Where NA, EC50, C, and n are the normalized luciferase activity, Gx-DiMan concentration giving 50% apparent inhibition, Gx-DiMan concentration, and inhibition coefficient, respectively. Here, the n value indicates how quickly an inhibitor can achieve complete inhibition by increasing concentration, with n < 1, = 1, or > 1 indicating an inhibition being negatively-, non-or positively-cooperative, respectively. In general, any viable viral inhibitors should have n ≥ 1 (with n = 1 being the most widely observed), so that they can achieve completely inhibit virus infection under a reasonable concentration. The normalised luciferase activities (infections) for samples after each treatment were plotted against the dose of Gx-DiMan and fitted by Eq. 9 and the results were shown in Fig. . The detailed fitting parameters were summarized in Table . It was exciting that all three Gx-DiMan (x = 5, 13, and 27) conjugates potently and non-cooperatively blocked DC-SIGN promoted EBOVpp entry into 293T cells, with impressively low EC50 values of 0.45 ± 0.002, 0.073 ± 0.007, and 0.023 ± 0.001 nM, respectively. Thus, their antiviral potency was found to be enhanced with the increasing GNP scaffold size. This was fully consistent with their enhanced DC-SIGN affinity measured by the GNP fluorescence quenching assay (Table ). Moreover, all three Gx-DiMan inhibitors were found to act in a non-cooperative fashion (n = 1), indicating that Gx-DiMan could serve as viable, potent inhibitor of DC-SIGN mediated viral infections. Notably, G27-DiMan, with an impressively low EC50 of 23±1 pM, is considerably more potent than some of the most potent glycoconjugate inhibitors reported in literature (e.g., the giant globular multivalent glycofullerenes, EC50: ~0.67 nM, the virus-like glycodendrinanoparticles, EC50: ~0.91 nM, and our previous QD-EG3-DiMan, EC50: ~0.70 nM, and G5-EG2-DiMan, EC50: ~0.095 nM ). Interestingly, compared to G5-EG2-DiMan (G5 coated by an identical LA-EGm-DiMan ligand except for the linker being two EG unit shorter), G5-DiMan here was found to be potent (EC50: ~0.45 nM vs. ~0.095 nM ), consistent to its weaker DC-SIGN binding affinity (Kd: ~5.8 nM vs. ~3.8 nM 11 ). Thus, increasing the EGm linker length weakened the DC-SIGN binding affinity and antiviral potency of GNP-glycans, similar to that observed previously with QD-DiMan conjugates. Nonetheless, a suitable EG linker length is required for glycan-nanoparticles to promote high stability and resisting non-specific interactions, which are essential for potential applications under the challenging in vivo conditions. The inhibition of DC-SIGNR-promoted EBOVpp entry by Gx-DiMan was also enhanced with the increasing GNP scaffold size (i.e., with EC50 values of 1.5 ± 0.2, 1.2 ± 0.1, and 0.049 ± 0.002 nM for G5-, G13-, and G27-DiMan, respectively), similar to that observed against DC-SIGN mediated infections. However, their inhibition cooperativity showed a clear scaffold size dependence: it changed from negative (n = ~0.5) to positive (n = ~1.6) and finally non-cooperative (n = 1) as GNP scaffold size increased from 5 to 27 nm. This may indicate a change of binding behaviour (or mode) for Gx-DiMan with cell surface DC-SIGNR receptors as scaffold size changes. While the smallest G5-DiMan may retain its crosslinking mode in binding to DC-SIGNR on the cell surface which makes it difficult to achieve complete inhibition (n < 1) due to cell membrane restrictions, the largest G27-DiMan may be able to bind simultaneously to a single DC-SIGNR receptor and completely block its binding to EBOV-GP, similar to that occurring with DC-SIGN on cell membrane, giving rise to non-cooperative inhibition (n = 1). Together with an impressively low EC50 of ~49 pM, these results indicate that G27-DiMan can serve as a potent, viable inhibitor against DC-SIGNR mediate viral infection. Given that both DC-SIGN and DC-SIGNR have shown to play an important role in facilitating SARS-CoV-2 infections, the excellent potency and non-cooperative inhibition behaviour observed with G27-DiMan may make it a highly promising, viable entry inhibitor against SARS-CoV-2 infections.