Skip to main content
See More

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Inhalable materials and biologics for lung defence and drug delivery

Nature Reviews Materials (2025)Cite this article

Subjects

Abstract

Airway mucus has a crucial role in protecting against inhaled pathogens and regulating water homeostasis, but it can also diminish the efficacy of therapeutic pulmonary delivery. Recent development in inhalable materials and biologics has introduced strategies to modify mucus properties, strengthening mucosal protection, advancing drug delivery and targeting and supporting effective water regulation. In this Review, we thoroughly examine the structure and function of airway mucus, along with the challenges and opportunities it presents for inhaled treatments. We explore new methods that enhance the protective role of mucus through physical reinforcement, pathogen neutralization, muco-trapping and rehydration, as well as strategies that overcome the mucus barrier to improve drug delivery, including physical modulation, mucoadhesive design, muco-penetrating design, mucolytics and active targeting. Finally, we discuss the clinical implications of these promising strategies, emphasizing the need to balance mucosal function with optimized therapeutic delivery. We seek to explore prospective ways to improve inhalation therapies for both infectious and chronic lung diseases by reviewing recent progress in inhalable materials and biologics.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Airway mucus structure and function.
Fig. 2: Timeline of inhalable materials and biologics development for mucus barrier enhancement and pulmonary drug delivery.
Fig. 3: Strategies to enhance mucus barrier function.
Fig. 4: Physical and biological barriers for pulmonary drug delivery.
Fig. 5: Strategies for material and biologic pulmonary delivery, categorized by delivered agent type for each strategy.
Fig. 6: Clinical implications and outlook of inhalable materials and biologics of next decade.

Similar content being viewed by others

References

  1. Edwards, D. A. et al. Global warming risks dehydrating and inflaming human airways. Commun. Earth Environ. 6, 193 (2025).

    PubMed  PubMed Central  Google Scholar 

  2. Lillehoj, E. P. & Kim, K. C. Airway mucus: its components and function. Arch. Pharm. Res. 25, 770–780 (2002).

    CAS  PubMed  Google Scholar 

  3. Ridley, C. & Thornton, D. J. Mucins: the frontline defence of the lung. Biochem. Soc. Trans. 46, 1099–1106 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Hill, D. B., Button, B., Rubinstein, M. & Boucher, R. C. Physiology and pathophysiology of human airway mucus. Physiol. Rev. 102, 1757–1836 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Zanin, M., Baviskar, P., Webster, R. & Webby, R. The interaction between respiratory pathogens and mucus. Cell Host Microbe 19, 159–168 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Evans, C. M. & Koo, J. S. Airway mucus: the good, the bad, the sticky. Pharmacol. Ther. 121, 332–348 (2009).

    CAS  PubMed  Google Scholar 

  7. Labiris, N. R. & Dolovich, M. B. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 56, 588–599 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Subramani, P. K., Remya, P., Narayanasamy, D. & Kumar, P. The role of pulmonary drug delivery in modern therapeutics: an overview. Cureus 16, e68639 (2024).

    Google Scholar 

  9. He, S. et al. A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases. J. Nanobiotechnol. 20, 101 (2022).

    CAS  Google Scholar 

  10. Nyström, A. & Bruckner-Tuderman, L. Gene therapy for epidermolysis bullosa: sticky business. Mol. Ther. 24, 2035–2036 (2016).

    PubMed  PubMed Central  Google Scholar 

  11. Chen, D., Liu, J., Wu, J. & Suk, J. S. Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung. Expert Opin. Drug Deliv. 18, 595–606 (2021).

    PubMed  Google Scholar 

  12. Yue, L. et al. Inhaled drug delivery: past, present, and future. Nano Today 52, 101942 (2023).

    CAS  Google Scholar 

  13. Pangeni, R. et al. Airway mucus in pulmonary diseases: muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers. Int. J. Pharm. 634, 122661 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lai, S. K., Wang, Y.-Y., Wirtz, D. & Hanes, J. Micro-and macrorheology of mucus. Adv. Drug Deliv. Rev. 61, 86–100 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Brockhausen, I., Schachter, H. & Stanley, P. in Essentials of Glycobiology 2nd edn Ch. 9 (eds Varki, A. et al.) (Cold Spring Harbor Laboratory Press, 2009).

  16. Stanley, P., Sundaram, S., Tang, J. & Shi, S. Molecular analysis of three gain-of-function CHO mutants that add the bisecting GlcNAc to N-glycans. Glycobiology 15, 43–53 (2005).

    CAS  PubMed  Google Scholar 

  17. Button, B. et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337, 937–941 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ganesan, S., Comstock, A. T. & Sajjan, U. S. Barrier function of airway tract epithelium. Tissue Barriers 1, e24997 (2013).

    PubMed  PubMed Central  Google Scholar 

  19. Lai, S. K., Wang, Y.-Y., Cone, R., Wirtz, D. & Hanes, J. Altering mucus rheology to ‘solidify’ human mucus at the nanoscale. PLoS ONE 4, e4294 (2009).

    PubMed  PubMed Central  Google Scholar 

  20. Fais, F. et al. Drug-free nasal spray as a barrier against SARS-CoV-2 and its delta variant: in vitro study of safety and efficacy in human nasal airway epithelia. Int. J. Mol. Sci. 23, 4062 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Joseph, J. et al. Toward a radically simple multi-modal nasal spray for preventing respiratory infections. Adv. Mater. 36, 2406348 (2024).

    CAS  Google Scholar 

  22. Zaderer, V. et al. ColdZyme protects airway epithelia from infection with BA.4/5. Respir. Res. 23, 300 (2022).

    PubMed  Google Scholar 

  23. Posch, W. et al. ColdZyme maintains integrity in SARS-CoV-2-infected airway epithelia. mBio 12, 00904-21 (2021).

    Google Scholar 

  24. Moakes, R. J., Davies, S. P., Stamataki, Z. & Grover, L. M. Formulation of a composite nasal spray enabling enhanced surface coverage and prophylaxis of SARS-COV-2. Adv. Mater. 33, 2008304 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bentley, K. & Stanton, R. J. Hydroxypropyl methylcellulose-based nasal sprays effectively inhibit in vitro SARS-CoV-2 infection and spread. Viruses 13, 2345 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Eccles, R. et al. Efficacy and safety of an antiviral iota-carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold. Respir. Res. 11, 1–10 (2010).

    Google Scholar 

  27. Robinson, T. E., Moakes, R. J. & Grover, L. M. Low acyl gellan as an excipient to improve the sprayability and mucoadhesion of iota carrageenan in a nasal spray to prevent infection with SARS-CoV-2. Front. Med. Technol. 3, 687681 (2021).

    PubMed  PubMed Central  Google Scholar 

  28. Pyrć, K. et al. SARS-CoV-2 inhibition using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray. Sci. Rep. 11, 20012 (2021).

    PubMed  PubMed Central  Google Scholar 

  29. Masutomi, Y., Goto, T. & Ichikawa, T. Mouth breathing reduces oral function in adolescence. Sci. Rep. 14, 3810 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mei, X. et al. An inhaled bioadhesive hydrogel to shield non-human primates from SARS-CoV-2 infection. Nat. Mater. 22, 903–912 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Deng, J. et al. Electrical bioadhesive interface for bioelectronics. Nat. Mater. 20, 229–236 (2021).

    CAS  PubMed  Google Scholar 

  32. Haut, B. et al. Comprehensive analysis of heat and water exchanges in the human lungs. Front. Physiol. 12, 649497 (2021).

    PubMed  PubMed Central  Google Scholar 

  33. Crouzier, T. A defensive blanket against viral infection of the lungs. Nat. Mater. 22, 803–804 (2023).

    CAS  PubMed  Google Scholar 

  34. Balmforth, D. et al. Evaluating the efficacy and safety of a novel prophylactic nasal spray in the prevention of SARS-CoV-2 infection: a multi-centre, double blind, placebo-controlled, randomised trial. J. Clin. Virol. 155, 105248 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bovard, D. et al. Iota-carrageenan extracted from red algae is a potent inhibitor of SARS-CoV-2 infection in reconstituted human airway epithelia. Biochem. Biophys. Rep. 29, 101187 (2022).

    CAS  PubMed  Google Scholar 

  36. Paull, J. R. et al. Protective effects of astodrimer sodium 1% nasal spray formulation against SARS-CoV-2 nasal challenge in K18-hACE2 mice. Viruses 13, 1656 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018 (2020).

    CAS  PubMed  Google Scholar 

  38. Dussupt, V. et al. Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations. Nat. Immunol. 22, 1503–1514 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ju, B. et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 584, 115–119 (2020).

