Both the QEs for DC-SIGN/R binding with Gx-DiMan were found to be strongly dependent on pH, but with notable differences (Fig. ). For DC-SIGN, its binding affinity (represented by QE) was high and remained almost constant as pH was reduced from 7.4 (normal physiological pH) to 5.4, and further reduction of pH led to significantly reduced QE (Fig. ). In contrast, the QE for DC-SIGNR displayed an inverse V shaped response with pH, it peaked at ∼pH = 5.4, and then decreased with the increasing deviation from this point (with pH going either higher or lower). Changing the GNP scaffold size (G13 vs. G27) did not significantly affect the trend of their QE -pH relationships. DC-SIGNR appeared to bind progressively more strongly (displaying higher QE) with Gx-DiMan as pH reduced from 7.4 to 5.4, suggesting no pH triggered release of bound ligands for DC-SIGNR over this pH range. This result is consistent with an earlier report that DC-SIGNR does not release its ligands at earlier endosomal pHs (∼6.0). DC-SIGNR binding was found to be weakened as pH reduced further to < 5.4, suggesting it may release ligands in late endosomes (pH ∼5.0) or lysosomes (pH ∼4.6). DC-SIGN, on the other hand, may bind ligands stability over normal physiological to endosomal pH range (i.e., pH 7.4 to ∼5.5), which then readily release them as pH is further reduced.