Reprogramming Immunogenicity of Iron Oxide Nanoparticles through Sulfated Glycan Presentation

ABSTRACT Heparin (HP) and dextran sulfate (DS) are well‐known for their anti‐thrombotic and immunomodulatory properties; however, a direct comparison of their immunological responses when used in drug delivery applications is lacking. 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‐SPIONs and DS‐SPIONs effectively suppressed complement activation, as shown by reduced C3bc, C3bBbP, and TCC levels. Notably, HP‐SPIONs activated monocytes (CD11b) and endothelial cells (ICAM‐1, CD62P/E), whereas DS‐SPIONs suppressed endothelial activation. DS‐SPIONs were preferentially internalized by myeloid cells (∼50% neutrophils, ∼42% macrophages, ∼55% dendritic cells), while HP‐SPIONs showed significantly lower uptake (<25% dendritic cells, ∼5% neutrophils). DS‐SPIONs induced an immunosuppressive, pro‐healing phenotype in murine and human macrophages, whereas HP‐SPIONs drove a pro‐inflammatory, M1‐like response. In healthy mice, intravenous DS‐SPIONs elicited a modest increase in splenic immune cell populations compared to HP‐SPIONs, indicating early immune engagement. Collectively, both SPIONs attenuate complement activation, indicating high biocompatibility. Based on the early immunological responses, DS‐SPIONs display a pro‐healing immune profile suitable for regenerative drug delivery, whereas HP‐SPIONs induce pro‐inflammatory responses that may be leveraged for anticancer immunotherapy.