Over the past five years, there has been a growing interest in the health-related issue of toxicity of engineered nanomaterials. Cells have various routes for uptake of molecules and particles through their cell membranes to control their internal environment including highly selective membrane proteins and peptides as well as protein mediated endocytosis and phagocytosis. Nanoparticle (NP) based drug delivery and molecular imaging applications that deliver NP into cells typically use biochemical functionalization which promote specific signaling and uptake. The lipid bilayers that make up cellular membranes are believed to be impenetrable to ions and unfunctionalized macromolecules, however, epidemiological studies have shown that unfunctionalized NPs can, under some conditions, cross or disrupt the cell membrane through passive, unmediated routes causing acute cellular toxicity and cell death. The unmediated NP adsorption onto and the uptake into cells is poorly understood. Recent research focuses on either collection of empirical epidemiological data (e.g. uptake of NP by cells, toxicity to organisms such as rats or fish) or precise NP characterization (e.g. size, shape, degree of aggregation, charge, and surface chemistry). However, it is almost impossible to transition from these measurements to detailed understanding of the mechanisms responsible for unmediated NP uptake into cells and disruption of the bilayer. Quantitative measures of nanomaterial bioavailability and toxicity need to be assessed so that the impact of nanotechnology on human health and the environment can be addressed.

The intellectual merit of the proposed work is to understand the mechanisms and conditions under which engineered nanomaterials can cause disruption of, and passive transport through, simplified model cell membranes, namely lipid bilayers. The,investigators hypothesize that under some conditions engineered NPs can passively translocate across, and cause nanoscale defects in, bilayers which plays a role in cellular toxicity. The interaction of nanoparticles and lipid bilayers are unique because the particle and membranes have nearly the same length scale

Fundamental understanding of the interaction between NP and lipid bilayers is potentially transformative because it may: (1) improve our understanding of toxicity of engineered and environmental NP; (2) enable rational design of benign NP for delivery of drugs and biomedical/molecular imaging; (3) result in high-throughput toxicity testing protocols; and (4) evidence-based regulation and protocols of nanomaterials. An experimental platform and methods will be developed for quantifying the NP transport through lipid membranes in real time as a function of the NP and lipid properties and the physicochemical environment. A "bottom-up" approach will be employed to increase the complexity of the bilayer through incorporation of membrane proteins as well as glycolipids to form an artificial glycocalyx.

Engineered nanoparticles are largely unregulated because the transport, fate, and toxicity of NP have not been adequately assessed. The proposed research focuses on the interactions of engineered nanomaterials with lipid bilayers, arguably the most important interface between life and the environment. This proposal addresses NP toxicity and has strong implications on the regulation of NP production, distribution, and application in medicine, clothing, cosmetics, etc. As an integral part of the proposed work, the PI aims to increase engineering and physical science graduate students' awareness of the societal and ethical implications of nano science and technology through: (1) development of a cross-listed graduate level course on the societal and ethical implications of nanotechnology; and (2) organization of a two week student workshop in Washington, DC which examines scientific policy and culture. The PI will also build upon his strong commitment to undergraduate research by funding underrepresented undergraduate researchers.