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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.

Nanomedicine involves the use of nanoparticles for therapeutic and diagnostic purposes. During the past two decades, a growing number of nanomedicines have received regulatory approval and many more show promise for future clinical translation. In this context, it is important to evaluate the safety of nanoparticles in order to achieve biocompatibility and desired activity. However, it is unwarranted to make generalized statements regarding the safety of nanoparticles, since the field of nanomedicine comprises a multitude of different manufactured nanoparticles made from various materials. Indeed, several nanotherapeutics that are currently approved, such as Doxil and Abraxane, exhibit fewer side effects than their small molecule counterparts, while other nanoparticles (e.g. metallic and carbon-based particles) tend to display toxicity. However, the hazardous nature of certain nanomedicines could be exploited for the ablation of diseased tissue, if selective targeting can be achieved. This review discusses the mechanisms for molecular, cellular, organ, and immune system toxicity, which can be observed with a subset of nanoparticles. Strategies for improving the safety of nanoparticles by surface modification and pretreatment with immunomodulators are also discussed. Additionally, important considerations for nanoparticle safety assessment are reviewed. In regards to clinical application, stricter regulations for the approval of nanomedicines might not be required. Rather, safety evaluation assays should be adjusted to be more appropriate for engineered nanoparticles.

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