Toxicokinetics of nanoparticles under chronic inhalation exposure (literature review)

The intensive use of nanomaterials and their unique physicochemical characteristics determine the relevance of establishing their effects on the body. Nanoparticles (NPs) are able to penetrate deep into the lungs causing pathophysiological response, but the patterns of their intrapulmonary biodistribution remain understudied. Our objective was to analyze recent publications describing the main routes of entry and pulmonary distribution of nanoparticles in mammals following inhalation exposure.

We analyzed scientific papers published in peer-reviewed journals since 2000, indexed in the Scopus and Web of Science databases, and found using PubMed, Google Scholar, eLibrary, and CyberLeninka. Studies of toxicokinetics of particles larger than 100 nm were not eligible for inclusion in the review.

We found unique physicochemical properties of nanoparticles and exposure duration to contribute the most to the development and course of pathological processes. Cells of the immune system, especially macrophages, play a major role in the distribution, clearance, and deposition of inhaled NPs. Elimination of nanoparticles usually occurs through the mucociliary escalator, either by phagocytosis or translocation to other organs and tissues.

Conclusion. A wide range of adverse effects of nanoparticles on living systems necessitates further research concerning the patterns of their toxicokinetics and toxicodynamics.

Contribution:
Shabardina L.V. – data collection and processing, draft manuscript preparation;
Bateneva V.A. – data collection and processing;
Sutunkova M.P., Minigalieva I.A. – study conception and design, editing;
Fedotova L.A. – editing.
All authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study had no sponsorship.

Received: March 18, 2025 / Accepted: April 29, 2025 / Published: June 27, 2025

1. Khlebtsov N.G., Dykman L.A. Optical properties and biomedical applications of plasmonic nanoparticles. J. Quant. Spectrosc. Radiat. Transf. 2010; 111(1): 1–35. https://doi.org/10.1016/j.jqsrt.2009.07.012

2. Zhang J.Z. Optical properties of metal oxide nanomaterials. In: Optical Properties and Spectroscopy of Nanomaterials. World Scientific; 2009: 181–203. https://doi.org/10.1142/9789812836663_0006

3. Khan I., Saeed K., Khan I. Nanoparticles: Properties, applications and toxicities. Arab. J. Chem. 2019; 12(7): 908–31. https://doi.org/10.1016/j.arabjc.2017.05.011

4. Oberdörster G., Oberdörster E., Oberdörster J. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ. Health Perspect. 2005; 113(7): 823–39. https://doi.org/10.1289/ehp.7339

5. Lu X., Zhu T., Chen C., Liu Y. Right or left: the role of nanoparticles in pulmonary diseases. Int. J. Mol. Sci. 2014; 15(10): 17577–600. https://doi.org/10.3390/ijms151017577

6. Hadrup N., Sørli J.B., Sharma A.K. Pulmonary toxicity, genotoxicity, and carcinogenicity evaluation of molybdenum, lithium, and tungsten: A review. Toxicology. 2022; 467: 153098. https://doi.org/10.1016/j.tox.2022.153098

7. Johncy S.S., Dhanyakumar G., Samuel T.V., Ajay K.T., Bondade S.Y. Acute lung function response to dust in street sweepers. J. Clin. Diagn. Res. 2013; 7(10): 2126–9. https://doi.org/10.7860/JCDR/2013/5818.3449

8. Srinivas A, Rao P.J., Selvam G., Murthy P.B., Reddy P.N. Acute inhalation toxicity of cerium oxide nanoparticles in rats. Toxicol. Lett. 2011; 205(2): 105–15. https://doi.org/10.1016/j.toxlet.2011.05.1027

9. Marczynski M., Lieleg O. Forgotten but not gone: Particulate matter as contaminations of mucosal systems. Biophys. Rev. (Melville). 2021; 2(3): 031302. https://doi.org/10.1063/5.0054075

10. Braakhuis H.M., Park M.V., Gosens I., De Jong W.H., Cassee F.R. Physicochemical characteristics of nanomaterials that affect pulmonary inflammation. Part. Fibre Toxicol. 2014; 11: 18. https://doi.org/10.1186/1743-8977-11-18

11. Ross M.H., Pawlina W. Histology: A Text and Atlas with Correlated Cell and Molecular Biology. Lippincott Williams & Wilkins; 2016.

