Introduction to the Special Issue: Nanomaterials—Toxicology and medical applications

Nanotechnology is one of the most rapidly developing fields in the 21st century. Nanomaterials have extraordinarily high surface-to-volume ratios, and possess unique physiological and chemical properties. The novel applications of engineered nanomaterials for various commercial uses is growing exponentially, including in industry, agriculture, business, medicine, clothing, cosmetics, food, and public health. With many commercial engineered nanomaterial products being introduced into our daily life, the safety and toxicity of nanomaterials have become a major concern to the public. This is because nanomaterials are very reactive or have catalytic activity, and thus can be potentially toxic. To date, cytotoxic and genotoxic data for most manufactured nanomaterials have not been established at a rate corresponding to their use and the mechanisms underlying nanomaterial toxicity are not fully understood.

This Special Issue, Nanomaterials—toxicology and medical applications, consists of 12 review articles, representing a cross section of state-of-the-art science in the fields of nanotoxicity and nanomedicine. The first two reviews briefly address nanomedicine issues and the other 10 reviews focus on toxicology, of which two reviews evaluate the general methods to measure toxicity, and the following six reviews describe the toxicity and mechanisms involved in the toxicity of various nanomaterials, including metals, nano metal oxides, and carbon (e.g., graphene). The last two reviews discuss the impact of nanomaterials on aquatic systems and neurotoxicity. The invited contributors are experts in their fields, with papers published in prestigious journals, such as Chemical Reviews, Nature Nanotechnology, ACS Nano, Nanotoxicology, Biomaterials, and Journal of the American Chemical Society.

Theranostic nanomedicine is designed to improve the biodistribution of specific tumor-targeted drugs by integrating therapeutic and diagnostic functions into one nanoparticle. It is known that cancer cell dissemination occurs through the bloodstream via circulating tumor cells. In the first review, Dr. Ray, a pioneer and leading scientist in developing theranostic nanomedicine, and his co-workers provide a detailed description of their successful development of a multifunctional plasmonic shell-magnetic core nanotechnology-driven approach using Fe₃O₄-gold coating nanoparticles, coupled with an antibody for targeted diagnosis and isolation of circulating tumor cells at early stage. An overview of recent progress on theranostic nanomedicine is presented, and future research directions and potential challenges for theranostic nanomedicine are discussed.

The subsequent review by Dr. Chun-Ling Zhu and coworkers reports the application of mesoporous silica nanoparticles as drug delivery vehicles. The development of novel cell microenvironment stimuli-responsive smart controlled-release delivery systems is one of the current common interests of material science, pharmacology, and clinical medicine. Mesoporous silica nanoparticles have emerged as promising drug carriers, because of their unique characteristics and abilities to efficiently and specifically entrap cargo molecules. In this review, they focus on environmentally responsive mechanisms used in mesoporous silica nanoparticles, and highlight the use of pH-responsive, glutathione-responsive mechanisms in drug delivery.

Nanotoxicity is mainly dependent on the physical and chemical properties of the nanomaterial studied. Raman spectroscopy and electron spin resonance spectroscopy (ESR) have become the most commonly utilized instrumental methods for the study of nanotoxicity. Recent advances in electronics, lasers, optics, and nanotechnology have made Raman spectroscopy suitable for many applications. In the third review, Dr. Ying-Sing Li and Dr. Jeffrey S. Church discuss the applications of Raman spectroscopy in the analysis of foods and pharmaceutical nanomaterials. Basic Raman scattering theory, instrumentation, and statistical data analysis are introduced. With the advent of Raman enhancement mechanisms and the progress in metal nanotechnology, surface-enhanced Raman scattering spectroscopy has become an extra sensitive method for the analysis of food and pharmaceutical nanomaterials.

In general, most of the biologically generated free radicals, including reactive oxygen species (ROS), are short-lived, and thus are difficult to detect. ESR is a direct and reliable method to identify and quantify free radicals in both chemical and biological environments. In the fourth review, Dr. Jun-Jie Yin and co-workers introduce the theory of ESR and detail the different methodologies that use spin trapping and spin labeling probes for the identification of different types of free radicals. The use of ESR to elucidate the mechanisms of free radicals induced by nanomaterials is presented.

