Multivalent inhibitors that mimic the polysaccharide array on cells represent a new paradigm in the development of antiviral agents and antibiotics. Covalent ligand anchoring limits the affinity and, in turn, potency of these inhibitors with dissociation constants (Kd) commonly found in the micromolar or upper nanomolar range. Addressing this deficiency we here report on easily accessible gold core–shell nanoparticles (rSAM-NPs) featuring adaptable reversible self-assembled monolayer (rSAM)-based shells. The rSAMs are anchored by noncovalent amidinium-carboxylate interactions on gold nanoparticles at slightly alkaline pH resulting in laterally mobile pH-responsive assemblies that are functional at physiological pH. Introducing sialic acid ligands in the shell, we show that the rSAM-NPs strongly interact with the influenza virus surface protein hemagglutinin (limit of detection LoD < 2 nM) and deactivated bird flu virus H5N1 (LoD < 1 HAU) in allantoic liquid. Finally, we show that the rSAM-NPs effectively inhibit the interaction of the virus with red blood cells at concentrations in the low picomolar range. This represents a significant increase in potency with respect to multivalent inhibitors of similar size based on covalently anchored monosaccharides.