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The two mucus layers of the intestine and their function. a) Summary schematic illustrates the inner mucus layer and outer mucus layer on the surface of intestinal epithelium. b) The mucus mesh screens different sizes of nanomaterials penetrating the mucus layer.
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Engineered nanomaterials (ENMs) are used in food additives, food packages, and therapeutic purposes owing to their useful properties, Therefore, human beings are orally exposed to exogenous nanomaterials frequently, which means the intestine is one of the primary targets of nanomaterials. Consequently, it is of great importance to understand the in...
Citations
... By altering tight junctions and microvilli, which are intimately linked to the preservation of the integrity of the epithelial barrier, nanomaterials might jeopardize the structure of the nano-intestinal epithelial cell barrier. 24 In summary, the physicochemical properties of the GI tract have a major impact on the effectiveness and targeting of drugs in the GI tract and are important elements to take into consideration when designing and selecting the drug administration route. ...
Digestive system diseases, such as gastritis, gastric ulcers, chronic liver disease, inflammatory bowel disease (IBD), and colorectal cancer, represent a major group of diseases that have high morbidity and death rates worldwide. Their incidence continues to rise owing to factors such as dietary structure changes, accelerated lifestyles, increased environmental pollution, and population aging. Despite the rapid development of the medical technology, the treatment of digestive diseases still faces many challenges, such as addressing drug-resistant Helicobacter pylori infections, treating IBD, and improving the efficacy of advanced gastrointestinal tumor therapies. Fortunately, the emergence of drug-releasing materials has provided new insights that can be used in the treatment of digestive disorders. Drug-releasing materials are a category of specially designed carriers or systems capable of carrying drugs and controlling their release at specific time intervals on demand to achieve the desired therapeutic effect. This article reviews recent research progress of drug-releasing materials used to diagnose and treat digestive disorders. First, the limitations of traditional oral drug delivery methods, such as low bioavailability and nonspecific distribution, are discussed. Second, different types of drug-releasing materials, such as liposomes, dendritic polymers, micelles, nanogels, inorganic nanoparticles, and extracellular vesicles, along with their advantages in terms of improved drug stability, biocompatibility, targeting, and controlled release, are outlined. In addition, the application strategies and preclinical findings of various drug release materials for different digestive disorders are discussed in detail. This Review could help researchers explore more advanced nanomaterials for personalized treatment of drug delivery for digestive disorders.
... With rapid advances in nanotechnology, many oral drug delivery systems (ODDS) have been developed to enhance drug bioavailability and improve therapeutic efficiency [1,[4][5][6]. Nevertheless, traditional oral delivery systems have limited effects because they must passively overcome multiple physicochemical and biological barriers in the GI tract, including the highly acidic environment in the stomach; remain stable among the dynamic intestinal microbiota and degradative enzymes; penetrate the viscous mucus barrier and epithelial barrier; and evade efflux pumps to achieve therapeutic bioavailability [7][8][9][10][11]. Therefore, strategies that can transform these passive delivery systems into active and mobile delivery platforms are expected to open up new opportunities to overcome GI tract barriers, thereby improving oral drug absorption and the therapeutic index. ...
Introduction:
Oral delivery is the most commonly used route of drug administration owing to good patient compliance. However, the gastrointestinal (GI) tract contains multiple physiological barriers that limit the absorption efficiency of conventional passive delivery systems resulting in a low drug concentration reaching the diseased sites. Micro/nanorobots can convert energy to self-propulsive force, providing a novel platform to actively overcome GI tract barriers for noninvasive drug delivery and treatment.
Areas covered:
In this review, we first describe the microenvironments and barriers in the different compartments of the GI tract. Afterward, the applications of micro/nanorobots to overcome GI tract barriers for active drug delivery are highlighted and discussed. Finally, we summarize and discuss the challenges and future prospects of micro/nanorobots for further clinical applications.
Expert opinion:
Micro/nanorobots with the ability to autonomously propel themselves and to load, transport, and release payloads on demand are ideal carriers for active oral drug delivery. Although there are many challenges to be addressed, micro/nanorobots have great potential to introduce a new era of drug delivery for precision therapy.