    CAS  PubMed  Google Scholar 

  40. Pinto, D. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583, 290–295 (2020).

    CAS  PubMed  Google Scholar 

  41. Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shi, R. et al. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 584, 120–124 (2020).

    CAS  PubMed  Google Scholar 

  43. Rogers, T. F. et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 369, 956–963 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zost, S. J. et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443–449 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Oti, V. B., Idris, A. & McMillan, N. A. Intranasal antivirals against respiratory syncytial virus: the current therapeutic development landscape. Expert Rev. Anti Infect. Ther. 22, 647–657 (2024).

    CAS  PubMed  Google Scholar 

  46. Yang, B. et al. ZMapp reinforces the airway mucosal barrier against Ebola virus. J. Infect. Dis. 218, 901–910 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang, Z., Li, C., Song, Y., Ying, T. & Wu, Y. Inhalable antibodies for the treatment of COVID-19. Innovation 3, 100328 (2022).

    PubMed  PubMed Central  Google Scholar 

  48. Zhang, H. et al. Advances in developing ACE2 derivatives against SARS-CoV-2. Lancet Microbe 4, e369–e378 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tu, B., Gao, Y., An, X., Wang, H. & Huang, Y. Localized delivery of nanomedicine and antibodies for combating COVID-19. Acta Pharm. Sin. B 13, 1828–1846 (2023).

    CAS  PubMed  Google Scholar 

  50. El-Shennawy, L. et al. Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nat. Commun. 13, 405 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kuate, S., Cinatl, J., Doerr, H. W. & Überla, K. Exosomal vaccines containing the S protein of the SARS coronavirus induce high levels of neutralizing antibodies. Virology 362, 26–37 (2007).

    CAS  PubMed  Google Scholar 

  52. Li, G. et al. The therapeutic potential of exosomes in immunotherapy. Front. Immunol. 15, 1424081 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu, C. et al. Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles. Acta Pharm. Sin. B 12, 1523–1533 (2022).

    CAS  PubMed  Google Scholar 

  54. Xie, F. et al. Engineering extracellular vesicles enriched with palmitoylated ACE2 as COVID-19 therapy. Adv. Mater. 33, 2103471 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Li, Z. et al. Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19. Nat. Nanotechnol. 16, 942–951 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Conde, J., Langer, R. & Rueff, J. mRNA therapy at the convergence of genetics and nanomedicine. Nat. Nanotechnol. 18, 537–540 (2023).

    CAS  PubMed  Google Scholar 

  57. Chen, M. et al. Nanotraps for the containment and clearance of SARS-CoV-2. Matter 4, 2059–2082 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fang, R. H., Kroll, A. V., Gao, W. & Zhang, L. Cell membrane coating nanotechnology. Adv. Mater. 30, 1706759 (2018).

    Google Scholar 

  59. Liu, Y., Yao, S., Deng, L., Ming, J. & Zeng, K. Different mechanisms of action of isolated epiphytic yeasts against Penicillium digitatum and Penicillium italicum on citrus fruit. Postharvest Biol. Technol. 152, 100–110 (2019).

    Google Scholar 

  60. Liu, J., Spruijt, E., Miserez, A. & Langer, R. Peptide-based liquid droplets as emerging delivery vehicles. Nat. Rev. Mater. 8, 139–141 (2023).

    CAS  Google Scholar 

  61. Zhang, Q. et al. Cellular nanosponges inhibit SARS-CoV-2 infectivity. Nano Lett. 20, 5570–5574 (2020).

    CAS  PubMed  Google Scholar 

  62. Zhang, H. et al. Inhalable nanocatchers for SARS-CoV-2 inhibition. Proc. Natl Acad. Sci. USA 118, e2102957118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Mahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S. & Nabipour, I. COVID-19 cytokine storm: the anger of inflammation. Cytokine 133, 155151 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, Z. et al. Inhaled ACE2-engineered microfluidic microsphere for intratracheal neutralization of COVID-19 and calming of the cytokine storm. Matter 5, 336–362 (2022).

    PubMed  Google Scholar 

  65. Paiardi, G. et al. The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms. J. Biol. Chem. 298, 101507 (2022).

    CAS  PubMed  Google Scholar 

  66. Ai, X. et al. Surface glycan modification of cellular nanosponges to promote SARS-CoV-2 inhibition. J. Am. Chem. Soc. 143, 17615–17621 (2021).

    CAS  PubMed  Google Scholar 

  67. Qi, Y. et al. Delivery of therapeutic levels of heparin and low-molecular-weight heparin through a pulmonary route. Proc. Natl Acad. Sci. USA 101, 9867–9872 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Tu, B. et al. Inhaled heparin polysaccharide nanodecoy against SARS-CoV-2 and variants. Acta Pharm. Sin. B 12, 3187 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Clausen, T. M. et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell 183, 1043–1057.e15 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Baranova, E., Shastina, N. & Shvets, V. Polyanionic inhibitors of HIV adsorption. Russ. J. Bioorg. Chem. 37, 527–542 (2011).

    CAS  Google Scholar 

  71. Gao, Y., Liu, W., Wang, W., Zhang, X. & Zhao, X. The inhibitory effects and mechanisms of 3, 6-O-sulfated chitosan against human papillomavirus infection. Carbohydr. Polym. 198, 329–338 (2018).

    CAS  PubMed  Google Scholar 

  72. Karthik, R., Manigandan, V., Saravanan, R., Rajesh, R. P. & Chandrika, B. Structural characterization and in vitro biomedical activities of sulfated chitosan from Sepia pharaonis. Int. J. Biol. Macromol. 84, 319–328 (2016).

    CAS  PubMed  Google Scholar 

  73. Li, X., Wu, P., Gao, G. F. & Cheng, S. Carbohydrate-functionalized chitosan fiber for influenza virus capture. Biomacromolecules 12, 3962–3969 (2011).

    CAS  PubMed  Google Scholar 

  74. Schaefer, A. & Lai, S. K. The biophysical principles underpinning muco-trapping functions of antibodies. Hum. Vaccin. Immunother. 18, 1939605 (2022).

    PubMed  Google Scholar 

  75. Wang, Y.-Y. et al. IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections. Mucosal Immunol. 7, 1036–1044 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang, Y.-Y. et al. Influenza-binding antibodies immobilise influenza viruses in fresh human airway mucus. Eur. Respir. J. 49, 1601709 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. McSweeney, M. D. et al. Inhaled ‘muco-trapping’ monoclonal antibody effectively treats established respiratory syncytial virus (RSV) infections. Adv. Sci. 11, 2306729 (2024).

    CAS  Google Scholar 

  78. Syed, Y. Y. Regdanvimab: first approval. Drugs 81, 2133–2137 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. McSweeney, M. D. et al. Stable nebulization and muco-trapping properties of regdanvimab/IN-006 support its development as a potent, dose-saving inhaled therapy for COVID-19. Bioeng. Transl. Med. 8, e10391 (2023).

    CAS  Google Scholar 

  80. Moench, T. R. et al. A randomized, double-blind, phase 1, single- and multiple-dose placebo-controlled study of the safety and pharmacokinetics of IN-006, an inhaled antibody treatment for COVID-19 in healthy volunteers. EBioMedicine 113, 105582 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Wessler, T. et al. Using computational modeling to optimize the design of antibodies that trap viruses in mucus. ACS Infect. Dis. 2, 82–92 (2016).

    CAS  PubMed  Google Scholar 

  82. Müller, W. E. et al. Morphogenetic (mucin expression) as well as potential anti-corona viral activity of the marine secondary metabolite polyphosphate on A549 cells. Mar. Drugs 18, 639 (2020).

    PubMed  PubMed Central  Google Scholar 

  83. Roy, S., Jaiswar, A. & Sarkar, R. Dynamic asymmetry exposes 2019-nCoV prefusion spike. J. Phys. Chem. Lett. 11, 7021–7027 (2020).

    CAS  PubMed  Google Scholar 

  84. Saltzman, W. M., Radomsky, M. L., Whaley, K. J. & Cone, R. A. Antibody diffusion in human cervical mucus. Biophys. J. 66, 508–515 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Cruz-Teran, C. et al. Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy. Adv. Drug Deliv. Rev. 169, 100–117 (2021).

    CAS  PubMed  Google Scholar 

  86. Abrami, M. et al. Mucus structure, viscoelastic properties, and composition in chronic respiratory diseases. Int. J. Mol. Sci. 25, 1933 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Edwards, D. A. & Chung, K. F. Mucus transpiration as the basis for chronic cough and cough hypersensitivity. Lung 202, 17–24 (2024).