12. Harbacheva N.V., Kulich N.V., Kuzmina N.D. Accounting of the dispersed composition of the intraflaced fraction and the regularities of aerosol’s accumulation in various deposits of the respiratory tract when calculating doses of internal irradiation. Vestnik Universiteta grazhdanskoi zashchity MCHS Belarusi. 2017; 1(3): 291–8. https://doi.org/10.33408/2519-237X.2017.1-3.291 https://elibrary.ru/zfovkt (in Russian)

13. Wang L., Wang L., Ding W., Zhang F. Acute toxicity of ferric oxide and zinc oxide nanoparticles in rats. J. Nanosci. Nanotechnol. 2010; 10(12): 8617–24. https://doi.org/10.1166/jnn.2010.2483

14. Liu Q., Zhang X., Xue J., Chai J., Qin L., Guan J., et al. Exploring the intrinsic micro-/nanoparticle size on their in vivo fate after lung delivery. J. Control. Release. 2022; 347: 435–48. https://doi.org/10.1016/j.jconrel.2022.05.006

15. Schuster B.S., Suk J.S., Woodworth G.F., Hanes J. Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials. 2013; 34(13): 3439–46. https://doi.org/10.1016/j.biomaterials.2013.01.064

16. Braakhuis H.M., Gosens I., Krystek P., Boere J.A.F., Cassee F.R., Fokkens P.H.B., et al. Particle size dependent deposition and pulmonary inflammation after short-term inhalation of silver nanoparticles. Part. Fibre Toxicol. 2014; 11: 49. https://doi.org/10.1186/s12989-014-0049-1

17. Jachak A., Lai K.S., Hida K., Suk J.S., Markovic N., Biswal S., et al. Transport of metal oxide nanoparticles and single-walled carbon nanotubes in human mucus. Nanotoxicology. 2012; 6(6): 614–22. https://doi.org/10.3109/17435390.2011.598244

18. Fujihara J., Nishimoto N. Review of zinc oxide nanoparticles: Toxicokinetics, tissue distribution for various exposure routes, toxicological effects, toxicity mechanism in mammals, and an approach for toxicity reduction. Biol. Trace Elem. Res. 2023; 202(1): 9–23. https://doi.org/10.1007/s12011-023-03644-w

19. Lieleg O., Vladescu I., Ribbeck K. Characterization of particle translocation through mucin hydrogels. Biophys. J. 2010; 98(9): 1782–9. https://doi.org/10.1016/j.bpj.2010.01.012

20. Li L.D., Crouzier T., Sarkar A., Dunphy L., Han J., Ribbeck K. Spatial configuration and composition of charge modulates transport into a mucin hydrogel barrier. Biophys. J. 2013; 105(6): 1357–65. https://doi.org/10.1016/j.bpj.2013.07.050

21. Xu Y.M., Tan H.W., Zheng W., Liang Z.L., Yu F.Y., Wu D.D., et al. Cadmium telluride quantum dot-exposed human bronchial epithelial cells: A further study of the cellular response by proteomics. Toxicol. Res. (Camb.). 2019; 8(6): 994–1001. https://doi.org/10.1039/c9tx00126c

22. Geiser M., Casaulta M., Kupferschmid B., Schulz H., Semmler-Behnke M., Kreyling W. The role of macrophages in the clearance of inhaled ultrafine titanium dioxide particles. Am. J. Respir. Cell Mol. Biol. 2008; 38(3): 371–6. https://doi.org/10.1165/rcmb.2007-0138OC