... The human gut hosts a complex ecosystem of microbes that play pivotal roles in metabolism, food digestion and clearance of invading particles/pathogens, and active nutritive connection with other body organs, thus determining the human health (19,20). After CNMs enter the intestine, trillions of microbes act as both their first barrier and their primary targets (2,21,22). As a "forgotten organ," the gut microbiota exerts the functions of extracting and fermenting carbon compounds from dietary fibers for metabolite synthesis (23). ...
Carbon-based nanomaterials (CNMs) have recently been found in humans raising a
great concern over their adverse roles in the hosts. However, our knowledge of the in vivo behavior and fate of CNMs, especially their biological processes elicited by the gut microbiota, remains poor. Here, we uncovered the integration of CNMs (single-walled carbon nanotubes and graphene oxide) into the endogenous carbon flow through degradation and fermentation, mediated by the gut microbiota of mice using isotope tracing and gene sequencing. As a newly available carbon source for the gut microbiota, microbial fermentation leads to the incorporation of inorganic carbon from the CNMs into organic butyrate through the pyruvate pathway. Furthermore, the butyrate-producing bacteria are identified to show a preference for the CNMs as their favorable source, and excessive butyrate derived from microbial CNMs fermentation further impacts on the function (proliferation and differentiation) of intestinal stem cells in mouse and intestinal organoid models. Collectively, our results unlock the unknown fermentation processes of CNMs in the gut of hosts and underscore an urgent need for assessing the transformation of CNMs and their health risk via the gut-centric physiological and anatomical pathways.
... Similar results were observed in Caco-2 monolayers when monocaprylin was employed to dissolve atorvastatin in a self-microemulsifying drug delivery system (Bandivadeka et al., 2012), indicating that monocaprylin might have an important role at enhancing 5FU penetration in spheroids. The nanometric size is also an important factor that facilitates this process: smaller droplets are more likely to be taken up by cells than larger ones (Hillaireau and Couvreur, 2009;Apolinário et al., 2020;Cui et al., 2020). And thus are the formulation composition, type, and concentration of surfactants: hydrophilic and preferably ionic surfactants have demonstrated to alter the cellular membrane fluidity and improve the drug and oil phase penetration into the cell (Lu et al., 2016). ...
Colorectal cancer (CRC) is the third most common cancer in the world, but current chemotherapy options are limited due to adverse effects and low oral bioavailability of drugs. In this study, we investigated the obtainment parameters and composition of new multiple nanoemulsions (MN) based on microemulsions for oral co-delivery of 5-fluorouracil (5FU) and short-chain triglycerides (SCT, either tributyrin or tripropionin). The area of microemulsion formation was increased from 14% to 38% when monocaprylin was mixed with tricaprylin as oil phase. Addition of SCT reduced this value to 24-26%. Using sodium alginate aqueous dispersion as internal aqueous phase (to avoid phase inversion) did not further affected the area but increased microemulsion viscosity by 1.5-fold. To obtain the MN, selected microemulsions were diluted in an external aqueous phase; droplet size was 500 nm and stability improved using polyoxyethylene (den Besten et al., 2013) oleyl ether at 1-2.5% as surfactant in the external phase and a dilution ratio of 1:1 (v/v). 5FU in vitro release could be better described by the Korsmeyer-Peppas model. No pronounced changes in droplet size were observed when selected MNs were incubated in buffers mimicking gastrointestinal fluids. The 5FU cytotoxicity in monolayer cell lines presenting various mutations was influenced by its incorporation in the nanocarrier, presence of SCT and cell mutation status. The MNs selected reduced the viability of tumor spheroids (employed as 3D tumor models) by 2.2-fold compared to 5FU solution and did not affect the survival of the G. mellonella, suggesting effectiveness and safety.
... There is evidence that insoluble metal oxides, such as CdO, CuO, PbO, and ZnO, can be dissolved directly or indirectly by anaerobic microorganisms through enzymatic activity or microbial metabolites [30]. Metal NMs can also interact with anions in intestinal mucus by releasing metal cations for mucus-targeted therapy [31]. For example, natural polymers (such as hyaluronic acid, chitosan, and pectin) and synthetic polymers (such as acrylic derivatives) have been found to nonspecifically adhere to mucins [32]. ...
