Cell-derived nanomaterials for biomedical applications.

The ever-growing use of nature-derived materials creates exciting opportunities for novel development in various therapeutic biomedical applications. Living cells, serving as the foundation of nanoarchitectonics, exhibit remarkable capabilities that enable the development of bioinspired and biomimetic systems, which will be explored in this review. To understand the foundation of this development, we first revisited the anatomy of cells to explore the characteristics of the building blocks of life that is relevant. Interestingly, animal cells have amazing capabilities due to the inherent functionalities in each specialized cell type. Notably, the versatility of cell membranes allows red blood cells and neutrophils' membranes to cloak inorganic nanoparticles that would naturally be eliminated by the immune system. This underscores how cell membranes facilitate interactions with the surroundings through recognition, targeting, signalling, exchange, and cargo attachment. The functionality of cell membrane-coated nanoparticles can be tailored and improved by strategically engineering the membrane, selecting from a variety of cell membranes with known distinct inherent properties. On the other hand, plant cells exhibit remarkable capabilities for synthesizing various nanoparticles. They play a role in the synthesis of metal, carbon-based, and polymer nanoparticles, used for applications such as antimicrobials or antioxidants. One of the versatile components in plant cells is found in the photosynthetic system, particularly the thylakoid, and the pigment chlorophyll. While there are challenges in consistently synthesizing these remarkable nanoparticles derived from nature, this exploration begins to unveil the endless possibilities in nanoarchitectonics research.

We have highlighted the Cell-derived Nanomaterials for Biomedical Applications through the lenses of our team who have experiences with working on cell membrane, thylakoids, and studying the impact of nanoparticles on biological phenomenon such as nanomaterialsinduced endothelial leakiness (NanoEL). In this review, we have discussed the progress and the wide potential of nanoarchitectonics in plant systems, animal cells and microorganisms. Due to our unique backgrounds, our take on this topic may be the novelty of the review.

Brain Accumulation and Toxicity Profiles of Silica Nanoparticles: The Influence of Size and Exposure Route.

Nanoparticles (NPs) can make their way to the brain and cause in situ damage, which is a concern for nanomaterial application and airborne particulate matter exposure. Our recent study indicated that respiratory exposure to silica nanoparticles (SiO2 NPs) caused unexpected cardiovascular toxic effects. However, the toxicities of SiO2 NPs in other organs have warranted further investigation. To confirm the accumulation of SiO2 NPs in the brain, we introduced SiO2 NPs with different diameters into mice via intranasal instillation (INI) and intravenous injection (IVI) in parallel. We found that SiO2 NPs may target the brain through both olfactory and systemic routes, but the size of SiO2 NPs and delivery routes both significantly affected their brain accumulation. Surprisingly, while equivalent SiO2 NPs were found in the brain regions, brain lesions were distinctly much higher in INI than in the IVI group. Mechanistically, we showed that SiO2 NPs introduced via INI induced brain apoptosis and autophagy, while the SiO2 NPs introduced via IVI only induced autophagy in the brain.

Bio-interactive nanoarchitectonics with two-dimensional materials and environments.

Like the proposal of nanotechnology by Richard Feynman, the nanoarchitectonics concept was initially proposed by Masakazu Aono. The nanoarchitectonics strategy conceptually fuses nanotechnology with other research fields including organic chemistry, supramolecular chemistry, micro/nanofabrication, materials science, and bio-related sciences, and aims to produce functional materials from nanoscale components. In this review article, bio-interactive nanoarchitectonics and two-dimensional materials and environments are discussed as a selected topic. The account gives general examples of nanoarchitectonics of two-dimensional materials for energy storage, catalysis, and biomedical applications, followed by explanations of bio-related applications with two-dimensional materials such as two-dimensional biomimetic nanosheets, fullerene nanosheets, and two-dimensional assemblies of one-dimensional fullerene nanowhiskers (FNWs). The discussion on bio-interactive nanoarchitectonics in two-dimensional environments further extends to liquid-liquid interfaces such as fluorocarbon-medium interfaces and viscous liquid interfaces as new frontiers of two-dimensional environments for bio-related applications. Controlling differentiation of stem cells at fluidic liquid interfaces is also discussed. Finally, a conclusive section briefly summarizes features of bio-interactive nanoarchitectonics with two-dimensional materials and environments and discusses possible future perspectives.

