Finally, we report that the glycan-GNPs potently block DC-SIGN/R mediated pseudo-Ebola viral infection of host cells, with potencies being enhanced with the increasing GNP size. In particular, a 27 nm GNP capped with the pure LA-EG4-DiMan ligand (G27-DiMan) potently and robustly blocks both DC-SIGN and DC-SIGNR mediated virus infections with an EC50 value of ~23 and ~49 pM, respectively, making it the most potent glycoconjugate inhibitor against DC-SIGN/R mediated Ebola cellular infection. Together, our results have revealed the critical important role of GNP scaffold size in controlling their MLGI biophysical parameters and blocking DC-SIGN/R-mediated virus entry.