Cancer treatment is a challenge by its incredible complexity. As a key driver and player of cancer, gut microbiota influences the efficacy of cancer treatment. Modalities to manipulate gut microbiota have been reported to enhance antitumor efficacy in some cases. Nanomaterials (NMs) have been comprehensively applied in cancer diagnosis, imaging, and theranostics due to their unique and excellent properties, and their effectiveness is also influenced by gut microbiota. Nanotechnology is capable of targeting and manipulating gut microbiota, which offers massive opportunities to potentiate cancer treatment. Given the complexity of gut microbiota–host interactions, understanding NMs–gut interactions and NMs–gut microbiota interactions are important for applying nanotechnologies towards manipulating gut microbiota in cancer prevention and treatment. In this review, we provide an overview of NMs–gut interactions and NMs–gut microbiota interactions and highlight the influences of gut microbiota on the diagnosis and treatment effects of NMs, further illustrating the potential of nanotechnologies in cancer therapy. Investigation of the influences of NMs on cancer from the perspective of gut microbiota will boost the prospect of nanotechnology intervention of gut microbiota for cancer therapy.
... 07 expected to reduce their toxicity (Ekvall et al., 2021), although if the acquired corona results in some particle agglomeration the particles may become a more attractive food source and thus be taken up to a greater extent resulting in increased toxicity (Nasser and Lynch, 2016). Depending on their location in the intestine, NMs can acquire an unique eco-corona profile (Chetwynd et al., 2020;Cui et al., 2020), and undergo different transformations, for example, a pH-dependent dissolution (Cao et al., 2022). Due to the particularities of NMs, they are normally dispersed in the luminal liquid, rather than dissolved, and a wide diversity of macromolecules (solid-phase food, exudates, digestive enzymes, and proteins) present in or from the external environment can also be considered as additional colloidal components that can contribute to its dispersibility or not Van Der Zande et al., 2020). ...
... Due to the particularities of NMs, they are normally dispersed in the luminal liquid, rather than dissolved, and a wide diversity of macromolecules (solid-phase food, exudates, digestive enzymes, and proteins) present in or from the external environment can also be considered as additional colloidal components that can contribute to its dispersibility or not Van Der Zande et al., 2020). The composition of the digestive tract and the interaction forces between NMs and gut lumen matrix determine NMs bioavailability, potentiating or mitigating NM toxicity to daphnids (Cui et al., 2020). Consequently, the physicochemical characteristics of NMs and natural biological constituents must be studied in terms of their colloidal chemistry to determine their colloidal behaviour and impacts on daphnids' physiology (Christenson, 1984). ...
... The small size of daphnids and sample contamination (e.g., mucus and carapace) are the main limiting factors that influence data collection (Mattsson et al., 2016;Van Der Zande et al., 2020). Besides investigating nanointestinal epithelial cells interaction, understanding NMs interactions with Daphnia gut microbiota are necessary, since ingested NMs and other stressors change the composition and functioning of microorganisms that inhabit the gut (Akbar et al., 2020;Cui et al., 2020). The alteration of life history traits have also been shown to mediate the toxicity response , however, the understanding of life history and gut microbiome influence NM and MP toxicity are still in their infancy Akbar et al., 2020;Varg et al., 2022). ...
... 07 expected to reduce their toxicity (Ekvall et al., 2021), although if the acquired corona results in some particle agglomeration the particles may become a more attractive food source and thus be taken up to a greater extent resulting in increased toxicity (Nasser and Lynch, 2016). Depending on their location in the intestine, NMs can acquire an unique eco-corona profile (Chetwynd et al., 2020;Cui et al., 2020), and undergo different transformations, for example, a pH-dependent dissolution (Cao et al., 2022). Due to the particularities of NMs, they are normally dispersed in the luminal liquid, rather than dissolved, and a wide diversity of macromolecules (solid-phase food, exudates, digestive enzymes, and proteins) present in or from the external environment can also be considered as additional colloidal components that can contribute to its dispersibility or not Van Der Zande et al., 2020). ...
... Due to the particularities of NMs, they are normally dispersed in the luminal liquid, rather than dissolved, and a wide diversity of macromolecules (solid-phase food, exudates, digestive enzymes, and proteins) present in or from the external environment can also be considered as additional colloidal components that can contribute to its dispersibility or not Van Der Zande et al., 2020). The composition of the digestive tract and the interaction forces between NMs and gut lumen matrix determine NMs bioavailability, potentiating or mitigating NM toxicity to daphnids (Cui et al., 2020). Consequently, the physicochemical characteristics of NMs and natural biological constituents must be studied in terms of their colloidal chemistry to determine their colloidal behaviour and impacts on daphnids' physiology (Christenson, 1984). ...