    PubMed  Google Scholar 

  88. Wark, P., McDonald, V. M. & Smith, S. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst. Rev. 6, CD001506 (2023).

    PubMed  Google Scholar 

  89. Edwards, D. A. et al. Exhaled aerosol increases with COVID-19 infection, age, and obesity. Proc. Natl Acad. Sci. USA 118, e2021830118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Pritchard, M. F. et al. A new class of safe oligosaccharide polymer therapy to modify the mucus barrier of chronic respiratory disease. Mol. Pharm. 13, 863–872 (2016).

    CAS  PubMed  Google Scholar 

  91. Cho, D. Y. et al. Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia. Int. Forum Allergy Rhinol. 14, 1026–1035 (2024).

    PubMed  Google Scholar 

  92. Ehre, C. et al. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs. Proc. Natl Acad. Sci. USA 109, 16528–16533 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Roy, M. G. et al. Muc5b is required for airway defence. Nature 505, 412–416 (2014).

    CAS  PubMed  Google Scholar 

  94. Chhin, B. et al. Ciliary beating recovery in deficient human airway epithelial cells after lentivirus ex vivo gene therapy. PLoS Genet. 5, e1000422 (2009).

    PubMed  PubMed Central  Google Scholar 

  95. Coraux, C., Roux, J., Jolly, T. & Birembaut, P. Epithelial cell–extracellular matrix interactions and stem cells in airway epithelial regeneration. Proc. Am. Thorac. Soc. 5, 689–694 (2008).

    PubMed  Google Scholar 

  96. Mehrban, N. et al. α-Helical peptides on plasma-treated polymers promote ciliation of airway epithelial cells. Mater. Sci. Eng. C 122, 111935 (2021).

    CAS  Google Scholar 

  97. Zahm, J.-M., Milliot, M., Bresin, A., Coraux, C. & Birembaut, P. The effect of hyaluronan on airway mucus transport and airway epithelial barrier integrity: potential application to the cytoprotection of airway tissue. Matrix Biol. 30, 389–395 (2011).

    CAS  PubMed  Google Scholar 

  98. Ahmad, J. et al. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol. Sci. Appl. 8, 55–66 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Newman, S. P. Drug delivery to the lungs: challenges and opportunities. Ther. Deliv. 8, 647–661 (2017).

    CAS  PubMed  Google Scholar 

  100. Baryakova, T. H., Pogostin, B. H., Langer, R. & McHugh, K. J. Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nat. Rev. Drug Discov. 22, 387–409 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Haidl, P., Heindl, S., Siemon, K., Bernacka, M. & Cloes, R. M. Inhalation device requirements for patients’ inhalation maneuvers. Respir. Med. 118, 65–75 (2016).

    PubMed  Google Scholar 

  102. Scherließ, R., Bock, S., Bungert, N., Neustock, A. & Valentin, L. Particle engineering in dry powders for inhalation. Eur. J. Pharm. Sci. 172, 106158 (2022).

    PubMed  Google Scholar 

  103. Edwards, D. A. et al. Large porous particles for pulmonary drug delivery. Science 276, 1868–1872 (1997).

    CAS  PubMed  Google Scholar 

  104. Edwards, D. A., Ben-Jebria, A. & Langer, R. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85, 379–385 (1998).

    CAS  PubMed  Google Scholar 

  105. Vanbever, R. et al. Formulation and physical characterization of large porous particles for inhalation. Pharm. Res. 16, 1735–1742 (1999).

    CAS  PubMed  Google Scholar 

  106. Bartus, R. T. et al. A pulmonary formulation of L-dopa enhances its effectiveness in a rat model of Parkinson’s disease. J. Pharmacol. Exp. Ther. 310, 828–835 (2004).

    CAS  PubMed  Google Scholar 

  107. Paik, J. Levodopa inhalation powder: a review in Parkinson’s disease. Drugs 80, 821–828 (2020).

    CAS  PubMed  Google Scholar 

  108. Lee, W.-H., Loo, C.-Y., Traini, D. & Young, P. M. Inhalation of nanoparticle-based drug for lung cancer treatment: advantages and challenges. Asian J. Pharm. Sci. 10, 481–489 (2015).

    Google Scholar 

  109. Lee, W.-H. et al. The potential to treat lung cancer via inhalation of repurposed drugs. Adv. Drug Deliv. Rev. 133, 107–130 (2018).

    CAS  PubMed  Google Scholar 

  110. Huang, X. et al. The landscape of mRNA nanomedicine. Nat. Med. 28, 2273–2287 (2022).

    CAS  PubMed  Google Scholar 

  111. El-Sherbiny, I. M., El-Baz, N. M. & Yacoub, M. H. Inhaled nano- and microparticles for drug delivery. Glob. Cardiol. Sci. Pract. 2015, 2 (2015).

    PubMed  PubMed Central  Google Scholar 

  112. Kuzmov, A. & Minko, T. Nanotechnology approaches for inhalation treatment of lung diseases. J. Control. Release 219, 500–518 (2015).

    CAS  PubMed  Google Scholar 

  113. Hickey, A. J. Emerging trends in inhaled drug delivery. Adv. Drug Deliv. Rev. 157, 63–70 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gao, J., Karp, J. M., Langer, R. & Joshi, N. The future of drug delivery. Chem. Mater. 35, 359–363 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Murgia, X., Loretz, B., Hartwig, O., Hittinger, M. & Lehr, C.-M. The role of mucus on drug transport and its potential to affect therapeutic outcomes. Adv. Drug Deliv. Rev. 124, 82–97 (2018).

    CAS  PubMed  Google Scholar 

  116. Newby, J. M. et al. Technological strategies to estimate and control diffusive passage times through the mucus barrier in mucosal drug delivery. Adv. Drug Deliv. Rev. 124, 64–81 (2018).

    CAS  PubMed  Google Scholar 

  117. Arredouani, M. et al. The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles. J. Exp. Med. 200, 267–272 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Brune, K., Frank, J., Schwingshackl, A., Finigan, J. & Sidhaye, V. K. Pulmonary epithelial barrier function: some new players and mechanisms. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L731–L745 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Rezaee, F. & Georas, S. N. Breaking barriers. New insights into airway epithelial barrier function in health and disease. Am. J. Respir. Cell Mol. Biol. 50, 857–869 (2014).

    PubMed  PubMed Central  Google Scholar 

  120. Bustamante-Marin, X. M. & Ostrowski, L. E. Cilia and mucociliary clearance. Cold Spring Harb. Perspect. Biol. 9, a028241 (2017).

    PubMed  PubMed Central  Google Scholar 

  121. Murgia, X., de Souza Carvalho, C. & Lehr, C.-M. Overcoming the pulmonary barrier: new insights to improve the efficiency of inhaled therapeutics. Eur. J. Nanomed. 6, 157–169 (2014).

    CAS  Google Scholar 

  122. Ruge, C. A., Kirch, J. & Lehr, C.-M. Pulmonary drug delivery: from generating aerosols to overcoming biological barriers — therapeutic possibilities and technological challenges. Lancet Respir. Med. 1, 402–413 (2013).

    CAS  PubMed  Google Scholar 

  123. Eshaghi, B. et al. The role of engineered materials in mucosal vaccination strategies. Nat. Rev. Mater. 9, 29–45 (2024).

    CAS  Google Scholar 

  124. Wang, E. Y., Sarmadi, M., Ying, B., Jaklenec, A. & Langer, R. Recent advances in nano- and micro-scale carrier systems for controlled delivery of vaccines. Biomaterials 303, 122345 (2023).

    CAS  PubMed  Google Scholar 

  125. Tang, Z. et al. A materials-science perspective on tackling COVID-19. Nat. Rev. Mater. 5, 847–860 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Heyder, J. Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery. Proc. Am. Thorac. Soc. 1, 315–320 (2004).

    CAS  PubMed  Google Scholar 

  127. Martonen, T. B. & Katz, I. M. Deposition patterns of aerosolized drugs within human lungs: effects of ventilatory parameters. Pharm. Res. 10, 871–878 (1993).

    CAS  PubMed  Google Scholar 

  128. Sturm, R. & Hofmann, W. A theoretical approach to the deposition and clearance of fibers with variable size in the human respiratory tract. J. Hazard. Mater. 170, 210–218 (2009).

    CAS  PubMed  Google Scholar 

  129. Wang, C. C. et al. Airborne transmission of respiratory viruses. Science 373, eabd9149 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Sardeli, C. et al. Inhaled chemotherapy adverse effects: mechanisms and protection methods. Lung Cancer Manag. 8, LMT19 (2019).

