Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles.

Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.

Bridging Smart Nanosystems with Clinically Relevant Models and Advanced Imaging for Precision Drug Delivery.

Intracellular delivery of nano-drug-carriers (NDC) to specific cells, diseased regions, or solid tumors has entered the era of precision medicine that requires systematic knowledge of nano-biological interactions from multidisciplinary perspectives. To this end, this review first provides an overview of membrane-disruption methods such as electroporation, sonoporation, photoporation, microfluidic delivery, and microinjection with the merits of high-throughput and enhanced efficiency for in vitro NDC delivery. The impact of NDC characteristics including particle size, shape, charge, hydrophobicity, and elasticity on cellular uptake are elaborated and several types of NDC systems aiming for hierarchical targeting and delivery in vivo are reviewed. Emerging in vitro or ex vivo human/animal-derived pathophysiological models are further explored and highly recommended for use in NDC studies since they might mimic in vivo delivery features and fill the translational gaps from animals to humans. The exploration of modern microscopy techniques for precise nanoparticle (NP) tracking at the cellular, organ, and organismal levels informs the tailored development of NDCs for in vivo application and clinical translation. Overall, the review integrates the latest insights into smart nanosystem engineering, physiological models, imaging-based validation tools, all directed towards enhancing the precise and efficient intracellular delivery of NDCs.

Nano-Bio Interactions: Biofilm-Targeted Antibacterial Nanomaterials.

Biofilm is a spatially organized community formed by the accumulation of both microorganisms and their secretions, leading to persistent and chronic infections because of high resistance toward conventional antibiotics. In view of the tunable physicochemical properties and the related unique biological behavior (e.g., size-, shape-, and surface charge-dependent penetration, protein corona endowed targeting, catalytic- and electronic-related oxidative stress, optical- and magnetic-associated hyperthermia, etc.), nanomaterials-based therapeutics are widely used for the treatment of biofilm-associated infections. In this review, the biological characteristics of biofilm are introduced. And the nanomaterials-based antibacterial strategies are further discussed via biofilm targeting, including preventing biofilm formation, enhancing biofilm penetration, disrupting the mature biofilm, and acting as drug delivery systems. In which, the interactions between biofilm and nanomaterials include mechanical disruption, electron transfer, enzymatic degradation, oxidative stress, and hyperthermia. Additionally, the current advances of nanomaterials for antibacterial nanomaterials by biofilm targeting are summarized. This review aims to present a complete vision of antibacterial nanomaterials-biofilm (nano-bio) interactions, paving the way for the future development and clinical translation of effective antibacterial nanomedicines.

Citrus essential oils - Based nano-emulsions: Functional properties and potential applications.

Citrus essential oils are natural products with various bioactive properties (e.g., antimicrobial, antioxidant, and antimutagenic activities), that are generally recognized as safe (GRAS) by Food and Drug Administration (FDA) to be used as flavorings and food additives. Nonetheless, due to their high volatility, low solubility in water, low thermal stability, susceptibility to oxidation, and strong flavor, their applications in the food industry are limited. Nanotechnology allows the incorporation of citrus essential oils into nano-emulsion systems, thus protecting them from the deterioration caused by external factors and maintaining or even improving their functional properties. This study aims to summarize the antioxidant, antimicrobial, and antimutagenic effects of the nano-emulsions based on essential oils from citrus peels with emphasis on their mechanisms of action and potential applications in, e.g., foods, pharmaceuticals, and cosmetics.

Investigation of TiO2 nanoparticle interactions in the fibroblast NIH-3T3 cells via liquid-mode atomic force microscope.

