Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle 'isomers' with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio-and macro-molecules. Nanomaterials are of great interest for use in biomedicine as imaging tools 1-3 , phototherapy agents 4,5 and gene delivery carriers 6,7 . Their interactions with cell membranes are of central importance for all such applications. For example, many drugdelivery systems are based on the transport of therapeutic agents to the cytosol or nucleus of cells by nanoparticles; efficient delivery must be achieved while avoiding cytotoxicity during passage through cell membranes to reach intracellular target compartments 8,9 . Indeed, membrane penetration by synthetic 10 as well as by biologically derived 11 molecules/particles is currently under intense investigation. Some biomacromolecules, such as cell-penetrating peptides (CPPs), may be capable of penetrating membranes without overt lipid bilayer disruption/poration 12-15 . Likewise, synthetic nanomaterials with very small dimensions (molecules, metal nanoclusters 16 , small dendrimers 10 and carbon nanotubes 17 ) can also pass through cell membranes. However, to the best of our knowledge, no synthetic material larger than a few nanometres in size can pass through membranes without disrupting the integrity of these biological barriers. For example, charged particles (such as cationic quantum dots or dendrimers, mostly assisted by some degree of hydrophobicity) induce transient poration of cell membranes to enter cells, a process associated with cytotoxicity 18 . Alternatively, nanoparticles have been designed to explicitly disrupt endolysosomal membranes to enter the cell by force 19 or enter the cell aided by exogenous agents such as CPP chaperones 20 . In contrast, most nanoparticles are trapped in endosomes 21 and hence do not reach the cytosol.The surface properties of nanomaterials play a critical role in determining the outcome of their interactions with cells 22 . Recently, we found that when gold nanoparticles are coated with binary mixtures of hydrophobic and hydrophilic organic mo...

Several surfactant-like peptides undergo self-assembly to form nanotubes and nanovesicles having an average diameter of 30 -50 nm with a helical twist. The peptide monomer contains 7-8 residues and has a hydrophilic head composed of aspartic acid and a tail of hydrophobic amino acids such as alanine, valine, or leucine. The length of each peptide is Ϸ2 nm, similar to that of biological phospholipids. Dynamic light-scattering studies showed structures with very discrete sizes. The distribution becomes broader over time, indicating a very dynamic process of assembly and disassembly. Visualization with transmission electron microscopy of quickfreeze͞deep-etch sample preparation revealed a network of openended nanotubes and some vesicles, with the latter being able to ''fuse'' and ''bud'' out of the former. The structures showed some tail sequence preference. Many three-way junctions that may act as links between the nanotubes have been observed also. Studies of peptide surfactant molecules have significant implications in the design of nonlipid biological surfactants and the understanding of the complexity and dynamics of the self-assembly processes.amino acids ͉ charged and hydrophobic residues ͉ nonlipid surfactants ͉ simplicity to complexity ͉ prebiotic enclosures M olecular self-assembly recently has attracted considerable attention for its use in the design and fabrication of nanostructures leading to the development of advanced materials (1, 2). The self-assembly of biomolecular building blocks plays an increasingly important role in the discovery of new materials and scaffolds (3, 4), with a wide range of applications in nanotechnology and medical technologies such as regenerative medicine and drug delivery systems (5, 6). Recently, Hartgerink et al. (7) reported the design of a chimeric material consisting of a hydrophobic alkyl tail and a hydrophilic peptide containing phosphorylated serine with an RGD motif that facilitates directional alignment of mineralization of hydroxyapatite.We previously described a class of ionic self-complementary peptide that spontaneously self-assemble to form interwoven nanofibers in the presence of monovalent cations (8 -10). These nanofibers further form a hydrogel consisting of greater than 99.5% water. The constituent of the hydrogel scaffold is made of peptides with alternating hydrophilic and hydrophobic amino acids. Such a sequence has a tendency to form an unusually stable ␤-sheet structure in water (8 -10). When the peptides form a ␤-sheet, they exhibit two surfaces, a hydrophilic surface consisting of charged ionic side chains and a hydrophobic surface with hydrophobic side chains. As a result, the self-assembly of these peptides is facilitated by electrostatic interactions on one side and the hydrophobic interaction on the other, in addition to the conventional ␤-sheet hydrogen bond along the backbones. The self-assembling peptide scaffolds have been demonstrated to serve as substrate for tissuecell attachment, extensive neurite outgrowth, and formation of active n...

In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1alpha (HIF1-alpha); overexpression of HIF1-alpha is correlated with increased tumour invasiveness and resistance to chemotherapy. Here we report the disease-driven engineering of a drug delivery system, a 'nanocell', which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an 'integrative' approach in cancer therapy.

While intestinal transport systems for metabolites such as carbohydrates have been well characterized, the molecular mechanisms of fatty acid (FA) transport across the apical plasmalemma of enterocytes have remained largely unclear. Here, we show that FATP4, a member of a large family of FA transport proteins (FATPs), is expressed at high levels on the apical side of mature enterocytes in the small intestine. Further, overexpression of FATP4 in 293 cells facilitates uptake of long chain FAs with the same specificity as enterocytes, while reduction of FATP4 expression in primary enterocytes by antisense oligonucleotides inhibits FA uptake by 50%. This suggests that FATP4 is the principal fatty acid transporter in enterocytes and may constitute a novel target for antiobesity therapy.