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Although nanofibers may meet these criteria, their small diameters may enable them to adopt different shapes, affecting their toxicity. While nanofiber pathogenicity is still assessed using animal models, the development of alternative in vitro methods relies on a mechanistic understanding of toxicity. Here, we address nanofiber\u2010induced protein changes in alveolar macrophages by analyzing whole cell lysates and supernatants of NR8383 cells exposed to silicon carbide nanofibers, Mitsui\u20107 carbon nanotubes, and Printex\u201090. While all materials elicited a similar dose\u2010dependent cytotoxicity, there was a nanofiber\u2010specific release of TNF\u2010\u03b1 and glucuronidase. Proteomic profiling after treatment with low, non\u2010cytotoxic concentrations confirmed the inflammatory response and revealed a release of 20 lysosomal, luminal hydrolases, including six cathepsins, into the extracellular supernatant. In cell lysates, these hydrolases were decreased, while membrane\u2010associated lysosomal proteins remained unchanged, suggesting that macrophages engulfing long nanofibers release lysosomal content from open membrane pouches during frustrated phagocytosis. Additionally, 17 biomarkers of nanofiber\u2010induced toxicity were identified as potential targets for predictive, animal\u2010free screening. These early markers may be of value for assessing nanofiber toxicity.<\/jats:p>","DOI":"10.1002\/smll.202510530","type":"journal-article","created":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T09:40:47Z","timestamp":1768642847000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Proteomic Profiling of Alveolar Macrophages Identifies Loss of Lysosomal Content as an Indicator of Nanofiber\u2010Induced Frustrated Phagocytosis"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2839-1555","authenticated-orcid":false,"given":"Tobias","family":"Stobernack","sequence":"first","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Vennemann","sequence":"additional","affiliation":[{"name":"IBE R&amp;D Institute for Lung Health gGmbH  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Ribalta","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"},{"name":"Federal Institute for Occupational Safety and Health (BAuA) Materials and Particulate Hazardous Substances  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Schendel","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Gr\u00e4b","sequence":"additional","affiliation":[{"name":"IBE R&amp;D Institute for Lung Health gGmbH  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rico","family":"Ledwith","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Pink","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Haase","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"},{"name":"University of the Western Cape (UWC) Department of Chemical Sciences  Bellville South Africa"},{"name":"Freie Universit\u00e4t Berlin Institute of Pharmacy  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Wiemann","sequence":"additional","affiliation":[{"name":"IBE R&amp;D Institute for Lung Health gGmbH  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5091-4284","authenticated-orcid":false,"given":"Ver\u00f3nica I.","family":"Dumit","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute for Risk Assessment (BfR)  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.progpolymsci.2017.03.002"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11664\u2010022\u201009516\u20108"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mser.2016.08.002"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11051\u2010005\u20109026\u20109"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/48.3.797"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00593370"},{"key":"e_1_2_10_8_1","unstructured":"World Health Organization Determination of Airborne Fibre Number Concentrations: a Recommended Method by Phase\u2010contrast Optical Microscopy (membrane filter method). 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