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Silk fibroin (SF) is a natural polymer with exceptional mechanical strength and notable biological properties. In this study, the immunogenicity and inflammatory responses of silk fibroin nanoparticles (SFNPs) were characterized in primary human cells for the first time. SFNPs with a mean particle size of 213 \u00b1 9\u00a0nm were synthesized and characterized. Primary human immune cells were exposed to SFNPs at concentrations ranging from 0.1 to 0.01\u00a0mg\/mL. Cell viability remained above 80% under the tested conditions. No significant immune recognition was detected. Additionally, the levels of key pro\u2010inflammatory proteins, including inducible nitric oxide synthase, pro\u2010interleukin\u20101\n                    <jats:italic>\u03b2<\/jats:italic>\n                    , and cyclooxygenase\u20102, did not show significant upregulation compared to the control. Biodegradability assays demonstrated that SFNPs underwent degradation within 20 days, under physiological conditions. These findings indicate that SFNPs exhibit bio\u2010inert behavior and highlight the significant advantages of SF as a biomaterial for biomedical applications. Owing to these properties, SFNPs represent a versatile biomaterial for the next\u2010generation of drug delivery systems, offering substantial potential for improving clinical outcomes across a wide range of therapeutic areas.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71687","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T07:24:17Z","timestamp":1788852257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessing the Immunological Safety of Silk Fibroin Nanoparticles: An In Vitro Study With Primary Human Immune Cells"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2613-744X","authenticated-orcid":false,"given":"Beatriz","family":"Rodrigues","sequence":"first","affiliation":[{"name":"ToxFinder Lda and Center for Innovative Biomedicine and Biotechnology (CIBB) and Center for Neurosciences and Cell Biology (CNC) University of Coimbra  Coimbra Portugal"},{"name":"CEMMPRE ARISE Department of Chemical Engineering Faculty of Sciences and Technology University of Coimbra  Coimbra Portugal"},{"name":"Faculty of Pharmacy University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6773-1978","authenticated-orcid":false,"given":"Ana B.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9869-8651","authenticated-orcid":false,"given":"S\u00f3nia","family":"Silva","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Coimbra  Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB) and Coimbra Institute of Clinical and Biomedical Research (iCBR) University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7279-5728","authenticated-orcid":false,"given":"Rui F. P.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Centre of Chemistry University of Minho  Braga Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7145-2472","authenticated-orcid":false,"given":"Ana C.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"CEMMPRE ARISE Department of Chemical Engineering Faculty of Sciences and Technology University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8664-2757","authenticated-orcid":false,"given":"Arm\u00e9nio C.","family":"Serra","sequence":"additional","affiliation":[{"name":"CEMMPRE ARISE Department of Chemical Engineering Faculty of Sciences and Technology University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9351-1704","authenticated-orcid":false,"given":"Jorge F. 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