). However, these amplification effects of cellular uptake were more significant in the case of H-Tyra and H-Tyros at both tested concentrations, with H-Tyros causing the highest increase in cellular iron concentration (supplementary table ). It was reported that hemin nitrosylation facilitates its permeation through the cell membranes, and this explains the observed results of hemin . However, taking into consideration the affinity of the ironporphyrin macrocycles to aggregate, this causes partial inhibition of • NO-scavenging as reported in supplementary figs 35-38, and consequently decreases the levels of cellular internalization. Accordingly, those compounds with less resistance to aggregation, particularly H-Tyra and H-Tyros as explained in the aggregation and dimerization section, will be expected to have a higher affinity towards • NO, with a higher cellular uptake. This, in fact, is what was observed. Furthermore, it should be noted that in the absence of • NO, the increase in concentration of each tested compound enhances the probability of aggregation of the Fe-porphyrin macrocycles. This was found to partially inhibit the cellular internalization of hemin, H-Tyra and H-Styr. In contrast to the previous effects of nitrosylation, the cellular uptake of H-Styr was found to be inhibited in the presence of DETA-NO, suggesting certain implications following its nitrosylation in combination with its dimeric nature. In the case of iNOStransfected HCC1806 cells, similar results were observed with H-Tyra showing the highest significant levels of cellular uptake, followed by H-Styr (supplementary table ). Moreover, hemin and H-Tyros showed similar, but lower cellular internalization, particularly at 4 μM, while a higher uptake of H-Tyros was observed at 8 μM than that of hemin. This supports the previous observations, and confirms the higher affinity of hemin molecules to aggregate, which affects their permeation through the cell membrane. Furthermore, these results explain the high scavenging efficiency of H-Styr for the intracellular NO compared to other compounds (supplementary figs 45).