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This study addresses this gap by evaluating the immunological behavior of superparamagnetic iron oxide nanoparticles (SPIONs) coated with HP or DS in human whole blood, primary immune cells, endothelial cells, and in vivo. Both HP\u2010SPIONs and DS\u2010SPIONs effectively suppressed complement activation, as shown by reduced C3bc, C3bBbP, and TCC levels. Notably, HP\u2010SPIONs activated monocytes (CD11b) and endothelial cells (ICAM\u20101, CD62P\/E), whereas DS\u2010SPIONs suppressed endothelial activation. DS\u2010SPIONs were preferentially internalized by myeloid cells (\u223c50% neutrophils, \u223c42% macrophages, \u223c55% dendritic cells), while HP\u2010SPIONs showed significantly lower uptake (&lt;25% dendritic cells, \u223c5% neutrophils). DS\u2010SPIONs induced an immunosuppressive, pro\u2010healing phenotype in murine and human macrophages, whereas HP\u2010SPIONs drove a pro\u2010inflammatory, M1\u2010like response. In healthy mice, intravenous DS\u2010SPIONs elicited a modest increase in splenic immune cell populations compared to HP\u2010SPIONs, indicating early immune engagement. Collectively, both SPIONs attenuate complement activation, indicating high biocompatibility. Based on the early immunological responses, DS\u2010SPIONs display a pro\u2010healing immune profile suitable for regenerative drug delivery, whereas HP\u2010SPIONs induce pro\u2010inflammatory responses that may be leveraged for anticancer immunotherapy.<\/jats:p>","DOI":"10.1002\/smll.202508613","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T07:33:41Z","timestamp":1770017621000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reprogramming Immunogenicity of Iron Oxide Nanoparticles through Sulfated Glycan Presentation"],"prefix":"10.1002","volume":"22","author":[{"given":"Negin","family":"Pournoori","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heela","family":"Sarlus","sequence":"additional","affiliation":[{"name":"Department of 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