Retooling Cancer Nanotherapeutics' Entry into Tumors to Alleviate Tumoral Hypoxia.

Anti-hypoxia cancer nanomedicine (AHCN) holds exciting potential in improving oxygen-dependent therapeutic efficiencies of malignant tumors. However, most studies regarding AHCN focus on optimizing structure and function of nanomaterials with presupposed successful entry into tumor cells. From such a traditional perspective, the main barrier that AHCN needs to overcome is mainly the tumor cell membrane. However, such an oversimplified perspective would neglect that real tumors have many biological, physiological, physical, and chemical defenses preventing the current state-of-the-art AHCNs from even reaching the targeted tumor cells. Fortunately, in recent years, some studies are beginning to intentionally focus on overcoming physiological barriers to alleviate hypoxia. In this Review, the limitations behind the traditional AHCN delivery mindset are addressed and the key barriers that need to be surmounted before delivery to cancer cells and some good ways to improve cell membrane attachment, internalization, and intracellular retention are summarized. It is aimed to contribute to Review literature on this emerging topic through refreshing perspectives based on this work and what is also learnt from others. This Review would therefore assist AHCNs researchers to have a quick overview of the essential information and glean thought-provoking ideas to advance this sub-field in cancer nanomedicine.

Assembling Defined DNA Nanostructure with Nitrogen-Enriched Carbon Dots for Theranostic Cancer Applications.

DNA nanostructures as scaffolds for drug delivery, biosensing, and bioimaging are hindered by its vulnerability in physiological settings, less favorable of incorporating arbitrary guest molecules and other desirable functionalities. Noncanonical self-assembly of DNA nanostructures with small molecules in an alternative system is an attractive strategy to expand their applications in multidisciplinary fields and is rarely explored. This work reports a nitrogen-enriched carbon dots (NCDs)-mediated DNA nanostructure self-assembly strategy. Given the excellent photoluminescence and photodynamic properties of NCDs, the obtained DNA/NCDs nanocomplex holds great potential for bioimaging and anticancer therapy. NCDs can mediate DNA nanoprism (NPNCD ) self-assembly isothermally at a large temperature and pH range in a magnesium-free manner. To explore the suitability of NPNCD in potential biomedical applications, the cytotoxicity and cellular uptake efficiency of NPNCD are evaluated. NPNCD with KRAS siRNA (NPNCD K) is further conjugated for KRAS-mutated nonsmall cell lung cancer therapy. The NPNCD K shows excellent gene knockdown efficiency and anticancer effect in vitro. The current study suggests that conjugating NCDs with programmable DNA nanostructures is a powerful strategy to endow DNA nanostructures with new functionalities, and NPNCD may be a potential theranostic platform with further fine-tuned properties of CDs such as near-red fluorescence or photothermal activities.

Nanoparticles' interactions with vasculature in diseases.

The ever-growing use of inorganic nanoparticles (NPs) in biomedicine provides an exciting approach to develop novel imaging and drug delivery systems, owing to the ease with which these NPs can be functionalized to cater to various applications. In cancer therapeutics, nanomedicine generally relies on the enhanced permeability and retention (EPR) effect observed in tumour vasculature to deliver anti-cancer drugs across the endothelium. However, such a phenomenon is dependent on the tumour microenvironment and is not consistently observed in all tumour types, thereby limiting drug transport to the tumour site. On the other hand, there is a rise in utilizing inorganic NPs to intentionally induce endothelial leakiness, creating a window of opportunity to control drug delivery across the endothelium. While this active targeting approach creates a similar phenomenon compared to the EPR effect arising from tumour tissues, its drug delivery applications extend beyond cancer therapeutics and into other vascular-related diseases. In this review, we summarize the current findings of the EPR effect and assess its limitations in the context of anti-cancer drug delivery systems. While the EPR effect offers a possible route for drug passage, we further explore alternative uses of NPs to create controllable endothelial leakiness within short exposures, a phenomenon we coined as nanomaterial-induced endothelial leakiness (NanoEL). Furthermore, we discuss the main mechanistic features of the NanoEL effect that make it unique from conventionally established endothelial leakiness in homeostatic and pathologic conditions, as well as examine its potential applicability in vascular-related diseases, particularly cancer. Therefore, this new paradigm changes the way inorganic NPs are currently being used for biomedical applications.

