Even though CTB is not able to complex all of the Le x glycans in the model glycocalyx, it still showed a greater binding enhancement than for the StxB-Gb3 system, and it also had the greater level of superselectivity (Figure ). The superselective recognition of CTB and StxB relying on the target glycan density in the glycocalyx was not reported previously, yet is clearly apparent through slopes α > 1 in Figures . It is also in contrast to the widely observed phenomenon that increasing ganglioside GM1 concentration in a membrane leads to a reduction in binding affinity for CTB. This phenomenon has been attributed to clustering of GM1 in the membrane at higher concentrations. We would not expect a similar clustering phenomenon in our 3D glycocalyx model based on HA polymers. Following previous theoretical and experimental work with other interaction systems (reviewed in Ref. ), we propose that the main driver for superselective binding is the combinatorial entropy associated with linking multiple receptors (here glycans on the mucin-like structures) to multiple ligands (here glycan binding sites on the lectin). In particular, our observation of enhanced superselectivity with decreasing lectin concentration (Figures ) is indeed predicted by theoretical models of multivalent binding that take into account the combinatorial entropy effects. The clear superselective recognition that we have evidenced here raises the intriguing possibility that AB5 toxins exploit subtle differences in target glycan densities to discriminate between cell types and bind their target cells with high selectivity. In the case of cholera toxin, it has been shown that fucosylated glycoproteins, including mucins, enhance cell binding and intoxication. In contrast, binding to fucosylated glycolipids confers protection to the cells. Superselective binding to structures bearing Le x higher in the glycocalyx (e.g., mucins) could direct the toxin to cells where it is most likely to have greatest biological effect.