Recently, we have developed the "active" nano-scaffold strategy for MLGI research, where we have not only exploited the nano-scaffolds' unique optical properties as new MLGI affinity assays but also their nanoscale size and high TEM contrast to reveal key MLGI structural information. We have employed the dendritic cell tetrameric lectin, DC-SIGN, and a closely-related endothelial cell lectin, DC-SIGNR, (collectively abbreviated as DC-SIGN/R here after) as model lectins. These lectins play a key role in mediating or facilitating the infection of many viruses, e.g., HIV, HCV, Ebola, Zika, and SARS-CoV-2. Despite displaying identical CRD-mannose monovalent binding motifs, and almost identical tetrameric architectures, DC-SIGN/R in fact exhibit distinct virus transmitting properties. For example, DC-SIGN is more effective than DC-SIGNR in transmitting the HIV infection, while only DC-SIGNR, but not DC-SIGN, is able to transmit the West Nile virus infection. The structural mechanisms underlying such differences in DC-SIGN/R remain not fully understood. By displaying glycans polyvalently onto a CdSe/ZnS quantum dot (QD) or a small gold nanoparticle (GNP) scaffold as multifunctional probes, we have developed a new ratiometric QD-FRET (Förster resonance energy transfer) or GNP-fluorescence quenching affinity assay for MLGIs. We have found that glycan-nanoparticles exhibit greatly enhanced MLGI affinities than the corresponding monovalent binding (up to 1.8 million folds) and the enhancement with DC-SIGN is significantly greater than that with DC-SIGNR (by ~20-200 folds), arising from their distinct binding modes: DC-SIGN binds tetravalently with all 4 CRDs to one glycan-nanoparticle, while DC-SIGNR crosslinks with multiple glycan-nanoparticles. These glycan-nanoparticles was found to potently block DC-SIGN-, but not DC-SIGNR-, mediated pseudo-Ebola virus infections with sub-nM levels of EC50 values (EC50: the concentration giving 50% inhibition). Despite success, our previous studies are built upon small nanoparticle scaffolds (e.g., ~4 nm QD or 5 nm GNP), which may not optimal for maximising the MLGI affinity, specificity, and antiviral potency.