Studies have demonstrated that some nanomaterials, depending on exposure, composition, and properties, can disrupt the plasma membrane, a lipid bilayer that surrounds all cells, thereby causing cell toxicity. However, the role of the individual leaflets of the plasma membrane in regulating the disruptive effects of nanomaterials is not known. The plasma membrane is composed of two leaflets: an inner leaflet facing the cell and an outer leaflet facing the outside environment. Red blood cells provide an ideal model to study plasma membrane-nanoparticle interactions due to being one of the few cells for which the lipid composition of both leaflets is known. In addition, disruption of red blood cells by nanomaterials can be easily tracked by the release of hemoglobin, which has a distinct red color. The investigator has recently shown that disruption of red blood cells by nanoparticles is dependent on the lipid composition of the outer leaflet with little to no contribution from the inner leaflet. In this proposal, the investigator will examine how the lipid composition of the outer leaflet regulates nanoparticle-membrane interactions. To this aim, the investigator will study the interactions of a set of engineered nanoparticles with healthy and diseased red blood cells in which the outer leaflet lipid composition is altered. Chronic myeloid leukemia, a form of blood cancer, will be used as the diseased model. This disease does not commonly show symptoms in its early phases but induces changes in the lipid composition of the outer leaflet of red blood cells. Completion of this project provides benefits to society through 1) elucidating the role of the outer leaflet lipids in regulating nanoparticle toxicity, 2) providing information on the toxicity of nanoparticles to red blood cells in healthy vs. leukemic individuals, and 3) the development of a rapid screening assay for chronic myeloid leukemia. This project will involve undergraduate students in research, facilitate hands-on nanotechnology education, and educate the public through demonstrations focused on nanotechnology in a local non-profit.
Nanomaterials, depending on exposure and physicochemical properties, can disrupt the cell plasma membrane. The plasma membrane is an asymmetric lipid bilayer and the composition of lipids in the outer leaflet (facing the outside environment) is different from the lipids in the inner leaflet (facing the cytoplasm). The investigator 's previous research, using engineered silica nanoparticles and vesicles that mimic each leaflet of the plasma membrane of red blood cells, has shown that the lipid composition of the outer leaflet is the primary regulator of nanoparticle-induced membrane damage. In this project, the investigator will examine the interactions of engineered nanoparticles with the plasma membrane of healthy and diseased red blood cells in which membrane lipid asymmetry is disrupted, to examine how the lipid composition of the outer leaflet regulates nanoparticle-cell membrane interactions. Chronic myeloid leukemia, a form of blood cancer, will be used as the diseased model. This disease is asymptomatic in its early phases but is known to disrupt the asymmetry of the plasma membrane in red blood cells. In this project, the PI will first investigate how engineered silica nanoparticles bind to, deform, or disrupt healthy vs. leukemic red blood cells. The PI will then characterize the outer leaflet lipid composition of healthy and leukemic red blood cells to elucidate how the outer leaflet lipids regulate nanoparticle-cell membrane interactions. This project is high risk-high payoff. While significant differences are expected in nanoparticle-induced membrane disruption in healthy vs. diseased red blood cells, which have different outer leaflet lipid compositions, there is the risk distinguishing and characterizing these differences is extremely difficult. However, if significant differences are observed, this project could be the stepping-stone for the use of nanoparticles for screening of diseases in which the plasma membrane lipid composition is altered. This is a transformative approach, which can lead to a plethora of novel screening assays in the future. This project will also provide new information concerning the biological behavior of nanomaterials. Successful conclusion of this research will shed light on the role of nanomaterial physicochemical properties which induce damage in the membranes of mammalian cells and characterize differences in nanoparticle-induced toxicity for different cells which are a function of the lipid composition of the outer leaflet of cell membranes.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
