With this double information at hand, we next verified whether the G2 PAMAM could still operate heparin binding in the presence of serum, and compared the relevant results with those obtained using protamine in the same environment. Very pleasingly we found that, under these substantially more challenging conditions, while protamine worsened its performance (EC50,serum = 3.51 µM, CE50,serum = 0.79, and dose = 0.49 mg/100 heparin IU) the G2 dendrimer slightly enhanced its binding affinity for the polyanion (EC50,serum = 2.15 µM, CE50,serum = 0.32, and dose = 0.21 mg/100 heparin IU). Notwithstanding these highly encouraging results we ultimately reasoned that, even if low generation PAMAM dendrimers are often overlooked for biomedical applications despite their good toxicological profiles [35], a substantially more degradable, less expensive, and easier-to produce system could be more desirable for safe and effectual production under good-manufacturing-practice (GMP) quantities required for the translation of a new protamine replacer to the clinic. Bearing this belief in mind, we then plunged ourselves into the sea of self-assembly nanoscale multivalent surfaces in the hope of finding an alternative, even more responsive, synthetic, protamine-mimic heparin binder.