23. Geiser M., Rothen-Rutishauser B., Kapp N., Schürch S.N., Kreyling W., Schulz H., et al. Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ. Health Perspect. 2005; 113(11): 1555–60. https://doi.org/10.1289/ehp.8006

24. Kim Y.H., Fazlollahi F., Kennedy I.M., Yacobi N.R., Hamm-Alvarez S.F., Borok Z., et al. Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure. Am. J. Respir. Crit. Care Med. 2010; 182(11): 1398–409. https://doi.org/10.1164/rccm.201002-0185OC

25. Lipka J., Semmler-Behnke M., Sperling R.A., Wenk A., Takenaka S., Schleh C., et al. Biodistribution of PEG-modified gold nanoparticles following intratracheal instillation and intravenous injection. Biomaterials. 2010; 31(25): 6574–81. https://doi.org/10.1016/j.biomaterials.2010.05.009

26. Shah P., Lalan M., Jani D. Toxicological aspects of carbon nanotubes, fullerenes and graphenes. Curr. Pharm. Des. 2021; 27(4): 556–64. https://doi.org/10.2174/1381612826666200916143741

27. Vysloužil J., Kulich P., Zeman T., Vaculovič T., Tvrdoňová M., Mikuška P., et al. Subchronic continuous inhalation exposure to zinc oxide nanoparticles induces pulmonary cell response in mice. J. Trace Elem. Med. Biol. 2020; 61: 126511. https://doi.org/10.1016/j.jtemb.2020.126511

28. Cai D., Gao W., Li Z., Zhang Y., Xiao L., Xiao Y. Current development of nano-drug delivery to target macrophages. Biomedicines. 2022; 10(5): 1203. https://doi.org/10.3390/biomedicines10051203

29. Pauluhn J. Poorly soluble particulates: searching for a unifying denominator of nanoparticles and fine particles for DNEL estimation. Toxicology. 2011; 279(1–3): 176–88. https://doi.org/10.1016/j.tox.2010.10.009

30. Molina R.M., Konduru N.V., Queiroz P.M., Figueroa B., Fu D., Ma-Hock L., et al. Fate of barium sulfate nanoparticles deposited in the lungs of rats. Sci. Rep. 2019; 9(1): 8163. https://doi.org/10.1038/s41598-019-44551-2

31. Laberko E.L., Bogomilskiy M.R. Modern view on mucociliary clearance regulation: A literature review. Vestnik Rossiiskogo gosudarstvennogo meditsinskogo universiteta. 2015; (1): 60–4. https://elibrary.ru/ulxxrp (in Russian)

32. Johncy S.S., Dhanyakumar G., Kanyakumari K., Samuel T.V. Chronic exposure to dust and lung function impairment: A study on female sweepers in India. Natl. J. Physiol. Pharm. Pharmacol. 2014; 4(1): 15–9. https://doi.org/10.5455/njppp.2014.4.140620131

33. Jin J., Zhou K.K., Park K., Hu Y., Xu X., Zheng Z., et al. Anti-inflammatory and antiangiogenic effects of nanoparticle-mediated delivery of a natural angiogenic inhibitor. Invest. Ophthalmol. Vis. Sci. 2011; 52(9): 6230–7. https://doi.org/10.1167/iovs.10-6229

34. Geiser M., Kreyling W.G. Deposition and biokinetics of inhaled nanoparticles. Part. Fibre Toxicol. 2010; 7: 2. https://doi.org/10.1186/1743-8977-7-2

35. Kirch J., Guenther M., Doshi N., Schaefer U.F., Schneider M., Mitragotri S., et al. Mucociliary clearance of micro- and nanoparticles is independent of size, shape and charge – an ex vivo and in silico approach. J. Control. Release. 2012; 159(1): 128–34. https://doi.org/10.1016/j.jconrel.2011.12.015

