2024.101544
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
Cullis, P. R., & Hope, M. J. (2024). Lipid nanoparticle systems for enabling gene therapies. Molecular Therapy, 25(7), 1467–1475. https://doi.org/10.1016/j.ymthe.2017.03.013
Fan, Y., Zhou, Y., Zhao, J., & Zhao, Y. (2025). Advances in inhaled nanoparticle drug delivery for pulmonary disease management. The FASEB Journal, 39, e71191. https://doi.org/10.1096/fj.202501191
Geller, D. E., Crowley, C., Froehlich, J., et al. (2024). WS10.03 inhaled LUNAR®-CFTR mRNA (ARCT-032) is safe and well-tolerated: A phase 1 study. Journal of Cystic Fibrosis, 23, S19. https://doi.org/10.1016/S1569-1993(24)00166-8
Geurts, M. H., de Poel, E., Amatngalim, G. D., Oka, R., Meijers, F. M., Kruisselbrink, E., van Mourik, P., Berkers, G., de Winter-de Groot, K. M., Michel, S., et al. (2020). CRISPR-based adenine editors correct nonsense mutations in a cystic fibrosis organoid biobank. Cell Stem Cell, 26(4), 503–510. https://doi.org/10.1016/j.stem.2020.01.019
Hourihane, E., & Hixon, K. R. (2024). Nanoparticles as drug delivery vehicles for people with cystic fibrosis. Biomimetics, 9, 574. https://doi.org/10.3390/biomimetics9090574
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
Kim, J., Jozic, A., Lin, Y., Eygeris, Y., Bloom, E., Tan, X., Acosta, C., MacDonald, K. D., Welsher, K. D., & Sahay, G. (2022). Engineering lipid nanoparticles for enhanced intracellular delivery of mRNA through inhalation. ACS Nano, 16(9), 14792–14806. https://doi.org/10.1021/acsnano.2c05647
Lange, K. S., Wiesner, L. M., Susat, K., Köhler, V., Lenger, M., Michalek, C. A., Baack, A. L., Mundt, P. F., Kanthak, K., Guckes, I. A., Sanfilippo, L., Haverkamp, L., Mahajan, U. A., Zimmer, F. H., Zimmermann, S., Radukic, M. T., Klages, L. J., Kalinowski, J., & Müller, K. M. (2025). Towards effective cystic fibrosis gene therapy by optimizing prime editing and pulmonary-targeted LNPs. Frontiers in Systems Biology, 5, 1603749. https://doi.org/10.3389/fsysb.2025.1603749
Lin, Y., Li, M., Luo, Z., Meng, Y., Zong, Y., Ren, H., Yu, X., Tan, X., Liu, F., Wei, T., & Cheng, Q. (2026). Tissue-specific mRNA delivery and prime editing with peptide–ionizable lipid nanoparticles. Nature Materials, 25, 133–145. https://doi.org/10.1038/s41563-025-02320-9
Liu, Y., Guo, X., Hu, Q., Gan, C., Nie, S., Xiang, J., Liu, Y., Zou, J., Wu, X., Li, C., & Tang, Y. (2026). Overcoming hepatic tropism: Precision engineering of lipid nanoparticles for extrahepatic RNA delivery. Materials Today Bio, 40, 103568. https://doi.org/10.1016/j.mtbio.2026.103568
Maeda, Y., & Whitsett, J. A. (2025/2026). Targeted delivery of modified mRNA encapsulated in lipid-polymer hybrid nanoparticles to specific lung cells in vivo. Molecular Therapy, 33(12), 101244. https://doi.org/10.1016/j.ymthe.2025.12.040
Mall, M. A., Burgel, P. R., Castellani, C., Davies, J. C., Salathe, M., & Taylor-Cousar, J. L. (2024). Cystic fibrosis. Nature Reviews Disease Primers, 10(1), 53. https://doi.org/10.1038/s41572-024-00538-6
Martini, N., Deßloch, L., Sych, T., Berninghausen, O., Merl-Pham, J., Dijkstra, S., Carneiro, S. P., Frankenberger, M., Beckmann, R., Schuberth-Wagner, C., Yildirim, A. Ö., Jürgens, D. C., Sezgin, E., Merkel, O. M., & Winkeljann, B. (2026). Understanding excipient interactions unlocks untapped potential of RNA-lipid nanoparticles in dry powder formulations for local pulmonary delivery. Journal of Controlled Release, 390, 114539. https://doi.org/10.1016/j.jconrel.2025.114539
Munir, M., Butcher, N. J., Werder, R. B., Ranganathan, S. C., Burow, R., Venables, A., & Kaminskas, L. M. (2026). Inhalable gene and RNA therapy for cystic fibrosis: Perspectives and progress in clinical development. Nanomedicine, 28(7), 1003–1025. https://doi.org/10.1080/17435889.2026.1793322
Qiu, B., Manzanares, D., Li, Y., Wang, X., Li, Z., Terreau, S., He, Z., Lyu, J., Wang, W., & Lara-Sáez, I. (2024). Highly branched poly β-amino ester/CpG-depleted CFTR plasmid nanoparticles for non-viral gene therapy in lung cystic fibrosis disease. Molecular Therapy: Methods & Clinical Development, 32, 102135. https://doi.org/10.1016/j.omtn.2024.102135
Robinson, E., MacDonald, K. D., Slaughter, K., McKinney, M., Patel, S., Sun, C., Sun, C., & Sahay, G. (2018). Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis. Molecular Therapy, 26(8), 2034–2046. https://doi.org/10.1016/j.ymthe.2018.05.014
Rowe, S. M., & Engelhardt, J. F. (2025). Lipid nanoparticle (LNP)-based delivery of CFTR mRNA holds promise for treating pulmonary manifestations of cystic fibrosis. Molecular Therapy, 33(12), 101244. https://doi.org/10.1016/j.ymthe.2025.12.040
Rowe, S. M., Zuckerman, J. B., Dorgan, D., Lascano, J., McCoy, K., Jain, M., Schechter, M. S., Lommatzsch, S., Indihar, V., Lechtzin, N., McBennett, K., Callison, J., Brown, C., Liou, T. G., MacDonald, K. D., Nasr, S. Z., Bodie, S., Meltzer, E. B., & Barbier, A. J. (2023). Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. Journal of Cystic Fibrosis, 22(4), 656–664. https://doi.org/10.1016/j.jcf.2023.04.008
Santos, L., Alves, J., Farinha, C., & Harrison, P. (2026). Development of an improved adenine base editor to correct W1282X-CFTR with reduced bystander effects. Journal of Cystic Fibrosis, 22(S3), S133–S134.