    CAS  Google Scholar 

  131. Wang, X. et al. Effects of L-leucine on the properties of spray-dried swellable microparticles with wrinkled surfaces for inhalation therapy of pulmonary fibrosis. Int. J. Pharm. 610, 121223 (2021).

    CAS  PubMed  Google Scholar 

  132. Hassan, M. S. & Lau, R. W. M. Effect of particle shape on dry particle inhalation: study of flowability, aerosolization, and deposition properties. AAPS PharmSciTech 10, 1252–1262 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Liu, C., Jiang, X., Gan, Y. & Yu, M. Engineering nanoparticles to overcome the mucus barrier for drug delivery: design, evaluation and state-of-the-art. Med. Drug Discov. 12, 100110 (2021).

    CAS  Google Scholar 

  134. Das Neves, J., Bahia, M. F., Amiji, M. M. & Sarmento, B. Mucoadhesive nanomedicines: characterization and modulation of mucoadhesion at the nanoscale. Expert Opin. Drug Deliv. 8, 1085–1104 (2011).

    PubMed  Google Scholar 

  135. Pardeshi, C. V., Agnihotri, V. V., Patil, K. Y., Pardeshi, S. R. & Surana, S. J. Mannose-anchored N,N,N-trimethyl chitosan nanoparticles for pulmonary administration of etofylline. Int. J. Biol. Macromol. 165, 445–459 (2020).

    CAS  PubMed  Google Scholar 

  136. Shi, X. et al. In vivo approach of simply constructed pyrazinamide conjugated chitosan-g-polycaprolactone micelles for methicillin resistance Staphylococcus aureus. Int. J. Biol. Macromol. 158, 636–647 (2020).

    CAS  PubMed  Google Scholar 

  137. Yuan, X. et al. Mucoadhesive guargum hydrogel inter-connected chitosan-g-polycaprolactone micelles for rifampicin delivery. Carbohydr. Polym. 206, 1–10 (2019).

    CAS  PubMed  Google Scholar 

  138. Perrone, M. et al. Preactivated thiolated glycogen as mucoadhesive polymer for drug delivery. Eur. J. Pharm. Biopharm. 119, 161–169 (2017).

    CAS  PubMed  Google Scholar 

  139. Racaniello, G. F. et al. Spray-dried mucoadhesive microparticles based on S-protected thiolated hydroxypropyl-β-cyclodextrin for budesonide nasal delivery. Int. J. Pharm. 603, 120728 (2021).

    CAS  PubMed  Google Scholar 

  140. Watchorn, J., Stuart, S., Burns, D. C. & Gu, F. X. Mechanistic influence of polymer species, molecular weight, and functionalization on mucin–polymer binding interactions. ACS Appl. Polym. Mater. 4, 7537–7546 (2022).

    CAS  Google Scholar 

  141. Schuster, B. S., Suk, J. S., Woodworth, G. F. & Hanes, J. Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials 34, 3439–3446 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Suk, J. S. et al. The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles. Biomaterials 30, 2591–2597 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Coucke, D. et al. Spray-dried powders of starch and crosslinked poly(acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine. Vaccine 27, 1279–1286 (2009).

    CAS  PubMed  Google Scholar 

  144. Vasquez-Martínez, N., Guillen, D., Moreno-Mendieta, S. A., Sanchez, S. & Rodríguez-Sanoja, R. The role of mucoadhesion and mucopenetration in the immune response induced by polymer-based mucosal adjuvants. Polymers 15, 1615 (2023).

    PubMed  PubMed Central  Google Scholar 

  145. Gao, X. et al. Mucus adhesion vs. mucus penetration? Screening nanomaterials for nasal inhalation by MD simulation. J. Control. Release 353, 366–379 (2023).

    CAS  PubMed  Google Scholar 

  146. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    CAS  PubMed  Google Scholar 

  147. Murgia, X. et al. Size-limited penetration of nanoparticles into porcine respiratory mucus after aerosol deposition. Biomacromolecules 17, 1536–1542 (2016).

    CAS  PubMed  Google Scholar 

  148. Boylan, N. J. et al. Highly compacted DNA nanoparticles with low MW PEG coatings: in vitro, ex vivo and in vivo evaluation. J. Control. Release 157, 72–79 (2012).

    CAS  PubMed  Google Scholar 

  149. Chen, D. et al. A two-pronged pulmonary gene delivery strategy: a surface-modified fullerene nanoparticle and a hypotonic vehicle. Angew. Chem. Int. Ed. 60, 15225–15229 (2021).

    CAS  Google Scholar 

  150. Guo, Y. et al. Mucus penetration of surface-engineered nanoparticles in various pH microenvironments. ACS Nano 17, 2813–2828 (2023).

    CAS  PubMed  Google Scholar 

  151. Huang, G. et al. To enhance mucus penetration and lung absorption of drug by inhalable nanocrystals-in-microparticles. Pharmaceutics 14, 538 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Huang, X. et al. Protein nanocages that penetrate airway mucus and tumor tissue. Proc. Natl Acad. Sci. USA 114, E6595–E6602 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Huckaby, J. T. & Lai, S. K. PEGylation for enhancing nanoparticle diffusion in mucus. Adv. Drug Deliv. Rev. 124, 125–139 (2018).

    CAS  PubMed  Google Scholar 

  154. Kim, Y. C. et al. Strategy to enhance dendritic cell-mediated DNA vaccination in the lung. Adv. Ther. 3, 2000013 (2020).

    CAS  Google Scholar 

  155. Lai, S. K. et al. Drug carrier nanoparticles that penetrate human chronic rhinosinusitis mucus. Biomaterials 32, 6285–6290 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Mastorakos, P. et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc. Natl Acad. Sci. USA 112, 8720–8725 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Porsio, B., Craparo, E. F., Mauro, N., Giammona, G. & Cavallaro, G. Mucus and cell-penetrating nanoparticles embedded in nano-into-micro formulations for pulmonary delivery of ivacaftor in patients with cystic fibrosis. ACS Appl. Mater. Interfaces 10, 165–181 (2018).

    CAS  PubMed  Google Scholar 

  158. Suk, J. S. et al. Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier. J. Control. Release 178, 8–17 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Wang, Y.-Y. et al. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that ‘slip’ through the human mucus barrier. Angew. Chem. Int. Ed. 47, 9726 (2008).

    CAS  Google Scholar 

  160. Yang, M. et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew. Chem. 50, 2597 (2011).

    CAS  Google Scholar 

  161. Hu, M., Li, X., You, Z., Cai, R. & Chen, C. Physiological barriers and strategies of lipid-based nanoparticles for nucleic acid drug delivery. Adv. Mater. 36, 2303266 (2024).

    CAS  Google Scholar 

  162. Witten, J., Hu, Y., Langer, R. & Anderson, D. G. Recent advances in nanoparticulate RNA delivery systems. Proc. Natl Acad. Sci. USA 121, e2307798120 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Paul, P. K., Nakpheng, T., Paliwal, H., Ananth, K. P. & Srichana, T. Inhalable solid lipid nanoparticles of levofloxacin for potential tuberculosis treatment. Int. J. Pharm. 660, 124309 (2024).

    CAS  PubMed  Google Scholar 

  164. De Leo, V. et al. Preparation of drug-loaded small unilamellar liposomes and evaluation of their potential for the treatment of chronic respiratory diseases. Int. J. Pharm. 545, 378–388 (2018).

    PubMed  Google Scholar 

  165. Scialabba, C., Craparo, E. F., Cabibbo, M., Drago, S. E. & Cavallaro, G. Exploiting inhalable microparticles incorporating hybrid polymer-lipid nanoparticles loaded with Iloprost manages lung hyper-inflammation. Int. J. Pharm. 666, 124813 (2024).

    CAS  PubMed  Google Scholar 

  166. Tafech, B. et al. Exploring mechanisms of lipid nanoparticle–mucus interactions in healthy and cystic fibrosis conditions. Adv. Healthc. Mater. 13, 2304525 (2024).

    CAS  Google Scholar 

  167. Popov, A., Enlow, E., Bourassa, J. & Chen, H. Mucus-penetrating nanoparticles made with ‘mucoadhesive’ poly (vinyl alcohol). Nanomed. Nanotechnol. Biol. Med. 12, 1863–1871 (2016).

    CAS  Google Scholar 

  168. Mansfield, E. D. et al. Side chain variations radically alter the diffusion of poly (2-alkyl-2-oxazoline) functionalised nanoparticles through a mucosal barrier. Biomater. Sci. 4, 1318–1327 (2016).