Long before we recognized how significant they were, nanoparticles were already all around in the environment. Since then, an extensive number of synthetic nanoparticles have been engineered to improve our quality of life through rigorous scientific research on their uses in practically every industry, including semiconductor devices, food, medicine, and agriculture. The extensive usage of nanoparticles in commodities that come into proximity with human skin and internal organs through medicine has raised significant concerns over the years. TiO2 nanoparticles (NPs) are widely employed in a wide range of industries, such as cosmetics and food packaging. The interaction and internalization of TiO2 NPs in living cells have been studied by the scientific community for many years. In the present study, we investigated the cell viability, nanomechanical characteristics, and fluorescence response of NIH-3T3 cells treated with sterile DMEM TiO2 nanoparticle solution using a liquid-mode atomic force microscope and a fluorescence microscope. Two different sorts of response systems have been observed in the cells depending on the size of the NPs. TiO2 nanoparticles smaller than 100 nm support its initial stages cell viability, and cells internalize and metabolize NPs. In contrast, bigger TiO2 NPs (> 100 nm) are not completely metabolized and cannot impair cell survival. Furthermore, bigger NPs above 100 nm could not be digested by the cells, therefore hindering cell development, whereas below 100 nm TiO2 stimulated uncontrolled cell growth akin to cancerous type cells. The cytoskeleton softens as a result of particle internalization, as seen by the nanomechanical characteristics of the nanoparticle treated cells. According to our investigations, TiO2 smaller than 100 nm facilitates unintended cancer cell proliferation, whereas larger NPs ultimately suppress cell growth. Before being incorporated into commercial products, similar effects or repercussions that could result from employing different NPs should be carefully examined.

Antibacterial Nanomaterials: Mechanisms, Impacts on Antimicrobial Resistance and Design Principles.

Antimicrobial resistance (AMR) is one of the biggest threats to the environment and health. AMR rapidly invalidates conventional antibiotics, and antimicrobial nanomaterials have been increasingly explored as alternatives. Interestingly, several antimicrobial nanomaterials show AMR-independent antimicrobial effects without detectable new resistance and have therefore been suggested to prevent AMR evolution. In contrast, some are found to trigger the evolution of AMR. Given these seemingly conflicting findings, a timely discussion of the two faces of antimicrobial nanomaterials is urgently needed. This review systematically compares the killing mechanisms and structure-activity relationships of antibiotics and antimicrobial nanomaterials. We then focus on nano-microbe interactions to elucidate the impacts of molecular initiating events on AMR evolution. Finally, we provide an outlook on future antimicrobial nanomaterials and propose design principles for the prevention of AMR evolution.

Overview of nanomaterials and cellular interactions

In the last three decades, there has been wide progress in nanomaterials development, and several studies are being performed to show its biological effects and cellular interaction for biomedical applications. Due to the exponential increase in nanomaterial diversity, production, and possibilities of applications in different areas, there is an important concern about its toxicity for humans, animals, and ecosystems. There is a great effort to minimize experimental assays in animals, and this is a commendable initiative. Several alternatives in vitro assays are available; however, several new protocols have been introduced to elucidate the mechanisms of cell-nanomaterial interaction. Wide and fast progress in nanotechnology has been observed. Nonetheless, the nanomaterial interaction with cells or biological systems is still not totally described. In this aspect, this paper is a brief overview of nanomaterials and cellular interactions (nano-bio interaction).

Elasticity regulates nanomaterial transport as delivery vehicles: Design, characterization, mechanisms and state of the art.

Nanobiotechnology and nanomedicine are rapidly growing fields, in which nanomaterials (NMs) can lead to enhanced therapeutic efficacy by achieving efficient transport and drug delivery in vivo. The physicochemical properties of NMs have a great impact on their interactions with biological environments and hence determine their biological fates and drug delivery efficiency. Despite rapid advances in understanding the significance of NM properties, such as shape, size, and surface charge, there is a pressing need to engineer and discover how elasticity shapes NM transport. Recently, advances in material synthesis and characterization have promoted investigations into the macroscopic roles and microscopic mechanisms of elasticity to modulate nano-bio interactions. This review will highlight (1) the basic definitions of elasticity and strategies for modulating NM elasticity; (2) advanced techniques for evaluating the effects of elasticity on nano-bio interactions; (3) the macroscopic role of elasticity in the biological fates of NMs, including blood circulation, biodistribution, biological hydrogel penetration, cellular uptake, and intracellular trafficking; and (4) the potential microscopic mechanisms probed by these advanced characterization techniques. Additionally, challenges and future prospects are included. The advanced research discussed in this review will provide guidance to extensively explore the effects and detailed mechanism of elasticity in nano-bio interactions for enhanced drug delivery and developed nanomedicines.

