Breath and Life: Emerging Nanotechnologies for Cystic Fibrosis Therapy

Abstract

The treatment of cystic fibrosis (CF) remains challenging due to formidable biological barriers in the lungs, including thick mucus and resilient biofilms that severely limit the efficacy of conventional therapies. Nanotechnology, engineered to overcome these barriers, is emerging as a transformative approach for CF therapy. This opinion highlighted the most recent and advanced nanotechnologies, categorizing them into four strategic frontiers: (1) nanocarriers that achieve mucus penetration through surface modifications; (2) nanoplatforms for efficient delivery of genetic therapeutics; (3) nanocarriers for antimicrobial delivery to cure infections associated with CF; and (4) combinatorial nanomedicines for synchronized delivery of multiple drugs. We concluded that, with the help of these nanotechnologies, therapies for CF will now undergo a paradigm shift, moving CF from a fatal disease to a treatable and potentially curable one. Although the clinical transition is challenging, it holds immense promise for revolutionizing CF management.

Keywords

Cystic fibrosis / Nanotechnology / Gene therapy / Antimicrobial / Mucus penetration

Author Contributions

Conceptualization, X.Z. and Z.H.; Investigation, D.P.; Writing—Original Draft Preparation, D.P.; Writing—Review & Editing, X.Z. and Z.H.; Supervision, X.Z. and Z.H.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Funding

This work was supported by Guangdong Natural Science Foundation (No.2024A1515010896) and Youth S&T Talent Support Program of Guangdong Provincial Association for Science and Technology (Grant No.SKXRC2025338).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Mall MA, Burgel PR, Castellani C, Davies JC, Salathe M, Taylor-Cousar JL. Cystic fibrosis. Nat. Rev. Dis. Primers. 2024, 10, 53. doi:10.1038/s41572-024-00538-6.

[2] Polgreen PM, Comellas AP. Clinical Phenotypes of Cystic Fibrosis Carriers. Annu. Rev. Med. 2022, 73, 563-574. doi:10.1146/annurev-med-042120-020148.

[3] Grasemann H, Ratjen F. Cystic Fibrosis. N. Engl. J. Med. 2023, 389, 1693-1707. doi:10.1056/NEJMra2216474.

[4] Jia SJ, Taylor-Cousar JL. Cystic Fibrosis Modulator Therapies. Annu. Rev. Med. 2023, 74, 413-426. doi:10.1146/annurev-med-042921-021447.

[5] Graeber SY, Mall MA. The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches. Lancet 2023, 402, 1185-1198. doi:10.1016/S0140-6736(23)01608-2.

[6] George M, Boukherroub R, Sanyal A, Szunerits S. Treatment of lung diseases via nanoparticles and nanorobots: Are these viable alternatives to overcome current treatments? Mater. Today Bio. 2025, 31, 101616. doi:10.1016/j.mtbio.2025.101616.

[7] Suk JS, Lai SK, Wang YY, Ensign LM, Zeitlin PL, Boyle MP, et al. The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles. Biomaterials 2009, 30, 2591-2597. doi:10.1016/j.biomaterials.2008.12.076.

[8] Zhao J, Qin L, Song RX, Su J, Yuan Y, Zhang X, et al. Elucidating inhaled liposome surface charge on its interaction with biological barriers in the lung. Eur. J. Pharm. Biopharm. 2022, 172, 101-111. doi:10.1016/j.ejpb.2022.01.009.

[9] Leal J, Peng XJ, Liu XQ, Arasappan D, Wylie DC, Schwartz SH, et al. Peptides as surface coatings of nanoparticles that penetrate human cystic fibrosis sputum and uniformly distribute in vivo following pulmonary delivery. J. Control. Release 2020, 322, 457-469. doi:10.1016/j.jconrel.2020.03.032.

[10] Hu SS, Yang ZX, Wang S, Wang LP, He QQ, Tang H, et al. Zwitterionic polydopamine modified nanoparticles as an efficient nanoplatform to overcome both the mucus and epithelial barriers. Chem. Eng. J. 2022, 428, 132107. doi:10.1016/j.cej.2021.132107.

[11] Huckaby JT, Lai SK. PEGylation for enhancing nanoparticle diffusion in mucus. Adv. Drug Deliv. Rev. 2018, 124, 125-139. doi:10.1016/j.addr.2017.08.010.

[12] Christopher Boyd A, Guo SL, Huang LL, Kerem B, Oren YS, Walker AJ, et al. New approaches to genetic therapies for cystic fibrosis. J. Cyst. Fibros. 2020, 19, S54-S59. doi:10.1016/j.jcf.2019.12.012.