    CAS  PubMed  Google Scholar 

  169. Nafee, N., Forier, K., Braeckmans, K. & Schneider, M. Mucus-penetrating solid lipid nanoparticles for the treatment of cystic fibrosis: proof of concept, challenges and pitfalls. Eur. J. Pharm. Biopharm. 124, 125–137 (2018).

    CAS  PubMed  Google Scholar 

  170. Castellani, S. et al. Mucopenetration study of solid lipid nanoparticles containing magneto sensitive iron oxide. Eur. J. Pharm. Biopharm. 178, 94–104 (2022).

    CAS  PubMed  Google Scholar 

  171. Li, M. et al. Modified PEG-lipids enhance the nasal mucosal immune capacity of lipid nanoparticle mRNA vaccines. Pharmaceutics 16, 1423 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Kim, J. et al. Engineering lipid nanoparticles for enhanced intracellular delivery of mRNA through inhalation. ACS Nano 16, 14792–14806 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Soto, M. R. et al. Discovery of peptides for ligand-mediated delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia. Mol. Ther. Nucleic Acids 35, 102375 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Conte, G. et al. Hybrid lipid/polymer nanoparticles to tackle the cystic fibrosis mucus barrier in siRNA delivery to the lungs: does PEGylation make the difference? ACS Appl. Mater. Interfaces 14, 7565–7578 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Fang, Y. et al. Cleavable PEGylation: a strategy for overcoming the ‘PEG dilemma’ in efficient drug delivery. Drug Deliv. 24, 22–32 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Degors, I. M., Wang, C., Rehman, Z. U. & Zuhorn, I. S. Carriers break barriers in drug delivery: endocytosis and endosomal escape of gene delivery vectors. Acc. Chem. Res. 52, 1750–1760 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Lokugamage, M. P. et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat. Biomed. Eng. 5, 1059–1068 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Mahmoudzadeh, M., Magarkar, A., Koivuniemi, A., Róg, T. & Bunker, A. Mechanistic insight into how PEGylation reduces the efficacy of pH-sensitive liposomes from molecular dynamics simulations. Mol. Pharm. 18, 2612–2621 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Labouta, H. I. et al. Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective. Drug Deliv. Transl. Res. 12, 2581–2588 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Patel, A. K. et al. Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium. Adv. Mater. 31, 1805116 (2019).

    Google Scholar 

  182. Chen, Z. Surface hydration and antifouling activity of zwitterionic polymers. Langmuir 38, 4483–4489 (2022).

    CAS  PubMed  Google Scholar 

  183. Qu, K. et al. Structures, properties, and applications of zwitterionic polymers. ChemPhysMater 1, 294–309 (2022).

    CAS  Google Scholar 

  184. Ma, Y. et al. pH-mediated mucus penetration of zwitterionic polydopamine-modified silica nanoparticles. Nano Lett. 23, 7552–7560 (2023).

    CAS  PubMed  Google Scholar 

  185. Hu, S. et al. Zwitterionic polydopamine modified nanoparticles as an efficient nanoplatform to overcome both the mucus and epithelial barriers. Chem. Eng. J. 428, 132107 (2022).

    CAS  Google Scholar 

  186. Hernandez, K. E. C., Lee, J., Kim, S., Cartwright, Z. & Herrera-Alonso, M. Boronic acid-mediated mucin/surface interactions of zwitterionic polymer brushes. Soft Matter 21, 3125–3136 (2025).

    Google Scholar 

  187. Cao, Z. & Jiang, S. Super-hydrophilic zwitterionic poly (carboxybetaine) and amphiphilic non-ionic poly (ethylene glycol) for stealth nanoparticles. Nano Today 7, 404–413 (2012).

    CAS  Google Scholar 

  188. Jiang, S. & Cao, Z. Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv. Mater. 22, 920–932 (2010).

    CAS  PubMed  Google Scholar 

  189. Zhang, Y. et al. Fundamentals and applications of zwitterionic antifouling polymers. J. Phys. D Appl. Phys. 52, 403001 (2019).

    CAS  Google Scholar 

  190. de Sousa, I. P. et al. Mucus permeating carriers: formulation and characterization of highly densely charged nanoparticles. Eur. J. Pharm. Biopharm. 97, 273–279 (2015).

    Google Scholar 

  191. Bogaert, B. et al. Selective replacement of cholesterol with cationic amphiphilic drugs enables the design of lipid nanoparticles with improved RNA delivery. Nano Lett. 24, 2961–2971 (2024).

    CAS  PubMed  Google Scholar 

  192. Aghapour, M. et al. Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD. Eur. Respir. Rev. 31, 210112 (2022).

    PubMed  PubMed Central  Google Scholar 

  193. Jiang, A. Y. et al. Zwitterionic polymer-functionalized lipid nanoparticles for the nebulized delivery of mRNA. J. Am. Chem. Soc. 146, 32567–32574 (2024).

    CAS  PubMed  Google Scholar 

  194. Wang, W. et al. Engineered lipid liquid crystalline nanoparticles as an inhaled nanoplatform for mucus penetration enhancement. Drug Deliv. Transl. Res. 13, 2834–2846 (2023).

    CAS  PubMed  Google Scholar 

  195. Carneiro, S. P., Greco, A., Chiesa, E., Genta, I. & Merkel, O. M. Shaping the future from the small scale: dry powder inhalation of CRISPR–Cas9 lipid nanoparticles for the treatment of lung diseases. Expert Opin. Drug Deliv. 20, 471–487 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Shak, S., Capon, D. J., Hellmiss, R., Marsters, S. A. & Baker, C. L. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc. Natl Acad. Sci. USA 87, 9188–9192 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Dawson, M., Wirtz, D. & Hanes, J. Enhanced viscoelasticity of human cystic fibrotic sputum correlates with increasing microheterogeneity in particle transport. J. Biol. Chem. 278, 50393–50401 (2003).

    CAS  PubMed  Google Scholar 

  198. Carlson, T., Lock, J. & Carrier, R. Engineering the mucus barrier. Annu. Rev. Biomed. Eng. 20, 197–220 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Müller, C. et al. Preparation and characterization of mucus-penetrating papain/poly (acrylic acid) nanoparticles for oral drug delivery applications. J. Nanopart. Res. 15, 1–13 (2013).

    Google Scholar 

  200. Henke, M. O. & Ratjen, F. Mucolytics in cystic fibrosis. Paediatr. Respir. Rev. 8, 24–29 (2007).

    PubMed  Google Scholar 

  201. App, E. et al. Dose-finding and 24-h monitoring for efficacy and safety of aerosolized Nacystelyn in cystic fibrosis. Eur. Respir. J. 19, 294–302 (2002).

    CAS  PubMed  Google Scholar 

  202. Vasconcellos, C. A. et al. Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin. Science 263, 969–971 (1994).

    CAS  PubMed  Google Scholar 

  203. Rubin, B. K., Kater, A. P. & Goldstein, A. L. Thymosin β4 sequesters actin in cystic fibrosis sputum and decreases sputum cohesivity in vitro. Chest 130, 1433–1440 (2006).

    PubMed  Google Scholar 

  204. Macciò, A., Madeddu, C., Panzone, F. & Mantovani, G. Carbocysteine: clinical experience and new perspectives in the treatment of chronic inflammatory diseases. Expert Opin. Pharmacother. 10, 693–703 (2009).

    PubMed  Google Scholar 

  205. Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Netsomboon, K. & Bernkop-Schnürch, A. Mucoadhesive vs. mucopenetrating particulate drug delivery. Eur. J. Pharm. Biopharm. 98, 76–89 (2016).

    CAS  PubMed  Google Scholar 

  207. Charbaji, R. et al. Design and testing of efficient mucus-penetrating nanogels — pitfalls of preclinical testing and lessons learned. Small 17, 2007963 (2021).

    CAS  Google Scholar 

  208. Müller, C., Perera, G., König, V. & Bernkop-Schnürch, A. Development and in vivo evaluation of papain-functionalized nanoparticles. Eur. J. Pharm. Biopharm. 87, 125–131 (2014).

    PubMed  Google Scholar 

  209. Cheng, K. & Kalluri, R. Guidelines for clinical translation and commercialization of extracellular vesicles and exosomes based therapeutics. Extracell. Vesicle 2, 100029 (2023).

