The Role of Surface Functionality in Determining Nanoparticle Cytotoxicity

Surface properties dictate the behavior of nanomaterials in vitro, in vivo, and in the environment. Such properties include surface charge and hydrophobicity. Also key are more complex supramolecular interactions such as aromatic stacking and hydrogen bonding, and even surface topology from the structural to the atomic level. Surface functionalization of nanoparticles (NPs) provides an effective way to control the interface between nanomaterials and the biological systems they are designed to interact with. In medicine, for instance, proper control of surface properties can maximize therapeutic or imaging efficacy while minimizing unfavorable side effects. Meanwhile, in environmental science, thoughtful choice of particle coating can minimize the impact of manufactured nanomaterials on the environment. A thorough knowledge of how NP surfaces with various properties affect biological systems is essential for creating NPs with such useful therapeutic and imaging properties as low toxicity, stability, biocompatibility, favorable distribution throughout cells or tissues, and favorable pharmacokinetic profiles-and for reducing the potential environmental impact of manufactured nanomaterials, which are becoming increasingly prominent in the marketplace. In this Account, we discuss our research and that of others into how NP surface properties control interactions with biomolecules and cells at many scales, including the role the particle surface plays in determining in vivo behavior of nanomaterials. These interactions can be benign, beneficial, or lead to dysfunction in proteins, genes and cells, resulting in cytotoxic and genotoxic responses. Understanding these interactions and their consequences helps us to design minimally invasive imaging and delivery agents. We also highlight in this Account how we have fabricated nanoparticles to act as therapeutic agents via tailored interactions with biomacromolecules. These particles offer new therapeutic directions from traditional small molecule therapies, and with potentially greater versatility than is possible with proteins and nudeic acids.