These results clearly highlight a major difference in the behavior of covalent and self-assembled nanostructures: While in human serum the former can withstand interfering blood components during heparin binding, the latter ones loose (at least in part) their polyanion binding ability when tested in competitive media. We ascribed the reason of this suboptimal performance to a partial disaggregation of the C22G1 self-assembled dendrimers (most likely operated by human albumin, the highly negatively charged, most abundant serum protein with specific binding sites for hydrophobic units) into their individual building blocks. As such the isolated C22G1 molecules, we verified (data not shown), were indeed unable to bind heparin effectively. Nonetheless, since the C22G1 self-assembly was not abrogated but only moderately compromised in the presence of serum with respect to the covalent counterparts, we considered the in-serum heparin binding performance of our systems still effective (CE50 < 1) and that the use of self-assembled dendrimers for this specific application could ultimately bring further advantages, as discussed below.