    Google Scholar 

  210. Zhang, Y. et al. Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int. J. Nanomed. 15, 6917–6934 (2020).

    CAS  Google Scholar 

  211. Hessvik, N. P. & Llorente, A. Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci. 75, 193–208 (2018).

    CAS  PubMed  Google Scholar 

  212. Dinh, P.-U. C. et al. Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis. Nat. Commun. 11, 1064 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Wang, Z. et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine. Nat. Biomed. Eng. 6, 791–805 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Liu, M., Hu, S., Yan, N., Popowski, K. D. & Cheng, K. Inhalable extracellular vesicle delivery of IL-12 mRNA to treat lung cancer and promote systemic immunity. Nat. Nanotechnol. 19, 565–575 (2024).

    CAS  PubMed  Google Scholar 

  215. Raimondo, T. M., Reed, K., Shi, D., Langer, R. & Anderson, D. G. Delivering the next generation of cancer immunotherapies with RNA. Cell 186, 1535–1540 (2023).

    CAS  PubMed  Google Scholar 

  216. Popowski, K. D. et al. Inhalable dry powder mRNA vaccines based on extracellular vesicles. Matter 5, 2960–2974 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Popowski, K. D. et al. Inhalable exosomes outperform liposomes as mRNA and protein drug carriers to the lung. Extracell. Vesicle 1, 100002 (2022).

    PubMed  PubMed Central  Google Scholar 

  218. Warren, M. R. et al. Milk exosomes with enhanced mucus penetrability for oral delivery of siRNA. Biomater. Sci. 9, 4260–4277 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Zhang, C. et al. Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery. Biomater. Sci. 12, 634–649 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Rezaie, J., Feghhi, M. & Etemadi, T. A review on exosomes application in clinical trials: perspective, questions, and challenges. Cell Commun. Signal. 20, 145 (2022).

    PubMed  PubMed Central  Google Scholar 

  221. Chae, J., Choi, Y., Tanaka, M. & Choi, J. Inhalable nanoparticles delivery targeting alveolar macrophages for the treatment of pulmonary tuberculosis. J. Biosci. Bioeng. 132, 543–551 (2021).

    CAS  PubMed  Google Scholar 

  222. Kirtane, A. R. et al. Nanotechnology approaches for global infectious diseases. Nat. Nanotechnol. 16, 369–384 (2021).

    CAS  PubMed  Google Scholar 

  223. Truzzi, E. et al. In vivo biodistribution of respirable solid lipid nanoparticles surface-decorated with a mannose-based surfactant: a promising tool for pulmonary tuberculosis treatment? Nanomaterials 10, 568 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Yu, W., Liu, C., Liu, Y., Zhang, N. & Xu, W. Mannan-modified solid lipid nanoparticles for targeted gene delivery to alveolar macrophages. Pharm. Res. 27, 1584–1596 (2010).

    CAS  PubMed  Google Scholar 

  225. Tang, Z. et al. Inhaled mRNA nanoparticles dual-targeting cancer cells and macrophages in the lung for effective transfection. Proc. Natl Acad. Sci. USA 120, e2304966120 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Tagalakis, A. D. et al. A receptor-targeted nanocomplex vector system optimized for respiratory gene transfer. Mol. Ther. 16, 907–915 (2008).

    CAS  PubMed  Google Scholar 

  227. Zhang, M. et al. Airway epithelial cell-specific delivery of lipid nanoparticles loading siRNA for asthma treatment. J. Control. Release 352, 422–437 (2022).

    CAS  PubMed  Google Scholar 

  228. Kan, S. et al. TLR7 agonist loaded airway epithelial targeting nanoparticles stimulate innate immunity and suppress viral replication in human bronchial epithelial cells. Int. J. Pharm. 617, 121586 (2022).

    CAS  PubMed  Google Scholar 

  229. Fleck, L. M. The costs of caring: who pays? Who profits? Who panders? Hastings Cent. Rep. 36, 13–17 (2006).

    PubMed  Google Scholar 

  230. Zhang, F. et al. Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia. Nat. Mater. 21, 1324–1332 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Zhang, F. et al. Biohybrid microrobots locally and actively deliver drug-loaded nanoparticles to inhibit the progression of lung metastasis. Sci. Adv. 10, eadn6157 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Li, Z. et al. Inhalable biohybrid microrobots: a non-invasive approach for lung treatment. Nat. Commun. 16, 666 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Zhou, J. et al. Codelivery of antigens and adjuvant in polymeric nanoparticles coated with native parasite membranes induces protective mucosal immunity against Giardia lamblia. J. Infect. Dis. 226, 319–323 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Bjanes, E. et al. Outer membrane vesicle-coated nanoparticle vaccine protects against Acinetobacter baumannii pneumonia and sepsis. Adv. Nanobiomed. Res. 3, 2200130 (2023).

    CAS  PubMed  Google Scholar 

  235. Krishnan, N. et al. Bacterial membrane vesicles for vaccine applications. Adv. Drug Deliv. Rev. 185, 114294 (2022).

    CAS  PubMed  Google Scholar 

  236. John, A. E. et al. Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. Nat. Commun. 11, 4659 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Zhu, M. et al. A novel inhalable nanobody targeting IL-4Rα for the treatment of asthma. J. Allergy Clin. Immunol. 154, 1008–1021 (2024).

    CAS  PubMed  Google Scholar 

  238. Detalle, L. et al. Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. Antimicrob. Agents Chemother. 60, 6–13 (2016).

    CAS  PubMed  Google Scholar 

  239. Van Heeke, G. et al. Nanobodies as inhaled biotherapeutics for lung diseases. Pharmacol. Ther. 169, 47–56 (2017).

    PubMed  Google Scholar 

  240. Hida, K. et al. Common gene therapy viral vectors do not efficiently penetrate sputum from cystic fibrosis patients. PLoS ONE 6, e19919 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Duncan, G. A. et al. An adeno-associated viral vector capable of penetrating the mucus barrier to inhaled gene therapy. Mol. Ther. Methods Clin. Dev. 9, 296–304 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Vahey, M. D. & Fletcher, D. A. Influenza A virus surface proteins are organized to help penetrate host mucus. eLife 8, e43764 (2019).

    PubMed  PubMed Central  Google Scholar 

  243. Ribbeck, K. Do viruses use vectors to penetrate mucus barriers? Biosci. Hypotheses 2, 359–362 (2009).

    Google Scholar 

  244. Yoo, J., Park, C., Yi, G., Lee, D. & Koo, H. Active targeting strategies using biological ligands for nanoparticle drug delivery systems. Cancers 11, 640 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Yu, Y., Ni, M., Zheng, Y. & Huang, Y. Airway epithelial-targeted nanoparticle reverses asthma in inhalation therapy. J. Control. Release 367, 223–234 (2024).

    CAS  PubMed  Google Scholar 

  246. Valente, A. X., Langer, R., Stone, H. A. & Edwards, D. A. Recent advances in the development of an inhaled insulin product. Biodrugs 17, 9–17 (2003).

    CAS  PubMed  Google Scholar 

  247. Abubakar-Waziri, H. et al. Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency. ERJ Open Res. 10, 00241–02024 (2024).

    PubMed  PubMed Central  Google Scholar 

  248. Charrier, C. et al. Cysteamine (Lynovex), a novel mucoactive antimicrobial & antibiofilm agent for the treatment of cystic fibrosis. Orphanet J. Rare Dis. 9, 1–11 (2014).

    Google Scholar 

  249. Devereux, G. et al. Cysteamine as a future intervention in cystic fibrosis against current and emerging pathogens: a patient-based ex vivo study confirming its antimicrobial and mucoactive potential in sputum. EBioMedicine 2, 1507–1512 (2015).

    PubMed  PubMed Central  Google Scholar 

  250. Ferrari, E. et al. Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation. Cell Death Dis. 8, e2544 (2018).

    Google Scholar 

  251. Boyle, M. P. & De Boeck, K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir. Med. 1, 158–163 (2013).

    PubMed  Google Scholar 

  252. Tosco, A. et al. A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR. Cell Death Differ. 23, 1380–1393 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Li, B. et al. Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry. Nat. Mater. 23, 1002–1008 (2024).

    CAS  PubMed  Google Scholar 

  254. Witten, J. et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02490-y (2024).

  255. Xu, Y. et al. AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery. Nat. Commun. 15, 6305 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Langer, R. & Peppas, N. A. A bright future in medicine for chemical engineering. Nat. Chem. Eng. 1, 10–12 (2024).

    Google Scholar 

  257. Reker, D. et al. Computationally guided high-throughput design of self-assembling drug nanoparticles. Nat. Nanotechnol. 16, 725–733 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Sarmadi, M. et al. Modeling, design, and machine learning-based framework for optimal injectability of microparticle-based drug formulations. Sci. Adv. 6, eabb6594 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Yu, F., Wei, C., Deng, P., Peng, T. & Hu, X. Deep exploration of random forest model boosts the interpretability of machine learning studies of complicated immune responses and lung burden of nanoparticles. Sci. Adv. 7, eabf4130 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Kumar, G. & Ardekani, A. M. Machine-learning framework to predict the performance of lipid nanoparticles for nucleic acid delivery. ACS Appl. Bio Mater. 8, 3717–3727 (2025).

