In summary, we have presented a new glycan-QR based multifunctional biophysical probe for MLGIs. By combining FRET, hydrodynamic size and S/TEM imaging analysis, we have dissected the geometric influences of glyconanomaterials on MLGI properties using DC-SIGN and DC-SIGNR, a pair of tetrameric lectin models having almost identical monovalent binding motifs but distinct binding site arrangements. We demonstrate that, given ample polyvalent glycan density and area, scaffold curvature has a fundamental impact on the binding modes of MLGIs. Here, DC-SIGNR is able to distinguish between the end and middle sections of QR-DiMan, forming strong simultaneous tetravalent binding at the central cylindrical section but bisbivalent crosslinking at the spherical ends. Whereas, DC-SIGN binds with strong simultaneous tetravalent binding irrespective of the QR section. We have further predicted that only curvatures affording a separation distance between the protein contact area and the glycan ligand surface (𝑑) smaller than the compression length of the glycan ligands (𝑙) can result in the strong simultaneous binding of all binding sites. However, if 𝑑 is greater than 𝑙, then only weak crosslinking or other lower valency binding interactions can occur. This result thus demonstrates how multimeric lectins like DC-SIGN/R differentiate glycan displays with different geometries, which may help explain some of their differences in virus-binding and transmitting properties. This new information will be useful for guiding the design of specific multivalent glycans for targeting such MLGIs.