Multifaceted ligand design facilitates chemical- or peptide-mediated linking of hollow gold nanoshells with tuned interparticle distance, interference and cytotoxicities

We report a versatile methodology to covalently link hollow gold nanoshells (HAuNS) through modular design of multi-tasking ligands and bio-adaptable chemistry. The biocompatible ligand composition includes strategically placed two polyethylene glycol (PEG) chains, protected thiol-terminated tetraethylene glycol, and a reactive functional group, on a core. HAuNS are functionalized through an in situ one-pot deprotection/thiol-Au binding. The ligand-functionalized HAuNS with surface exposed COOH or OH entities are employed in constructing linked-HAuNS conjugated through a short chemical- or a longer bio-spacer (GPLGVRG peptide), in which (i) the length of the PEG chains plays an important role in minimizing oligomerization during covalent linking of HAuNS; (ii) inter-particle distance and interference of HAuNS surface plasmon resonance are regulated through chemical/peptide junctions, with UV-Vis-NIR absorption maxima red-shifted in chem-linked HAuNS; and (iii) chem-linked HAuNS-to-monomer conversion leads to amplification of the photoacoustic signal. Ligand stabilized monomeric and linked-HAuNS are less cytotoxic than citrate protected HAuNS. The synthetic tools and facile chemistry described here provide opportunities in designing linked metal nanoparticles for broad applications in biology.