    CAS  PubMed  Google Scholar 

  261. Öztürk, A. A., Gündüz, A. B. & Ozisik, O. Supervised machine learning algorithms for evaluation of solid lipid nanoparticles and particle size. Comb. Chem. High Throughput Screen. 21, 693–699 (2018).

    PubMed  Google Scholar 

  262. Bae, S. H. et al. Rational design of lipid nanoparticles for enhanced mRNA vaccine delivery via machine learning. Small 21, 2405618 (2025).

    CAS  PubMed  Google Scholar 

  263. Ding, D. Y., Zhang, Y., Jia, Y. & Sun, J. Machine learning-guided lipid nanoparticle design for mRNA delivery. Preprint at https://arxiv.org/abs/2308.01402 (2023).

  264. Harrison, P. J. et al. Deep-learning models for lipid nanoparticle-based drug delivery. Nanomedicine 16, 1097–1110 (2021).

    CAS  PubMed  Google Scholar 

  265. Hanafy, B. I. et al. Advancing cellular-specific delivery: machine learning insights into lipid nanoparticles design and cellular tropism. Adv. Healthc. Mater. 14, 2500383 (2025).

    CAS  Google Scholar 

  266. Sun, Z. Developing Graph Based Chemical Representation for Synthetic Lipid and Evaluating its Application for AI-based Predication for siRNA Delivery. MSc Thesis, Tufts Univ. (2021).

  267. Lu, Z. et al. Noise-resistant graph neural networks with manifold consistency and label consistency. Expert Syst. Appl. 245, 123120 (2024).

    Google Scholar 

  268. Moayedpour, S. et al. Representations of lipid nanoparticles using large language models for transfection efficiency prediction. Bioinformatics 40, btae342 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Wu, K. et al. Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling. Front. Pharmacol. 15, 1330855 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Agrahari, V., Choonara, Y. E., Mosharraf, M., Patel, S. K. & Zhang, F. The role of artificial intelligence and machine learning in accelerating the discovery and development of nanomedicine. Pharm. Res. 41, 2289–2297 (2024).

    CAS  PubMed  Google Scholar 

  271. de Witt, C. S. & Hornigold, T. Stratospheric aerosol injection as a deep reinforcement learning problem. Preprint at https://arxiv.org/abs/1905.07366 (2019).

  272. Maharjan, R., Kim, K. H., Lee, K., Han, H.-K. & Jeong, S. H. Machine learning-driven optimization of mRNA-lipid nanoparticle vaccine quality with XGBoost/Bayesian method and ensemble model approaches. J. Pharm. Anal. 14, 100996 (2024).

    PubMed  PubMed Central  Google Scholar 

  273. Li, B. et al. Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing. Nat. Biotechnol. 41, 1410–1415 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. Jiang, A. Y. et al. Combinatorial development of nebulized mRNA delivery formulations for the lungs. Nat. Nanotechnol. 19, 364–375 (2024).

    CAS  PubMed  Google Scholar 

  275. Xue, L. et al. Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery. Nat. Nanotechnol. 20, 132–143 (2025).

    CAS  PubMed  Google Scholar 

  276. Han, X. et al. Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo. Nat. Chem. 16, 1687–1697 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Xue, L. et al. High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models. Nat. Commun. 15, 1884 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Rhym, L. H., Manan, R. S., Koller, A., Stephanie, G. & Anderson, D. G. Peptide-encoding mRNA barcodes for the high-throughput in vivo screening of libraries of lipid nanoparticles for mRNA delivery. Nat. Biomed. Eng. 7, 901–910 (2023).

    CAS  PubMed  Google Scholar 

  279. Swingle, K. L. et al. Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia. Nature 637, 412–421 (2025).

    CAS  PubMed  Google Scholar 

  280. Dahlman, J. E. et al. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics. Proc. Natl Acad. Sci. USA 114, 2060–2065 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  281. Da Silva Sanchez, A. J. et al. Universal barcoding predicts in vivo ApoE-independent lipid nanoparticle delivery. Nano Lett. 22, 4822–4830 (2022).

    PubMed  Google Scholar 

  282. Radmand, A. et al. Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart. Proc. Natl Acad. Sci. USA 121, e2307801120 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Bonengel, S., Prüfert, F., Perera, G., Schauer, J. & Bernkop-Schnürch, A. Polyethylene imine-6-phosphogluconic acid nanoparticles — a novel zeta potential changing system. Int. J. Pharm. 483, 19–25 (2015).

    CAS  PubMed  Google Scholar 

  284. Chen, W. et al. Dynamic omnidirectional adhesive microneedle system for oral macromolecular drug delivery. Sci. Adv. 8, eabk1792 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Ying, B. et al. An electroadhesive hydrogel interface prolongs porcine gastrointestinal mucosal theranostics. Sci. Transl Med. 17, eadq1975 (2025).

    CAS  PubMed  Google Scholar 

  286. Subramanian, D. A., Langer, R. & Traverso, G. Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems. J. Nanobiotechnol. 20, 362 (2022).

    Google Scholar 

  287. Srinivasan, S. S. et al. RoboCap: robotic mucus-clearing capsule for enhanced drug delivery in the gastrointestinal tract. Sci. Robot. 7, eabp9066 (2022).

    PubMed  PubMed Central  Google Scholar 

  288. Abramson, A. et al. Ingestible transiently anchoring electronics for microstimulation and conductive signaling. Sci. Adv. 6, eaaz0127 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Edwards, D. A. Global warming risks dehydrating and inflaming human airways. Commun. Earth Environ. 6, 193 (2025).

    PubMed  PubMed Central  Google Scholar 

  290. Fahy, J. V. & Dickey, B. F. Airway mucus function and dysfunction. N. Engl. J. Med. 363, 2233–2247 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. Hasnain, S. Z. et al. Muc5ac: a critical component mediating the rejection of enteric nematodes. J. Exp. Med. 208, 893–900 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  292. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  293. Kawakubo, M. et al. Natural antibiotic function of a human gastric mucin against Helicobacter pylori infection. Science 305, 1003–1006 (2004).

    CAS  PubMed  Google Scholar 

  294. Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002).

    CAS  PubMed  Google Scholar 

  295. Tan, A., De La Peña, H. & Seifalian, A. M. The application of exosomes as a nanoscale cancer vaccine. Int. J. Nanomed. 889–900 (2010).

  296. Nair, P. et al. The effects of an epithelial barrier protective cationic aerosol on allergen-induced airway inflammation in asthma: a randomized, placebo-controlled clinical trial. Clin. Exp. Allergy 44, 1200–1203 (2014).

    CAS  PubMed  Google Scholar 

  297. Johler, S. M., Rejman, J., Guan, S. & Rosenecker, J. Nebulisation of IVT mRNA complexes for intrapulmonary administration. PLoS ONE 10, e0137504 (2015).

    PubMed  PubMed Central  Google Scholar 

  298. Stuart-Low, W. Mucin in desiccation, irritation, and ulceration of mucous membranes. Lancet 158, 972–976 (1901).

    Google Scholar 

  299. Hilding, A. Phagocytosis, mucous flow, and ciliary action. Arch. Environ. Health Int. J. 6, 61–73 (1963).

    CAS  Google Scholar 

  300. Green, G. M., Jakab, G. J., Low, R. B. & Davis, G. S. Defense mechanisms of the respiratory membrane. Am. Rev. Respir. Dis. 115, 479–514 (1977).

    CAS  PubMed  Google Scholar 

  301. Eccles, R. et al. Efficacy and safety of an antiviral iota-carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold. Respir. Res. 11, 108 (2010).

    PubMed  PubMed Central  Google Scholar 

  302. Khan, A. et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit. Care 21, 234 (2017).

    PubMed  PubMed Central  Google Scholar 

  303. Urano, E. et al. An inhaled ACE2 decoy confers protection against SARS-CoV-2 infection in preclinical models. Sci. Transl Med. 15, eadi2623 (2023).

    CAS  PubMed  Google Scholar 

  304. Holgate, S., Baldwin, C. & Tattersfield, A. β-Adrenergic agonist resistance in normal human airways. Lancet 310, 375–377 (1977).