Gold Nano-Bio-Interaction to Modulate Mechanobiological Responses for Cancer Therapy Applications.

In the present study, we investigate the mechanobiological responses of human lung cancer that may occur through their interactions with two different types of gold nanoparticles: nanostars and nanospheres. Hyperspectral images of nanoparticle-treated cells revealed different spatial distributions of nanoparticles in cells depending on their morphology, with nanospheres being more uniformly distributed in cells than nanostars. Gold nanospheres were also found to be more effective in mechanobiological modulations. They significantly suppressed the migratory ability of cells under different incubation times while lowering the bulk stiffness and adhesion of cells. This in vitro study suggests the potential applications of gold nanoparticles to manage cell migration. Nano-bio-interactions appeared to impact the cytoskeletal organization of cells and consequently alter the mechanical properties of cells, which could influence the cellular functions of cells. According to the results and migratory index model, it is thought that nanoparticle-treated cells experience mechanical changes in their body, which largely reduces their migratory potentials. These findings provide a better understanding of nano-bio-interaction in terms of cell mechanics and highlight the importance of mechanobiological responses in designing gold nanoparticles for cancer therapy.

Systematic and mechanistic analysis of AuNP-induced nanotoxicity for risk assessment of nanomedicine.

For decades, nanoparticles (NPs) have been widely implemented in various biomedical fields due to their unique optical, thermal, and tunable properties. Particularly, gold nanoparticles (AuNPs) have opened new frontiers in sensing, targeted drug delivery, imaging, and photodynamic therapy, showing promising results for the treatment of various intractable diseases that affect quality of life and longevity. Despite the tremendous achievements of AuNPs-based approaches in biomedical applications, few AuNP-based nanomedicines have been evaluated in clinical trials, which is likely due to a shortage of understanding of the biological and pathological effects of AuNPs. The biological fate of AuNPs is tightly related to a variety of physicochemical parameters including size, shape, chemical structure of ligands, charge, and protein corona, and therefore evaluating the effects of these parameters on specific biological interactions is a major ongoing challenge. Therefore, this review focuses on ongoing nanotoxicology studies that aim to characterize the effect of various AuNP characteristics on AuNP-induced toxicity. Specifically, we focus on understanding how each parameter alters the specific biological interactions of AuNPs via mechanistic analysis of nano-bio interactions. We also discuss different cellular functions affected by AuNP treatment (e.g., cell motility, ROS generation, interaction with DNA, and immune response) to understand their potential human health risks. The information discussed herein could contribute to the safe usage of nanomedicine by providing a basis for appropriate risk assessment and for the development of nano-QSAR models.

Nano-bio interfacial interactions determined the contact toxicity of nTiO2 to nematodes in various soils.

