Interfacing Nanomaterials with Biology through Ligand Engineering

Conspectus Nanoparticles (NPs) have incrediblepotential in biologyand biomedicine. Gold nanoparticles (AuNPs) have become a cornerstoneof the nanomedicine revolution due to their ease of synthesis, inertness,and versatility. The widespread use of AuNPs can be traced to thedevelopment of accessible, bottom-up wet synthesis methods that emphasizedthe role of ligands in controlling the size, dispersity, and stabilityof colloids in solution. Decoration of AuNPs with organic ligandscan be used to dictate the interactions of these nanomaterials withbiosystems on multiple scales. The tunability of the AuNP ligand monolayer via covalent and noncovalent approaches allows the use ofAuNPs in a broad range of biomedical fields. In this Account,we describe our use of AuNPs to answer a centralquestion in the ligand engineering of colloidal nanoparticles: canwe fabricate NPs that are nontoxic, modular, and functional in biologicalenvironments? We explored spherical AuNPs of different sizes and ligandstructures, empirically exploring the AuNP-biomolecule interaction.We show here how the atom-by-atom control provided by organic synthesiscan be used to create engineered ligands. Presenting these ligandson the surface of AuNPs creates multivalent constructs with uniqueand useful properties. Ligand design is a key feature of these AuNPs.We have developed ligands that have three distinct structural segments:1) a hydrophobic alkanethiol interior that imparts stability; 2) atetra-(ethylene glycol) segment that creates a noninteracting tabularasa surface; and 3) ligand headgroups that dictate how the AuNP interactswith the outside world. Our research into the design principles ofligands on AuNPs and their interactions with biological systems canbe translated to other nanoparticle systems. This Account alsosummarizes the trajectory of ligand engineeringin our laboratory and further afield. At the outset, experimentaland theoretical fundamental studies were focused on the interactionsbetween AuNPs and cellular components, such as proteins and lipidmembranes. Understanding these behaviors provided the direction forinvestigating how ligands mediate the interface of AuNPs with mammalianand bacterial cells. In these experiments, it was particularly noteworthythat the ligand hydrophobicity and charge play a significant rolein the uptake and toxicity of AuNPs. These revelations formed a basisfor translating AuNPs to physiological environments. We present howwe have integrated our synthetic abilities to construct AuNPs forbiomedical applications, including delivery, bioorthogonal catalysis,antimicrobial and antitumor therapeutics, and biosensing. Overall,we hope that this Account will give the reader insightinto how our research has evolved, changing AuNPs from synthetic curiositiesinto functional nanoplatforms for nanomedicine, all through the powerof ligand design and synthesis.