36. Blank F., Rothen-Rutishauser B., Gehr P. Dendritic cells and macrophages form a transepithelial network against foreign particulate antigens. Am. J. Respir. Cell Mol. Biol. 2007; 36(6): 669–77. https://doi.org/10.1165/rcmb.2006-0234OC

37. Areecheewakul S., Adamcakova-Dodd A., Haque E., Jing X., Meyerholz D.K., O’Shaughnessy P.T., et al. Time course of pulmonary inflammation and trace element biodistribution during and after sub-acute inhalation exposure to copper oxide nanoparticles in a murine model. Part. Fibre Toxicol. 2022; 19(1): 40. https://doi.org/10.1186/s12989-022-00480-z

38. Sacks D., Baxter B., Campbell B.C.V., Carpenter J.S., Cognard C., Dippel D., et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int. J. Stroke. 2018; 13(6): 612–32. https://doi.org/10.1177/1747493018778713

39. Blanco E., Shen H., Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015; 33(9): 941–51. https://doi.org/10.1038/nbt.3330

40. Du B., Jiang X., Das A., Zhou Q., Yu M., Jin R., et al. Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regime. Nat. Nanotechnol. 2017; 12(11): 1096–102. https://doi.org/10.1038/nnano.2017.170

41. Choi H.S., Liu W., Misra P., Tanaka E., Zimmer J.P., Itty Ipe B., et al. Renal clearance of quantum dots. Nat. Biotechnol. 2007; 25(10): 1165–70. https://doi.org/10.1038/nbt1340

42. Sun T., Zhang Y.S., Pang B., Hyun D.C., Yang M., Xia Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew. Chem. Int. Ed. Engl. 2014; 53(46): 12320–64. https://doi.org/10.1002/anie.201403036

43. de Barros A.B., Tsourkas A., Saboury B., Cardoso V.N., Alavi A. Emerging role of radiolabeled nanoparticles as an effective diagnostic technique. EJNMMI Res. 2012; 2(1): 39. https://doi.org/10.1186/2191-219X-2-39

44. Du B., Yu M., Zheng J. Transport and interactions of nanoparticles in the kidneys. Nat. Rev. Mater. 2018; 3(10): 358–74. https://doi.org/10.1038/s41578-018-0038-3

45. Schneider T., Mittag A., Westermann M., Glei M. Impact of pH changes on metal oxide nanoparticle behaviour during artificial digestion. Food Funct. 2021; 12(4): 1452–7. https://doi.org/10.1039/d0fo02842h

46. Laloux L., Kastrati D., Cambier S., Gutleb A.C., Schneider Y.J. The food matrix and the gastrointestinal fluids alter the features of silver nanoparticles. Small. 2020; 16(21): e1907687. https://doi.org/10.1002/smll.201907687

47. De Jong W.H., De Rijk E., Bonetto A., Wohlleben W., Stone V., Brunelli A., et al. Toxicity of copper oxide and basic copper carbonate nanoparticles after short-term oral exposure in rats. Nanotoxicology. 2019; 13(1): 50–72. https://doi.org/10.1080/17435390.2018.1530390

48. Sinnecker H., Krause T., Koelling S., Lautenschläger I., Frey A. The gut wall provides an effective barrier against nanoparticle uptake. Beilstein J. Nanotechnol. 2014; 5: 2092–101. https://doi.org/10.3762/bjnano.5.218

49. Bredeck G., Kämpfer A.A.M., Sofranko A., Wahle T., Büttner V., Albrecht C., et al. Ingested engineered nanomaterials affect the expression of mucin genes – an in vitro – in vivo comparison. Nanomaterials (Basel). 2021; 11(10): 2621. https://doi.org/10.3390/nano11102621

50. Bae S.H., Yu J., Go M.R., Kim H.J., Hwang Y.G., Choi S.J. Oral toxicity and intestinal transport mechanism of colloidal gold nanoparticle-treated red ginseng. Nanomaterials (Basel). 2016; 6(11): 208. https://doi.org/10.3390/nano6110208