A lipoic acid-tetra(ethylene glycol) based multifunctional glycan ligand, LA-EG4-psDiMan, was designed (Scheme 1). It contains three functional domains, a LA group for strong anchoring on the GNP surface by forming two strong Au-S bonds; a flexible tetra(ethylene glycol) linker to afford the terminal glycan with some flexibility and impose high water solubility, stability, and resisting non-specific interactions; and a terminal pseudo-α-1,2-mannobioside (psDiMan) for specific DC-SIGN binding. Besides, a LA-EG2 ligand containing an EG2-OH terminal group, abbreviated as LA-EG2-EG2-OH, was also designed as an inert spacer ligand to tailor the GNP surface glycan density (see Fig. ). Self-assembled monolayers terminated with oligo(ethylene glycol) groups are well-known for their ability to resist nonspecific adsorptions and interactions of biomolecules. Both ligands contain the same LA based GNP surface anchoring group with the same overall EG linker length, therefore, they should have the same GNP anchoring and surface display properties. This allows us to readily tune GNP surface glycan density by simply varying the glycan: spacer ligand ratio (but with a fixed total ligand: GNP ratio) used in the GNP-glycan preparation. The LA-EG4-psDiMan glycan and LA-EG2-EG2-OH spacer ligands were synthesized via the route shown schematically in Scheme 1. Briefly, lipoic acid was first coupled to the commercial H2N-EGn-C≡CH (n = 2 or 4) via dicyclohexylcarbodiimide/4-N,N-dimethylaminopyridine mediated amide coupling to give LA-EGn-C≡CH in good yields, e.g., 72% for n = 2, and 85% for n = 4. psDiMan appending an α-(CH2)2-N3 linker in the pseudo-anomeric position (psDiMan-C2-N3) was synthesized as described previously. Finally, LA-EGn-C≡CH was coupled to psDiMan-(CH2)2-N3 (n = 4) or HO-EG2-N3 (n = 2) via the copper-catalyzed click reaction in the presence of CuSO4, sodium ascorbate (for reducing Cu 2+ to Cu + ) and tris(benzyltriazolylmethyl)amine (for stabilizing the formed Cu + catalyst) and purified by size exclusion chromatography using a Biogel P2 column via our established protocols to give the desired LA-EG4-psDiMan or LA-EG2-EG2-OH ligand in ~80% or 85% yields, respectively. Their chemical structures were confirmed by 1 H/ C NMR and LC-MS spectra (supporting Information, SI, Figs. and).