Nanoarchitectonics beyond Self-Assembly: Challenges to Create Bio-Like Hierarchic Organization.

Incorporation of non-equilibrium actions in the sequence of self-assembly processes would be an effective means to establish bio-like high functionality hierarchical assemblies. As a novel methodology beyond self-assembly, nanoarchitectonics, which has as its aim the fabrication of functional materials systems from nanoscopic units through the methodological fusion of nanotechnology with other scientific disciplines including organic synthesis, supramolecular chemistry, microfabrication, and bio-process, has been applied to this strategy. The application of non-equilibrium factors to conventional self-assembly processes is discussed on the basis of examples of directed assembly, Langmuir-Blodgett assembly, and layer-by-layer assembly. In particular, examples of the fabrication of hierarchical functional structures using bio-active components such as proteins or by the combination of bio-components and two-dimensional nanomaterials, are described. Methodologies described in this review article highlight possible approaches using the nanoarchitectonics concept beyond self-assembly for creation of bio-like higher functionalities and hierarchical structural organization.

Toxicity of Two-Dimensional Layered Materials and Their Heterostructures.

Two-dimensional layered materials (2D LMs) are taking the scientific world by storm. Graphene epitomizes 2D LMs with many interesting properties and corresponding applications. Following the footsteps of graphene, many other types of 2D LMs such as transition metal dichalcogenides, black phosphorus, and graphitic-phase C3N4 nanosheets are emerging to be equally interesting as graphene and its derivatives. Some of these applications such as nanomedicine do have a high probability of human exposure. This review focuses on the biological and toxicity effects of 2D LMs and their associated mechanisms linking their chemistries to their biological end points. This review aims to help researchers to predict and mitigate any toxic effects. With understanding, redesign of newer and safer 2D LMs becomes possible.

Nano-TiO2 Drives Epithelial-Mesenchymal Transition in Intestinal Epithelial Cancer Cells.

The majority of cancer mortality is associated with cancer metastasis. Epithelial-to-mesenchymal transition (EMT) is a process by which cells attain migratory and invasive properties, eventually leading to cancer metastasis. Here, it is shown that titanium dioxide nanoparticles (nano-TiO2 ), a common food additive, can induce the EMT process in colorectal cancer cells. Nano-TiO2 exposure is observed to activate transforming growth factor-ß (TGF-ß)/mitogen-activated protein kinase (MAPK) and wingless (Wnt) pathways, and drive the EMT process. Similarly, silica nanoparticles (nano-SiO2 ) and hydroxyapatite nanoparticles (nano-HA), as food-based additives, can be ingested and accumulated in the stomach, and are found to be able to induce the EMT progression. The implication of this work can be profound for colorectal cancer patients where these food additives may unknowingly and unnecessarily hasten the progression of their cancers.

Titanium Dioxide Nanoparticles Enhance Leakiness and Drug Permeability in Primary Human Hepatic Sinusoidal Endothelial Cells.

Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to the progression of chronic liver diseases, including the loss of endothelial permeability. Therefore, modulating LSECs offers a possible way to restore sinusoidal permeability and thereby improve hepatic recovery. Herein, we showed that titanium dioxide nanoparticles (TiO2 NPs) could induce transient leakiness in primary human hepatic sinusoidal endothelial cells (HHSECs). Interestingly, HHSECs exposed to these NPs exhibited reduced protein kinase B (Akt) phosphorylation, an important protein kinase which regulates cell attachment. Using a 3D co-culture system, we demonstrated that TiO2 NPs diminished the attachment of HHSECs onto normal human hepatic cell LO2. To further illustrate the significance of leakiness in liver sinusoids, we showed that NP-induced leakiness promoted Sunitinib transport across the HHSEC layer, resulting in increased drug uptake and efficacy. Hence, TiO2 NPs have the potential to modulate endothelial permeability within the specialized sinusoidal endothelium, especially during events of fibrosis and occlusion. This study highlighted the possible use of inorganic NPs as a novel strategy to promote drug delivery targeting the diseased liver.

Clinically Relevant Detection of Streptococcus pneumoniae with DNA-Antibody Nanostructures.

