BACKGROUND: Iron toxicity is a major contributor to adverse pregnancy outcomes in women with transfusion-dependent thalassemia. Currently used iron chelators are not recommended during pregnancy, as they can cross the placenta causing potential risk to the fetus. However, ceasing medication may adversely affect the mother's health in both the short- and long-term. OBJECTIVE: We previously demonstrated that melanin nanoparticles can effectively chelate iron, and this has been confirmed by others in iron-overloaded mice. This study aims to assess whether these nanoparticles cross the placenta and evaluate their biocompatibility and haemocompatibility. STUDY DESIGN: A library of 50 nm, 200 nm, and 500 nm melanin nanoparticles were synthesized and coated with Polyethylene Glycol (PEG) to improve their stability. The particles were tested for chelating iron efficacy in and biocompatibility. An in vitro BeWo (choriocarcinoma) cell model and ex vivo human placental perfusion system were used to assess nanoparticle transplacental passage. RESULTS: Melanin nanoparticles of all sizes were able to chelate iron with a maximum adsorption of 14 mm iron/g of material; significantly higher than Desferrioxamine (DFO) of the same concentration. It was also determined that PEGylated melanin nanoparticles with appropriate size (cut off 200 nm) could be restricted from passing across the placental barrier in an in vitro model using a human choriocarcinoma cell line and in an ex vivo human placental perfusion model. The particles did not cause red cell haemolysis or blood clotting at concentrations up to 1 mM. CONCLUSION: It was demonstrated herein that transport of MNPs across the placental barrier is highly dependent on particle size (cut off size of 200 nm PEGylated MNPs). Findings suggest the possibility of providing a safe method of iron chelation during pregnancy. Future work using in vivo models will be applied to study systemic particle interactions.