The biological effect of soilborne nanoparticles (NPs) is a manifestation of soil-NMs-bio interactions. Soil factors are known to restructure NPs surfaces and thus influence the nanotoxicity. However, the mechanisms by which environmental factors affecting nano-bio interactions to aggravate or alleviate nanotoxicities are poorly understood. Herein, we compared the toxicity of TiO2 NPs (nTiO2) in five soils using the model nematode (Caenorhabditis elegans), and investigated the variation of nano-bio interactions under different conditions. A correlation analysis showed that pH and dissolved organic matter (DOM) were dominant regulators of nTiO2 toxicity. At the nano-bio interface, low pH (5.0) led to nTiO2 adhesion to micron-sized furrows and aggravated dermal wrinkling, while humid acid (HA) alleviated these impacts. Mechanically, low pH increased nTiO2 adhesion through enhanced electrostatic attraction and subsequent stimulation of mucin and collagen synthesis, resulting in a positive feed cycle of pH-dependent contact nanotoxicity. HA not only prevented nTiO2 adhesion onto the epidermis due to its negative charge, but also relieved the overstimulation of stress response pathways, thereby alleviating nanotoxicity. These findings broaden our knowledge of how NPs induce contact toxicity in soil invertebrates through specific biointerfacial interactions, and highlight the important role of DOM in alleviating the combined hazards of NPs and soil acidification.

Engineered nanoparticles enable deep proteomics studies at scale by leveraging tunable nano-bio interactions.

SignificanceDeep profiling of the plasma proteome at scale has been a challenge for traditional approaches. We achieve superior performance across the dimensions of precision, depth, and throughput using a panel of surface-functionalized superparamagnetic nanoparticles in comparison to conventional workflows for deep proteomics interrogation. Our automated workflow leverages competitive nanoparticle-protein binding equilibria that quantitatively compress the large dynamic range of proteomes to an accessible scale. Using machine learning, we dissect the contribution of individual physicochemical properties of nanoparticles to the composition of protein coronas. Our results suggest that nanoparticle functionalization can be tailored to protein sets. This work demonstrates the feasibility of deep, precise, unbiased plasma proteomics at a scale compatible with large-scale genomics enabling multiomic studies.

Cancer-Nano-Interaction: From Cellular Uptake to Mechanobiological Responses.

With the advancement of nanotechnology, the nano-bio-interaction field has emerged. It is essential to enhance our understanding of nano-bio-interaction in different aspects to design nanomedicines and improve their efficacy for therapeutic and diagnostic applications. Many researchers have extensively studied the toxicological responses of cancer cells to nano-bio-interaction, while their mechanobiological responses have been less investigated. The mechanobiological properties of cells such as elasticity and adhesion play vital roles in cellular functions and cancer progression. Many studies have noticed the impacts of cellular uptake on the structural organization of cells and, in return, the mechanobiology of human cells. Mechanobiological changes induced by the interactions of nanomaterials and cells could alter cellular functions and influence cancer progression. Hence, in addition to biological responses, the possible mechanobiological responses of treated cells should be monitored as a standard methodology to evaluate the efficiency of nanomedicines. Studying the cancer-nano-interaction in the context of cell mechanics takes our knowledge one step closer to designing safe and intelligent nanomedicines. In this review, we briefly discuss how the characteristic properties of nanoparticles influence cellular uptake. Then, we provide insight into the mechanobiological responses that may occur during the nano-bio-interactions, and finally, the important measurement techniques for the mechanobiological characterizations of cells are summarized and compared. Understanding the unknown mechanobiological responses to nano-bio-interaction will help with developing the application of nanoparticles to modulate cell mechanics for controlling cancer progression.

Mild adsorption of carbon nitride (C3N3) nanosheet on a cellular membrane reveals its suitable biocompatibility.