Streptococcus pneumoniae (SP) is a pathogenic bacterium and a major cause of community-acquired pneumonia that could be fatal if left untreated. Therefore, rapid and sensitive detection of SP is crucial to enable targeted treatment during SP infections. In this study, DNA tetrahedron (DNA TH) with a hollow structure is anchored on gold electrodes to construct an electrochemical immunosensor for rapid detection of pneumococcal surface protein A (PspA) peptide and SP lysate from synthetic and actual human samples. This DNA nanostructure-based immunosensor displays excellent electrochemical activity toward PspA with a sensitive linear region from 0 to 8 ng/mL of PspA peptide and a low limit of detection (LOD) of 0.218 ng/mL. In addition, this DNA-TH-based immunosensor exhibits good sensing performance toward SP lysate in a clinically relevant linear range from 5 to 100 CFU/mL with a LOD of 0.093 CFU/mL. Along with these attractive features, this electrochemical immunosensor is able to specifically recognize and detect the PspA peptide mixed with other physiologically relevant components like bovine serum albumin (BSA) and lipopolysaccharide. In addition, our sensor could detect SP lysate even when dispersed in BSA or Escherichia coli lysate. Lastly, uncultured samples from the nasal cavity, mouth, and axilla of a human subject could be successfully determined by this well-designed electrochemical immunosensor.

Emerging 0D Transition-Metal Dichalcogenides for Sensors, Biomedicine, and Clean Energy.

Following research on two-dimensional (2D) transition metal dichalcogenides (TMDs), zero-dimensional (0D) TMDs nanostructures have also garnered some attention due to their unique properties; exploitable for new applications. The 0D TMDs nanostructures stand distinct from their larger 2D TMDs cousins in terms of their general structure and properties. 0D TMDs possess higher bandgaps, ultra-small sizes, high surface-to-volume ratios with more active edge sites per unit mass. So far, reported 0D TMDs can be mainly classified as quantum dots, nanodots, nanoparticles, and small nanoflakes. All exhibited diverse applications in various fields due to their unique and excellent properties. Of significance, through exploiting inherent characteristics of 0D TMDs materials, enhanced catalytic, biomedical, and photoluminescence applications can be realized through this exciting sub-class of TMDs. Herein, we comprehensively review the properties and synthesis methods of 0D TMDs nanostructures and focus on their potential applications in sensor, biomedicine, and energy fields. This article aims to educate potential adopters of these excitingly new nanomaterials as well as to inspire and promote the development of more impactful applications. Especially in this rapidly evolving field, this review may be a good resource of critical insights and in-depth comparisons between the 0D and 2D TMDs.

Cellular processing and destinies of artificial DNA nanostructures.

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.

DNA Nanostructures Carrying Stoichiometrically Definable Antibodies.

Targeted drug delivery is one of the key challenges in cancer nanomedicine. Stoichiometric and spatial control over the antibodies placement on the nanomedicine vehicle holds a pivotal role to overcome this key challenge. Here, a DNA tetrahedral is designed with available conjugation sites on its vertices, allowing to bind one, two, or three cetuximab antibodies per DNA nanostructure. This stoichiometrically definable cetuximab conjugated DNA nanostructure shows enhanced targeting on the breast cancer cells, which results with higher overall killing efficacy of the cancer cells.

Sugar-Grafted Cyclodextrin Nanocarrier as a "Trojan Horse" for Potentiating Antibiotic Activity.

PURPOSE: The use of "Trojan Horse" nanocarriers for antibiotics to enhance the activity of antibiotics against susceptible and resistant bacteria is investigated. METHODS: Antibiotic carriers (CD-MAN and CD-GLU) are prepared from ß-cyclodextrin grafted with sugar molecules (D-mannose and D-glucose, respectively) via azide-alkyne click reaction. The sugar molecules serve as a chemoattractant enticing the bacteria to take in higher amounts of the antibiotic, resulting in rapid killing of the bacteria. RESULTS: Three types of hydrophobic antibiotics, erythromycin, rifampicin and ciprofloxacin, are used as model drugs and loaded into the carriers. The minimum inhibitory concentration of the antibiotics in the CD-MAN-antibiotic and CD-GLU-antibiotic complexes for Gram-negative Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii strains, and a number of Gram-positive Staphylococcus aureus strains, including the methicillin-resistant strains (MRSA), are reduced by a factor ranging from 3 to >100. The CD-MAN-antibiotic complex is also able to prolong the stability of the loaded antibiotic and inhibit development of intrinsic antibiotic resistance in the bacteria. CONCLUSIONS: These non-cytotoxic sugar-modfied nanocarriers can potentiate the activity of existing antibiotics, especially against multidrug-resistant bacteria, which is highly advantageous in view of the paucity of new antibiotics in the pipeline.

