Understanding as well as rapidly screening the interaction of nanoparticles with cell membranes is of central importance for biological applications such as drug and gene delivery. Recently, we have shown that "striped" mixed-monolayer-coated gold nanoparticles spontaneously penetrate a variety of cell membranes through a passive pathway. Here, we report an electrical approach to screen and readily quantify the interaction between nanoparticles and bilayer lipid membranes. Membrane adsorption is monitored through the capacitive increase of suspended planar lipid membranes upon fusion with nanoparticles. We adopt a Langmuir isotherm model to characterize the adsorption of nanoparticles by bilayer lipid membranes and extract the partition coefficient, K, and the standard free energy gain by this spontaneous process, for a variety of sizes of cell-membrane-penetrating nanoparticles. We believe that the method presented here will be a useful qualitative and quantitative tool to determine nanoparticle interaction with lipid bilayers and consequently with cell membranes.

The development of synthetic nanomaterials that could embed within, penetrate, or induce fusion between membranes without permanent disruption would have great significance for biomedical applications. Here we describe structure-function relationships of highly water-soluble gold nanoparticles comprised of an ∼1.5-5 nm diameter metal core coated by an amphiphilic organic ligand shell, which exhibit membrane embedding and fusion activity mediated by the surface ligands. Using an environment-sensitive dye anchored within the ligand shell as a sensor of membrane embedding, we demonstrate that particles with core sizes of ∼2-3 nm are capable of embedding within and penetrating fluid bilayers. At the nanoscale, these particles also promote spontaneous fusion of liposomes or spontaneously embed within intact liposomal vesicles. These studies provide nanoparticle design and selection principles that could be used in drug delivery applications, as membrane stains, or for the creation of novel organic/inorganic nanomaterial self-assemblies.

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We have reported that CD-6′SLN [6-sialyllactosamine (6′SLN)-modified β-cyclodextrin (CD)] can be a potential anti-influenza drug because it irreversibly deactivates virions. Indeed, in vivo, CD-6′SLN improved mice survival in an H1N1 infection model even when administered 24 h post-infection. Although CD-6′SLN was designed to target the viral envelope protein hemagglutinin (HA), a natural receptor of 6′SLN, it remains unclear whether other targets exist. In this study, we confirm that CD-6′SLN inhibits the influenza virus through an extracellular mechanism by interacting with HA, but not with neuraminidase (NA), despite the latter also having a binding pocket for the sialyl group. We find that CD-6′SLN interacts with the viral envelope as it elicits the release of a fluorophore embedded in the membrane. Two similar compounds were designed to test separately the effect of 6′SLN and of the undecyl moiety that links the CD to 6′SLN. Neither showed any interaction with the membrane nor the irreversible viral inhibition (virucidal), confirming that both components are essential to membrane interaction and virucidal action. Unlike similar antiviral cyclodextrins developed against other viruses, CD-6′SLN was not able to decapsulate viral RNA. Our findings support that combining viral protein-specific epitopes with hydrophobic linkers provides a strategy for developing antiviral drugs with a virucidal mechanism.

Nanoparticle-based magnetic resonance imaging T 2 negative agents are of great interest, and much effort is devoted to increasing cellloading capability while maintaining low cytotoxicity. Herein, two classes of mixed-ligand protected magnetic-responsive, bimetallic gold/iron nanoparticles (Au/Fe NPs) synthesized by a two-step method are presented. Their structure, surface composition, and magnetic properties are characterized. The two classes of sulfonated Au/Fe NPs, with an average diameter of 4 nm, have an average atomic ratio of Au to Fe equal to 7 or 8, which enables the Au/Fe NPs to be superparamagnetic with a blocking temperature of 56 K and 96 K. Furthermore, preliminary cellular studies reveal that both Au/Fe NPs show very limited toxicity. MRI phantom experiments show that r 2 /r 1 ratio of Au/Fe NPs is as high as 670, leading to a 66% reduction in T 2 relaxation time. These nanoparticles provide great versatility and potential for nanoparticle-based diagnostics and therapeutic applications and as imaging contrast agents.