Recently, the novel hole-containing carbon nitride C3N3 nanomaterial was successfully synthesized, featuring outstanding and unique mechanical and electrical properties. However, to fully exploit this nanomaterial in biomedical applications, information regarding its biocompatibility is necessary. Herein, by using all-atom molecular dynamics simulations, we evaluate the interactions between a C3N3 nanosheet and a critical cellular component, that is, a lipid membrane bilayer. Our results indicate that the C3N3 nanosheet is able to interact with the lipid bilayer surface without affecting the membrane's structural integrity. Moreover, our results showed that the C3N3 nanosheet is adsorbed on the surface of the lipid bilayer without inflicting any structural damage to the membrane, regardless of the conditions of the system (that is, with and without restrains in the C3N3 nanosheet). Also, we found that both energy contributions, namely vdW and Coulomb energies, conjointly mediated the C3N3 adsorption process. In comparison and as expected, pristine graphene significantly disturbed the membrane structure. Perpendicularly-oriented-sheet simulations described the significance of the surface charges of the C3N3 nanosheet in prohibiting its insertion into the membrane. Detailed analysis indicated that the electrostatic attraction between the pores in the C3N3 structure and the lipid head amino groups stabilized the interaction restricting the insertion of the C3N3 structure deeper into the membrane. Our results suggested the importance of the negatively charged C3N3 pores when interacting with lipid membranes. Our findings shed light on the potential compatibility of C3N3 with biomembranes and its underlying molecular mechanism, which might provide a useful foundation for the future exploration of this 2D nanomaterial in biomedical applications.

Organ-on-a-chip platforms for accelerating the evaluation of nanomedicine.

Nanomedicine involves the use of engineered nanoscale materials in an extensive range of diagnostic and therapeutic applications and can be applied to the treatment of many diseases. Despite the rapid progress and tremendous potential of nanomedicine in the past decades, the clinical translational process is still quite slow, owing to the difficulty in understanding, evaluating, and predicting nanomaterial behaviors within the complex environment of human beings. Microfluidics-based organ-on-a-chip (Organ Chip) techniques offer a promising way to resolve these challenges. Sophisticatedly designed Organ Chip enable in vitro simulation of the in vivo microenvironments, thus providing robust platforms for evaluating nanomedicine. Herein, we review recent developments and achievements in Organ Chip models for nanomedicine evaluations, categorized into seven broad sections based on the target organ systems: respiratory, digestive, lymphatic, excretory, nervous, and vascular, as well as coverage on applications relating to cancer. We conclude by providing our perspectives on the challenges and potential future directions for applications of Organ Chip in nanomedicine.

Characterization of the nano-bio interaction between metallic oxide nanomaterials and freshwater microalgae using flow cytometry.

Since nanomaterials (NMs) are particulate contaminants, their first contact with organisms is a physical encounter ruled by physic-chemical processes that can determinate the potential NMs accumulation, toxicity, and trophic transfer. Freshwater ecosystems often become a final depository for NMs, so they can get in contact with the biota, especially primary organisms as algae. There are almost none comparative studies of this interaction using various NMs in the same conditions. This work identifies, analyzes, and compares the algae-NMs interaction by flow cytometry after a short-term contact test in which three freshwater algae (Raphidocelis subcapitata, Desmodesmus subspicatus, and Chlorella vulgaris) interact individually with a set of twelve metallic oxide NMs. Dose-response profiles and differences in the algae-NMs interaction were found according to each algae species (C. vulgaris had the most affinity, starting the interaction from 0.5 mg/L and D. subspicatus had the less affinity starting at 5 mg/L). Flow cytometry results were confirmed by optical microscopy. Some NMs characteristics were identified as key-factors that govern the algae-NMs interaction: NMs composition (no interaction for SiO2 NMs), surface electric charge (higher interaction for the positively charged NMs and lower interaction for the negatively charged ones) and crystalline form (for TiO2 NMs). The presented method can be useful for a rapid determination of the interaction between free cells organisms as microalgae and (nano)particulate substances.

Proteomic analysis of intracellular protein corona of nanoparticles elucidates nano-trafficking network and nano-bio interactions.

