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Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

CONSPECTUS There are a growing range of innovations in the field of nanobiotechnology and nanomedicine. However, the increased number of engineered nanomaterials (ENMs) and their novel physicochemical properties pose a new challenge of understanding the full spectrum of their interactions at the nano/bio interface, including the potential to engage in hazardous interactions. A comprehensive understanding of these interactions is required, including the physicochemical properties that control bioavailability and how this knowledge could be used for safer nanomaterial design. To this end, considerable knowledge generation and exploration is required to understand how material properties influence ENM uptake, transport and fate, as well as the biological consequences of these interactions at cellular level. The toxicity mechanisms of different ENMs differ with nanosize/nanosurface which directly correlates to the physicochemical activities of ENMs in vivo. So, to explore their underlying physicochemical processes of ENMs in cells will be essentially helpful for definitely understanding the toxicity of ENMs. In addition, the in vitro results are indispensable for modeling the biokinetics of ENMs. Nevertheless, we need to proceed such extrapolation with due caution, because the dosage relevance between the in vitro and in vivo exposure largely influences outcomes of the toxic response. In this Account, we delineate our view of the impact of ENM physicochemical properties on cellular bioprocessing based on the research performed in our laboratories. Because organic, inorganic, and hybrid ENMs can be produced in various sizes, shapes, surface modifications and compositions, and their widely tunable compositions and structures that can be dynamically modified under different biological and environmental use conditions. Therefore, a description of how ENM chemical properties such as (1) hydrophobicity and hydropholicity, (2) material composition, (3) surface functionalization and charge, (4) dispersal state, and (5) adsorption of proteins on the surface determine ENM cellular uptake, intracellular biotransformation, and bioelimination or bioaccumulation, were included. We will also review how physical properties such as size, aspect ratio and surface area influence these interactions and their potential risks. We discuss this conceptual framework from the perspective of actual experimental findings and show how tuning of these properties can be used to control the uptake, biotransformation, fate and hazard of ENMs. The current review on ENM biological behavior and safety issues will provide specific and concentrated information with the principles of both nano-bio interactions and dominating natural biological rules. This knowledge gathering also assists us in developing safer nanotherapeutics and guiding the design of new materials that can execute novel functions at the nano-bio interface.

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Exosomes, molecular cargos secreted by almost all mammalian cells, are considered as promising biomarkers to identify many diseases including cancers. However, the small size of exosomes (30−200 nm) poses serious challenges in their isolation from complex media containing a variety of extracellular vesicles (EVs) of different sizes, especially in small sample volumes. Here we present a viscoelasticitybased microfluidic system to directly separate exosomes from cell culture media or serum in a continuous, size-dependent, and label-free manner. Using a small amount of biocompatible polymer as the additive in the media to control the viscoelastic forces exerted on EVs, we are able to achieve a high separation purity (>90%) and recovery (>80%) of exosomes. The proposed technique may serve as a versatile platform to facilitate exosome analyses in diverse biochemical applications.

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