[13] Maldonado I, Gallego I, Enriquez-Rodriguez L, Ibarra AI, Arbe A, Mashal M, et al. A novel gene delivery approach to face cystic fibrosis by non-viral vectors based on niocarbosomes. Surf. Interf. 2025, 68, 106639. doi:10.1016/j.surfin.2025.106639.

[14] Zhang MJ, Lu HY, Xie LK, Liu XL, Cun DM, Yang MS. Inhaled RNA drugs to treat lung diseases: Disease-related cells and nano-bio interactions. Adv. Drug Deliv. Rev. 2023, 203, 115144. doi:10.1016/j.addr.2023.115144.

[15] Bai X, Chen QJ, Li FQ, Teng YL, Tang MP, Huang J, et al. Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy. Nat. Commun. 2024, 15, 6844. doi:10.1038/s41467-024-51056-8.

[16] Zhang KQ, Zhou Y, Wang GL, Zhu B, Zhao ZY, Kong X, et al. Pulmonary mRNA delivery systems for the treatment of respiratory diseases: Current advances and challenges. Chin. Chem. Lett. 2025, 36, 111887. doi:10.1016/j.cclet.2025.111887.

[17] Davies JC, Polineni D, Boyd AC, Donaldson S, Gill DR, Griesenbach U, et al. Lentiviral gene therapy for cystic fibrosis: A promising approach and first-in-human trial. Am. J. Respir. Crit. Care Med. 2024, 210, 1398-1408. doi:10.1164/rccm.202402-0389CI.

[18] Gill NA, Fung V, VanKeulen-Miller R, Narasipura EA, Fenton OS. Non-viral mRNA cystic fibrosis therapies and their ongoing clinical trials. Expert Opin. Drug Deliv. 2025. doi:10.1080/17425247.2025.2586172.

[19] Taccetti G, Terlizzi V, Campana S, Dolce D, Ravenni N, Fevola C, et al. Antibiotic treatment of bacterial lung infections in cystic fibrosis. Eur. J. Pediatr. 2024, 184, 82. doi:10.1007/s00431-024-05905-9.

[20] Zou Y, Liang CM, Tang ZQ, Huang YT, Liang CF, Chen LM, et al. Biofilm-Responsive Nano-Antibiotics for Degradation of Extracellular Polymeric Substance Matrix and Reduction of Pathogenicity against Drug-Resistant Bacterial Infections. ACS Nano. 2025, 19, 29702-29716. doi:10.1021/acsnano.5c09764.

[21] Zhou Y, Huang JY, Wang GL, Zhai ZZ, Ahmed MU, Xia X, et al. Polymyxin B sulfate inhalable microparticles with high-lectin-affinity sugar carriers for efficient treatment of biofilm-associated pulmonary infections. Sci. Bull. 2023, 68, 3225-3239. doi:10.1016/j.scib.2023.11.004.

[22] Qin SG, Xiao W, Zhou CM, Pu QQ, Deng X, Lan LF, et al. Pseudomonas aeruginosa: Pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics. Signal Transduct. Target. Ther. 2022, 7, 199. doi:10.1038/s41392-022-01056-1.

[23] Blanco-Cabra N, Alcàcer-Almansa J, Admella J, Arévalo-Jaimes BV, Torrents E. Nanomedicine against biofilm infections: A roadmap of challenges and limitations. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2024, 16, e1944. doi:10.1002/wnan.1944.

[24] Al-Momani H, Albalawi H, Al Balawi D, Khleifat KM, Aolymat I, Hamed S, et al. Enhanced Efficacy of Some Antibiotics in the Presence of Silver Nanoparticles Against Clinical Isolate of Pseudomonas aeruginosa Recovered from Cystic Fibrosis Patients. IJN 2024, 19, 12461-12481. doi:10.2147/IJN.S479937.

[25] Maset RG, Hapeshi A, Lapage J, Harrington N, Littler J, Perrier S, et al. Combining SNAPs with antibiotics shows enhanced synergistic efficacy against S. aureus and P. aeruginosa biofilms. Npj Biofilms Microbiomes 2023, 9, 36. doi:10.1038/s41522-023-00401-8.

[26] Benderski K, Lammers T, Sofias AM. Analysis of multi-drug cancer nanomedicine. Nat. Nanotechnol. 2025, 20, 1163-1172. doi:10.1038/s41565-025-01932-1.

[27] Wei P, Ding YS, Liu SN, Jiang JH, Chen JH. Luminescent Nanocucurbits Enable Spatiotemporal Co-Delivery of Hydrophilic and Hydrophobic Chemotherapeutic Agents. Adv. Sci. 2025, 12, e09782. doi:10.1002/advs.202509782.