Understanding and exploiting nanoparticles' intimacy with the blood vessel and blood.

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.

Storage of gold nanoclusters in muscle leads to their biphasic in vivo clearance.

Ultrasmall gold nanoclusters (Au NCs) show great potential in biomedical applications. Long-term biodistribution, retention, toxicity, and pharmacokinetics profiles are pre-requisites in their potential clinical applications. Here, the biodistribution, clearance, and toxicity of one widely used Au NC species-glutathione-protected Au NCs or GSH-Au NCs-are systematically investigated over a relatively long period of 90 days in mice. Most of the Au NCs are cleared at 30 days post injection (p.i.) with a major accumulation in liver and kidney. However, it is surprising that an abnormal increase of the Au amount in the heart, liver, spleen, lung, and testis is observed at 60 and 90 days p.i., indicating that the injected Au NCs form a V-shaped time-dependent distribution profile in various organs. Further investigations reveal that Au NCs are steadily accumulating in the muscle in the first 30 days p.i., and the as-stored Au NCs gradually release into the blood in 30-90 days p.i., which induces a re-distribution and re-accumulation of Au NCs in all blood-rich organs. Further hematology and biochemistry studies show that the re-accumulation of Au NCs still causes some liver toxicity at 30 days p.i. The muscle storage and subsequent release may give rise to the potential accumulation and toxicity risk of functional nanomaterials over long periods of time.

Toxicity profiling of water contextual zinc oxide, silver, and titanium dioxide nanoparticles in human oral and gastrointestinal cell systems.

Engineered nanoparticles (ENPs) are increasingly detected in water supply due to environmental release of ENPs as the by-products contained within the effluent of domestic and industrial run-off. The partial recycling of water laden with ENPs, albeit at ultra-low concentrations, may pose an uncharacterized threat to human health. In this study, we investigated the toxicity of three prevalent ENPs: zinc oxide, silver, and titanium dioxide over a wide range of concentrations that encompasses drinking water-relevant concentrations, to cellular systems representing oral and gastrointestinal tissues. Based on published in silico-predicted water-relevant ENPs concentration range from 100 pg/L to 100 µg/L, we detected no cytotoxicity to all the cellular systems. Significant cytotoxicity due to the NPs set in around 100 mg/L with decreasing extent of toxicity from zinc oxide to silver to titanium dioxide NPs. We also found that noncytotoxic zinc oxide NPs level of 10 mg/L could elevate the intracellular oxidative stress. The threshold concentrations of NPs that induced cytotoxic effect are at least two to five orders of magnitude higher than the permissible concentrations of the respective metals and metal oxides in drinking water. Based on these findings, the current estimated levels of NPs in potable water pose little cytotoxic threat to the human oral and gastrointestinal systems within our experimental boundaries.

Nanoparticles strengthen intracellular tension and retard cellular migration.

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.

Identification of a highly luminescent Au22(SG)18 nanocluster.

The luminescence property of thiolated gold nanoclusters (Au NCs) is thought to involve the Au(I)-thiolate motifs on the NC surface; however, this hypothesis remains largely unexplored because of the lack of precise molecular composition and structural information of highly luminescent Au NCs. Here we report a new red-emitting thiolated Au NC, which has a precise molecular formula of Au22(SR)18 and exhibits intense luminescence. Interestingly, this new Au22(SR)18 species shows distinctively different absorption and emission features from the previously reported Au22(SR)16, Au22(SR)17, and Au25(SR)18. In stark contrast, Au22(SR)18 luminesces intensely at ∼665 nm with a high quantum yield of ∼8%, while the other three Au NCs show very weak luminescence. Our results indicate that the luminescence of Au22(SR)18 originates from the long Au(I)-thiolate motifs on the NC surface via the aggregation-induced emission pathway. Structure prediction by density functional theory suggests that Au22(SR)18 has two RS-[Au-SR]3 and two RS-[Au-SR]4 motifs, interlocked and capping on a prolate Au8 core. This predicted structure is further verified experimentally by Au L3-edge X-ray absorption fine structure analysis.