A prototypical nanoparticle is produced by chemical synthesis, then coated with polymers, drugs, fluorophores, peptides, proteins, or oligonucleotides, and eventually administered into cell cultures. Nanoparticles were conceived of as benign carriers, but multiple studies have demonstrated that their design influences cell uptake, gene expression, and toxicity.
     More specifically, interactions between nanoparticle-bound ligands (the molecules that bind to nanoparticles) and cellular receptors depend on the engineered geometry and the ligand density of a nanomaterial. The nanoparticle acts as a scaffold whose design dictates the number of ligands that interact with the receptor target. A multivalent effect occurs when multiple ligands on the nanoparticle interact with multiple receptors on the cell. The binding strength of complexed ligands is more than the sum of individual affinities; the accumulated effect of multiple affinities is known as the avidity for the entire complex.
     This phenomenon is illustrated by the binding affinity of the antibody trastuzumab to the ErbB2 receptor, a protein whose overexpression has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. Trastuzumab's binding affinity to ErbB2 when liganded to a nanoparticle increases proportionally with the size of a nanoparticle, owing to a higher density of the ligand on the nanoparticle surface. However, when viewed in terms of the downstream signaling via the ErbB2 receptor, mid-sized gold nanoparticles induced the strongest effect, suggesting that factors beyond binding affinity must be considered.
     Furthermore, several studies have shown that nanoparticle design can generate effects not obtained simply by a free ligand in solution. For example, the aforementioned mid-sized trastuzumab-coated gold nanoparticles altered cellular apoptosis, the process of programmed cell death, by influencing the activation of the so-called "executioner" caspase enzymes. Similarly, receptor-specific peptides improved their ability to induce angiogenesis, the physiological process through which new blood vessels form from preexisting vessels, when these peptides are conjugated to a nanoparticle surface. Specifically, presentation of the peptide on a structured scaffold increased angiogenesis, which is dependent on receptor-mediated signaling. These findings highlight the advantages of a ligand bound to a nanoparticle over one free in solution. The nanoparticle surface creates a region of highly concentrated ligand, which increases avidity and, potentially, alters cell signaling.