Scialabba, C., Craparo, E. F., Cabibbo, M., Drago, S. E., & Cavallaro, G. (2024). Exploiting inhalable microparticles incorporating hybrid polymer-lipid nanoparticles loaded with iloprost manages lung hyper-inflammation. International Journal of Pharmaceutics, 666, 124813. https://doi.org/10.1016/j.ijpharm.2024.124813
Sinha, V., Ayoub, P. G., Juett, C. J., Lathrop, L. E., Foley, R. A., Sims, R. B., Long, J. D., Duggan, E. C., Fernandes, N. R., Illek, B., Gomperts, B. L., Jonas, S. J., & Kohn, D. B. (2026). Double-stranded DNA donors and CRISPR-Cas9 for universal correction of mutations causing cystic fibrosis in human airway cells. Molecular Therapy: Nucleic Acids, 37, 103049. https://doi.org/10.1016/j.omtn.2026.103049
Soto, M. R., Lewis, M. M., Leal, J., Pan, Y., Mohanty, R. P., Veyssi, A., Maier, E. Y., Heiser, B. J., & Ghosh, D. (2024). Discovery of peptides for ligand-mediated delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia. Molecular Therapy: Nucleic Acids, 35(4), 102375. https://doi.org/10.1016/j.omtn.2024.102375
Tafech, B., Carlaw, T., Sadhnani, G., Schmidt, K., Morin, T., Leung, J., Weiner, J., 3rd, An, K., Balázs, A., Ross, C., Beule, D., Mall, M. A., Fuchs, H., Kulkarni, J., Cullis, P. R., & Hedtrich, S. (2025). Lung tissue-optimized gene editing in human cystic fibrosis models following topical application of lipid nanoparticles. Journal of Controlled Release, 385, 114053. https://doi.org/10.1016/j.jconrel.2025.114053
Torge, A., Grützmacher, P., Mücklich, F., & Schneider, M. (2017b). The influence of mannitol on morphology and disintegration of spray-dried nano-embedded microparticles. European Journal of Pharmaceutical Sciences, 104, 171–179. https://doi.org/10.1016/j.ejps.2017.04.003
Torge, A., Wagner, S., Chaves, P. S., Oliveira, E. G., Guterres, S. S., Pohlmann, A. R., Titz, A., Schneider, M., & Beck, R. C. R. (2017a). Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis. International Journal of Pharmaceutics, 527(1–2), 92–102. https://doi.org/10.1016/j.ijpharm.2017.05.013
Torres, M., Boudko, D., Meleshkevitch, E., Coquelin, M., Yu, X., Eby, J., Ishimaru, D., Hennig, M., Bridges, R., & Wustman, B. (2021). Rescue of CFTR function in primary bronchial epithelial cells from patients with cystic fibrosis using lipid nanoparticle delivery of RNA-based therapies. Journal of Cystic Fibrosis, 20(S1), S17. https://doi.org/10.1016/S1569-1993(21)00965-6
Ugwu, O. P.-C., Ogenyi, F. C., Basajja, M., Ugwu, C. N., Mustafa, M. M., & Okon, M. B. (2026). Nanoparticle-mediated mRNA delivery for cancer, autoimmunity, and genetic diseases: A rapid review. Frontiers in Drug Delivery, 6, 1793322. https://doi.org/10.3389/fddev.2026.1793322
Witten, J., Egan, M., & Cereseto, A. (2026a). Progress and challenges in cystic fibrosis gene editing. Journal of Cystic Fibrosis, 25, 1021–1052. https://doi.org/10.1016/j.jcf.2026.04.007
Witten, J., Hu, Y., Langer, R., & Anderson, D. G. (2026b). Recent advances in nanoparticulate RNA delivery systems. Proceedings of the National Academy of Sciences, 121, e2307798120. https://doi.org/10.1073/pnas.2307798120