The merits of nanomedicines are significantly impacted by the surrounding biological environment. Similar to the protein corona generated on the surface of nanoparticles in the circulation system, the intracellular protein corona (IPC) might be formed on nanoparticles when transported inside the cells. However, little is known currently about the formation of IPC and its possible biological influence. Methods: Caco-2 cells, a classical epithelial cell line, were cultured in Transwell plates to form a monolayer. Gold nanoparticles (AuNPs) were prepared as the model nanomedicine due to their excellent stability. Here we focused on identifying IPC formed on the surface of AuNPs during cell transport. The nanoparticles in the basolateral side of the Caco-2 monolayer were collected and analyzed by multiple techniques to verify IPC formation. High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was utilized to analyze the composition of IPC proteins. In particular, we established a dual-filtration strategy to exclude various interference in IPC identification. Based on the subcellular localization of specific IPC proteins, we elicited the nano-trafficking network of AuNPs. The transport pathways of AuNPs identified by proteomic analysis were also verified by various conventional technologies. Finally, we explored the influence of IPC on the uptake and stress response of endothelium. Results: The existence of IPC was demonstrated on the surface of AuNPs, in which 227 proteins were identified. Among them, 40 proteins were finally ascertained as the specific IPC proteins. The subcellular location analysis indicated that these "specific" IPC proteins could back-track the transport pathways of nanoparticles in the epithelial cell monolayer. According to the subcellular distribution of IPC proteins and co-localization, we discovered a new pathway of nanoparticles from endosomes to secretory vesicles which was dominant during the transcytosis. After employing conventional imageology and pharmacology strategies to verify the result of proteomic analysis, we mapped a comprehensive intracellular transport network. Our study also revealed the merits of IPC analysis, which could readily elucidate the molecular mechanisms of transcytosis. Besides, the IPC proteins increased the uptake and stress response of endothelium, which was likely mediated by extracellular matrix and mitochondrion-related IPC proteins. Conclusion: The comprehensive proteomic analysis of IPC enabled tracing of transport pathways in epithelial cells as well as revealing the biological impact of nanoparticles on endothelium.

Graphene oxide-based nanomaterial interaction with human breast cancer cells.

Graphene and graphene-based nanomaterials have great potential for various biomedical applications due to their unique physicochemical properties. However, how graphene-based nanomaterials interact with biological systems has not been thoroughly studied. This study shows that 24, 48, and 72 hr exposure of 2.4 µg/cm2 of graphene oxide (GOX) and GOX modified with DAB-AM-16 and PAMAM dendrimers (GOXD and GOXP, respectively) did not exhibit toxicity to MCF-7 cells. However, higher graphene concentrations, such as 24 and 48 µg/cm2 , induced low cytotoxic effects. The GOX, GOXD, and GOXP particles have a strong affinity with the cellular membrane. Cells that internalized the nanomaterials presented morphological alterations and modifications in the organization of microfilaments and microtubules compared with control cells. Then, cells were treated with 24 µg/cm2 of GOX, GOXD or GOXP for 24 hr and recovered for an additional period of 24 hr in normal medium. Nanoparticles remained in the cytoplasm of some cells, apparently with no effect on cellular morphology, being consistent with the data found in the cell proliferation experiment, which showed that the cells remained alive up to 72 hr.

Phytotoxic effect of silver nanoparticles on seed germination and growth of terrestrial plants.

Silver nanoparticles (AgNP) exhibit size and concentration dependent toxicity to terrestrial plants, especially crops. AgNP exposure could decrease seed germination, inhibit seedling growth, affect mass and length of roots and shoots. The phytotoxic pathway has been partly understood. Silver (as element, ion or AgNP) accumulates in roots/leaves and triggers the defense mechanism at cellular and tissue levels, which alters metabolism, antioxidant activities and related proteomic expression. Botanical changes (either increase or decrease) in response to AgNP exposure include reactive oxygen species generation, superoxide dismutase activities, H2O2 level, total chlorophyll, proline, carotenoid, ascorbate and glutathione contents, etc. Such processes lead to abnormal morphological changes, suppression of photosynthesis and/or transpiration, and other symptoms. Although neutral or beneficial effects are also reported depending on plant species, adverse effects dominate in majority of the studies. More in depth research is needed to confidently draw any conclusions and to guide legislation and regulations.