    Google Scholar 

  305. Maggregor, A. G. Drug industry. Br. Med. J. 1, 696 (1968).

    PubMed Central  Google Scholar 

  306. Sturgess, J. M. Structural organization of mucus in the lung. In Pulmonary Macrophage and Epithelial Cells: Proc. Sixteenth Annu. Hanford Biol. Symp. (eds Sanders, C. L. et al.) 149–161 (1977).

  307. Illum, L., Jørgensen, H., Bisgaard, H., Krogsgaard, O. & Rossing, N. Bioadhesive microspheres as a potential nasal drug delivery system. Int. J. Pharm. 39, 189–199 (1987).

    CAS  Google Scholar 

  308. Lai, S. K., Wang, Y.-Y. & Hanes, J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv. Drug Deliv. Rev. 61, 158–171 (2009).

    CAS  PubMed  Google Scholar 

  309. Tang, B. C. et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc. Natl Acad. Sci. USA 106, 19268–19273 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  310. Meers, P. et al. Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections. J. Antimicrob. Chemother. 61, 859–868 (2008).

    CAS  PubMed  Google Scholar 

  311. Bissonnette, E. Y., Lauzon-Joset, J.-F., Debley, J. S. & Ziegler, S. F. Cross-talk between alveolar macrophages and lung epithelial cells is essential to maintain lung homeostasis. Front. Immunol. 11, 583042 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  312. Madl, A. K. & Pinkerton, K. E. Health effects of inhaled engineered and incidental nanoparticles. Crit. Rev. Toxicol. 39, 629–658 (2009).

    CAS  PubMed  Google Scholar 

  313. Jiao, J. & Zhang, L. Influence of intranasal drugs on human nasal mucociliary clearance and ciliary beat frequency. Allergy Asthma Immunol. Res. 11, 306–319 (2018).

    PubMed Central  Google Scholar 

  314. Inoue, D. et al. The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: application to the prediction of nasal drug absorption. Eur. J. Pharm. Sci. 117, 21–26 (2018).

    CAS  PubMed  Google Scholar 

  315. Grubb, B. R. et al. Reduced mucociliary clearance in old mice is associated with a decrease in Muc5b mucin. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L860–L867 (2016).

    PubMed  PubMed Central  Google Scholar 

  316. Lai, S. K., Wang, Y.-Y., Hida, K., Cone, R. & Hanes, J. Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses. Proc. Natl Acad. Sci. USA 107, 598–603 (2010).

    CAS  PubMed  Google Scholar 

  317. Munkholm, M. & Mortensen, J. Mucociliary clearance: pathophysiological aspects. Clin. Physiol. Funct. Imaging 34, 171–177 (2014).

    PubMed  Google Scholar 

  318. Linden, S., Sutton, P., Karlsson, N., Korolik, V. & McGuckin, M. Mucins in the mucosal barrier to infection. Mucosal Immunol. 1, 183–197 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  319. Bustos, N. A., Ribbeck, K. & Wagner, C. E. The role of mucosal barriers in disease progression and transmission. Adv. Drug Deliv. Rev. 200, 115008 (2023).

    CAS  PubMed  Google Scholar 

  320. Sharma, L., Feng, J., Britto, C. J. & Dela Cruz, C. S. Mechanisms of epithelial immunity evasion by respiratory bacterial pathogens. Front. Immunol. 11, 91 (2020).

    PubMed  PubMed Central  Google Scholar 

  321. Muggeo, A., Coraux, C. & Guillard, T. Current concepts on Pseudomonas aeruginosa interaction with human airway epithelium. PLoS Pathog. 19, e1011221 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  322. Li, Y. & Tang, X. X. Abnormal airway mucus secretion induced by virus infection. Front. Immunol. 12, 701443 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  323. Dickey, B. F., Chen, J. & Peebles, R. S. Airway mucus dysfunction in COVID-19. Am. J. Respir. Crit. Care Med. 206, 1304–1306 (2022).

    PubMed  PubMed Central  Google Scholar 

  324. Chilvers, M. et al. The effects of coronavirus on human nasal ciliated respiratory epithelium. Eur. Respir. J. 18, 965–970 (2001).

    CAS  PubMed  Google Scholar 

  325. Meyerholz, D. K. & Reznikov, L. R. Influence of SARS-CoV-2 on airway mucus production: a review and proposed model. Vet. Pathol. 59, 578–585 (2022).

    CAS  PubMed  Google Scholar 

  326. Roche, N., Chinet, T. & Huchon, G. Allergic and nonallergic interactions between house dust mite allergens and airway mucosa. Eur. Respir. J. 10, 719–726 (1997).

    CAS  PubMed  Google Scholar 

  327. Lloyd, C. & Robinson, D. Allergen-induced airway remodelling. Eur. Respir. J. 29, 1020–1032 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  328. Dahl, Ã… Pollen lipids can play a role in allergic airway inflammation. Front. Immunol. 9, 2816 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  329. Reinmuth-Selzle, K. et al. Air pollution and climate change effects on allergies in the Anthropocene: abundance, interaction, and modification of allergens and adjuvants. Environ. Sci. Technol. 51, 4119–4141 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  330. Huff, R. D., Carlsten, C. & Hirota, J. A. An update on immunologic mechanisms in the respiratory mucosa in response to air pollutants. J. Allergy Clin. Immunol. 143, 1989–2001 (2019).

    CAS  PubMed  Google Scholar 

  331. Idrose, N. S. et al. Outdoor pollen-related changes in lung function and markers of airway inflammation: a systematic review and meta-analysis. Clin. Exp. Allergy 51, 636–653 (2021).

    PubMed  Google Scholar 

  332. Michel, F. B., Marty, J. P., Quet, L. & Cour, P. Penetration of inhaled pollen into the respiratory tract. Am. Rev. Respir. Dis. 115, 609–616 (1977).

    CAS  PubMed  Google Scholar 

  333. Vinhas, R. et al. Pollen proteases compromise the airway epithelial barrier through degradation of transmembrane adhesion proteins and lung bioactive peptides. Allergy 66, 1088–1098 (2011).

    CAS  PubMed  Google Scholar 

  334. Roth-Walter, F. et al. Mucosal targeting of allergen-loaded microspheres by Aleuria aurantia lectin. Vaccine 23, 2703–2710 (2005).

    CAS  PubMed  Google Scholar 

  335. Whetstone, C. E., Ranjbar, M., Omer, H., Cusack, R. P. & Gauvreau, G. M. The role of airway epithelial cell alarmins in asthma. Cells 11, 1105 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  336. Ciprandi, G. et al. From IgE to clinical trials of allergic rhinitis. Expert Rev. Clin. Immunol. 11, 1321–1333 (2015).

    CAS  PubMed  Google Scholar 

  337. Bonser, L. R. & Erle, D. J. Airway mucus and asthma: the role of MUC5AC and MUC5B. J. Clin. Med. 6, 112 (2017).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

K.C. thanks grant support from the US National Institute of Health and American Heart Association. S.W.Z. and K.C. also thank C. Kaganov and her late husband A.L. Kaganov for their generous support that helped to make this work possible.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Columbia University, New York, NY, USA

    Savannah Weihang Zhang  (张苇杭) & Ke Cheng

  2. Center for Nanomedicine, Johns Hopkins University Medical School, Baltimore, MD, USA

    David A. Edwards

  3. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    David A. Edwards

  4. Sensory Cloud, Boston, MA, USA

    David A. Edwards

  5. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  6. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  7. Seymour, Paul and Gloria Milstein Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Ke Cheng

  8. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

    Ke Cheng

Authors
  1. Savannah Weihang Zhang  (张苇杭)
    View author publications

    Search author on:PubMed Google Scholar

  2. David A. Edwards
    View author publications

    Search author on:PubMed Google Scholar

  3. Robert Langer
    View author publications

    Search author on:PubMed Google Scholar

  4. Ke Cheng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

S.W.Z. searched and summarized literature for the article. All authors contributed substantially to the discussion. S.W.Z. drafted the article. All authors edited and approved the manuscript before submission.

Corresponding authors

Correspondence to Robert Langer or Ke Cheng.

Ethics declarations

Competing interests

D.A.E. is a co-founder of Sensory Cloud. K.C. is a co-founder of BreStem Therapeutics. A complete list of R.L.’s competing interests is provided in the Supplementary information. S.W.Z. declares no competing interests.

Peer review

Peer review information

Nature Reviews Materials thanks Jae-Won Shin and Daniela Traini, who co-reviewed with Jerry Wong, for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, S.W., Edwards, D.A., Langer, R. et al. Inhalable materials and biologics for lung defence and drug delivery. Nat Rev Mater (2025). https://doi.org/10.1038/s41578-025-00841-y

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41578-025-00841-y

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research