The use of nanomaterials has raised safety concerns, as their small size facilitates accumulation in and interaction with biological tissues. Here we show that exposure of endothelial cells to TiO 2 nanomaterials causes endothelial cell leakiness. This effect is caused by the physical interaction between TiO 2 nanomaterials and endothelial cells' adherens junction protein VE-cadherin. As a result, VE-cadherin is phosphorylated at intracellular residues (Y658 and Y731), and the interaction between VE-cadherin and p120 as well as b-catenin is lost. The resulting signalling cascade promotes actin remodelling, as well as internalization and degradation of VE-cadherin. We show that injections of TiO 2 nanomaterials cause leakiness of subcutaneous blood vessels in mice and, in a melanoma-lung metastasis mouse model, increase the number of pulmonary metastases. Our findings uncover a novel non-receptor-mediated mechanism by which nanomaterials trigger intracellular signalling cascades via specific interaction with VE-cadherin, resulting in nanomaterial-induced endothelial cell leakiness.

While the blood vessel is seldom the target tissue, almost all nanomedicine will interact with blood vessels and blood at some point of time along its life cycle in the human body regardless of their intended destination. Despite its importance, many bionanotechnologists do not feature endothelial cells (ECs), the blood vessel cells, or consider blood effects in their studies. Including blood vessel cells in the study can greatly increase our understanding of the behavior of any given nanomedicine at the tissue of interest or to understand side effects that may occur in vivo. In this review, we will first describe the diversity of EC types found in the human body and their unique behaviors and possibly how these important differences can implicate nanomedicine behavior. Subsequently, we will discuss about the protein corona derived from blood with foci on the physiochemical aspects of nanoparticles (NPs) that dictate the protein corona characteristics. We would also discuss about how NPs characteristics can affect uptake by the endothelium. Subsequently, mechanisms of how NPs could cross the endothelium to access the tissue of interest. Throughout the paper, we will share some novel nanomedicine related ideas and insights that were derived from the understanding of the NPs' interaction with the ECs. This review will inspire more exciting nanotechnologies that had accounted for the complexities of the real human body.

Nanoparticles can have profound effects on cell biology. Here, we show that after TiO2, SiO2, and hydroxyapatite nanoparticles treatment, TR146 epithelial cell sheet displayed slower migration. Cells after exposure to the nanoparticles showed increased cell contractility with significantly impaired wound healing capability however without any apparent cytotoxicity. We showed the mechanism is through nanoparticle-mediated massive disruption of the intracellular microtubule assembly, thereby triggering a positive feedback that promoted stronger substrate adhesions thus leading to limited cell motility.

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In nanomedicine design, emphasis is centered on the engineered impacts of the nanomaterials (NMs). However, failure to understand the unintended effects of nanomaterials on the cell biology can affect the overall performance, approval, and adoption in the clinic. Much of these unintended effects arise from unique physico-chemical properties of the NMs. This feature article discusses some of the key physico-chemical parameters of NMs and highlights how they could cause unexpected and novel biological responses, with some insights into their underlying mechanisms.

The endothelium presents a formidable barrier for cancer nanomedicine, as the intravenously introduced nanomedicine needs to leave the blood vessel at the tumor site. Endothelial permeability and retention effect (EPR) is not dependable since it is derived from tumors. Certain nanoparticles with specific characteristics are able to induce micrometer sized gaps between endothelial cells. This effect is called "nanoparticle induced endothelial leakiness" (NanoEL). NanoEL therefore allows the nanotechnology to control access to the tumor even in the absence of any EPR effect. Morever, NanoEL can be applicable to noncancer issues, thereby expanding its usefulness in other subfields of nanomedicine. In this paper, we have shown that Gold (Au) nanoparticles within the range of 10-30 nm are good NanoEL inducing particles. As not all endothelial cells have the same permeability, we found that human mammary endothelial cells and human skin endothelial cells are sensitive to Au induced NanoEL, while human umbilical vein endothelial cells are insensitive, reflective of their innate nature of endothelial permeability. The size window and endothelial cell type sensitivity then helps the nanotechnologists to design future nanoparticles that either exploit NanoEL as a nanotechnology driven strategy to access immature tumors, which do not induce the EPR effect, or avoid NanoEL as a nanotoxic side effect.

Rapid and precise in situ detection of gene expressions within a single cell is highly informative and offers valuable insights into its state. Detecting mRNA within single cells in real time and nondestructively remains an important challenge. Using DNA nanotechnology and inspired by nature's many examples of "protective-yet-accessible" exoskeletons, we designed our mRNA nanosensor, nano-snail-inspired nucleic acid locator (nano-SNEL), to illustrate these elements. The design of the nano-SNEL is composed of a sensory molecular beacon module to detect mRNA and a DNA nanoshell component, mimicking the functional anatomy of a snail. Accurate and sensitive visualization of mRNA is achieved by the exceptional protection conferred by the nanoshell to the sensory component from nucleases-mediated degradation by approximately 9-25-fold compared to its unprotected counterpart. Our nano-SNEL design strategy improved cell internalization is a demonstration of accurate, dynamic spatiotemporal resolved detection of RNA transcripts in living cells.

Since many bionanotechnologies are targeted at cells, understanding how and where their interactions occur and the subsequent results of these interactions is important. Changing the intrinsic properties of DNA nanostructures and linking them with interactions presents a holistic and powerful strategy for understanding dual nanostructure-biological systems. With the recent advances in DNA nanotechnology, DNA nanostructures present a great opportunity to understand the often convoluted mass of information pertaining to nanoparticle-biological interactions due to the more precise control over their chemistry, sizes, and shapes. Coupling just some of these designs with an understanding of biological processes is both a challenge and a source of opportunities. Despite continuous advances in the field of DNA nanotechnology, the intracellular fate of DNA nanostructures has remained unclear and controversial. Because understanding its cellular processing and destiny is a necessary prelude to any rational design of exciting and innovative bionanotechnology, in this review, we will discuss and provide a comprehensive picture relevant to the intracellular processing and the fate of various DNA nanostructures which have been remained elusive for some time. We will also link the unique capabilities of DNA to some novel ideas for developing next-generation bionanotechnologies.