The mechanisms underlying nanotoxicity have recently been studied intensively. The most important and commonly occurring mechanism is the generation of ROS. Overproduction of ROS results in oxidative stress, leading to DNA damage, unregulated cell signaling, change in cell motility, cytotoxicity, apoptosis, and cancer initiation. In the fifth review, Dr. Peter Fu and co-workers discuss the critical factors that can affect the generation of ROS. These include size, shape, particle surface, surface positive charges, surface-containing groups, particle dissolution, metal ion release from nano metals and nano metal oxides, UV light activation, aggregation, mode of interaction with cells, inflammation, and pH of the medium.

The generation of ROS is an important mechanism underlying nano TiO2 toxicity. In the sixth review, Dr. Meng Li et al provide a thorough discussion about current studies that use ESR as the primary method to unravel the mechanism of nano TiO2 toxicity. This study illustrates the use of both ESR spin label oximetry and immune-spin trapping techniques as promising tools for studying the oxidative damage caused by nanomaterials. In the seventh review, Dr. Haohao Wu et al summarize the activities of nano iron metals and nano iron oxides in the ROS-related redox processes. Well-known homogeneous and heterogeneous redox mechanisms are introduced, which are dependent on intrinsic properties of iron nanostructures, such as chemical composition, particle size, crystalline phase, and bio-microenvironmental factors, including physiological pH and buffers, biogenic reducing agents, and other organic substances.

To assess the nanomaterial-induced genotoxicity is timely and important because it can provide information whether or not a specific nanomaterial can cause genetic effects in humans. In the eighth review, Dr. Tao Chen and co-workers summarize the experimental results on the genotoxicity of nano TiO₂ and discuss the possible mechanisms leading to mutation. Based on the results from a variety of genotoxicity bioassays, they conclude that the genotoxicity of TiO₂-NP_s is mediated mainly through the generation of oxidative stress in cultured cells.

Graphene, a single-atom-thick nanosheet, has attracted great interest recently as a revolutionary nanomaterial usable for a variety of bio-applications. In the ninth review Dr. Xiaoqing Guo and Dr. Nan Mei describe the most recent findings on the toxicological activity of graphene-family nanomaterials (GFNs) in vitro and in vivo. Also discussed are the effects of functionalization of GFNs on diminishing their toxic interaction with cells, and the potential mechanisms of GFNs-induced toxicity. The material properties relevant to biological effects and the applications of GFNs in the field of drug delivery and food preparation are also covered in this article.

The 10th review summarizes recent advances, particularly molecular toxicity, of nanosilver. The surface of nanosilver can be oxidized and release Ag⁺, a known toxic ion. Both the nano and ionic form of silver contribute to the toxicity of nanosilver. The surface oxidation rate depends on surface coating, co-existing molecules, light, and interaction with biological macromolecules (DNA, protein, and lipid). Nanosilver can enter the cell and become internalized, and act as a source of Ag⁺. Nanosilver generates ROS and causes oxidative stresses such as DNA damage, activation of antioxidant enzymes, depletion of antioxidants, binding and disabling proteins, and cell membrane damage.

There is an increasing number of engineered nanomaterials being released into aquatic environments on a global basis. Conducting nano ecotoxicity studies is both multidimensional and multifocal. A holistic approach to conducting nano ecotoxicity studies will enable us to mirror the more sophisticated forms of nano-bio-eco interference that determine the threshold of exposure and its consequences. In the 11th review, Dr. Xiaojia He et al review toxicity tests involving various aquatic organisms for the elaboration of in vitro, in vivo, and in situ toxicity at different trophic levels. They show that a holistic approach is urgently needed to fulfill our knowledge gap regarding the safety of discharged engineered nanomaterials.

The interaction of engineered nanomaterials with the nervous system has received great attention in the nanotoxicology field. In the 12th review, Dr. Yongbin Zhang et al describe the biological effects of nano metals, nano metal oxides, and nanocarbon materials on the nervous system. The translocation of the nanoparticles through the blood–brain barrier or nose to the brain via the olfactory bulb route is discussed. In most cases, neurotoxicity is due to oxidative stress generated by nanomaterials.

The editor sincerely thanks the authors for their efforts and submission of their manuscripts in a timely manner. We hope this issue will provide guidance to professionals in toxicology, medical science, and the nanotechnology industry. The editor also thanks Dr. Lucy Sun Hwang, Executive Editor of the Journal of Food and Drug Analysis (JFDA), for inviting me to serve as Guest Editor of this Special Issue, and Ms. Hsiang-Pin Chiu and Ms. Chia-Hsin Wu of JFDA for technical assistance.