... The small size of daphnids and sample contamination (e.g., mucus and carapace) are the main limiting factors that influence data collection (Mattsson et al., 2016;Van Der Zande et al., 2020). Besides investigating nanointestinal epithelial cells interaction, understanding NMs interactions with Daphnia gut microbiota are necessary, since ingested NMs and other stressors change the composition and functioning of microorganisms that inhabit the gut (Akbar et al., 2020;Cui et al., 2020). The alteration of life history traits have also been shown to mediate the toxicity response , however, the understanding of life history and gut microbiome influence NM and MP toxicity are still in their infancy Akbar et al., 2020;Varg et al., 2022). ...
The importance of the cladoceran Daphnia as a model organism for ecotoxicity testing has been well-established since the 1980s. Daphnia have been increasingly used in standardised testing of chemicals as they are well characterised and show sensitivity to pollutants, making them an essential indicator species for environmental stress. The mapping of the genomes of D. pulex in 2012 and D. magna in 2017 further consolidated their utility for ecotoxicity testing, including demonstrating the responsiveness of the Daphnia genome to environmental stressors. The short lifecycle and parthenogenetic reproduction make Daphnia useful for assessment of developmental toxicity and adaption to stress. The emergence of nanomaterials (NMs) and their safety assessment has introduced some challenges to the use of standard toxicity tests which were developed for soluble chemicals. NMs have enormous reactive surface areas resulting in dynamic interactions with dissolved organic carbon, proteins and other biomolecules in their surroundings leading to a myriad of physical, chemical, biological, and macromolecular transformations of the NMs and thus changes in their bioavailability to, and impacts on, daphnids. However, NM safety assessments are also driving innovations in our approaches to toxicity testing, for both chemicals and other emerging contaminants such as microplastics (MPs). These advances include establishing more realistic environmental exposures via medium composition tuning including pre-conditioning by the organisms to provide relevant biomolecules as background, development of microfluidics approaches to mimic environmental flow conditions typical in streams, utilisation of field daphnids cultured in the lab to assess adaption and impacts of pre-exposure to pollution gradients, and of course development of mechanistic insights to connect the first encounter with NMs or MPs to an adverse outcome, via the key events in an adverse outcome pathway. Insights into these developments are presented below to inspire further advances and utilisation of these important organisms as part of an overall environmental risk assessment of NMs and MPs impacts, including in mixture exposure scenarios.
... Smaller ENM can intensify the binding capacity, the potential to generate reactive oxygen species (ROS), the adsorption rate and catalytic activity, which may affect in vivo residence time [1,6]. A few nanomaterials, including carbon nanotubes, graphene and graphene oxide, titania, ceria, zinc oxide, nano silica, and nano silver, may affect the immune function [7]. A growing body of evidence has suggested that ENM exposure can, directly or indirectly, interact with cardiovascular (CV) components, leading to adverse events and worsening CV complications [1]. ...
With the rapid development of engineered nanomaterials (ENMs) in biomedical applications, their biocompatibility and cytotoxicity need to be evaluated properly. Recently, it has been demonstrated that inflammasome activation may be a vital contributing factor for the development of biological responses induced by ENMs. Among the inflammasome family, NLRP3 inflammasome has received the most attention because it directly interacts with ENMs to cause the inflammatory effects. However, the pathways that link ENMs to NLRP3 inflammasome have not been thoroughly summarized. Thus, we reviewed recent findings on the role of major ENMs properties in modulating NLRP3 inflammasome activation, both in vitro and in vivo, to provide a better understanding of the underlying mechanisms. In addition, the interactions between ENMs and NLRP3 inflammasome activation are summarized, which may advance our understanding of safer designs of nanomaterials and ENM-induced adverse health effects.
... (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) occurring within GIT, such as digestion, transport, metabolism, biotransfomation and bioavailability [83,232]. Therefore, further understanding of these processes can provide important insights into the design of effective and safe INMs. ...
... (b) Schematic diagram of INM's penetration into the intestinal barrier and the important factors affecting INMs permeability across the intestinal barrier. Adapted with permission from ref[232]. ...
With excellent physicochemical properties, inorganic nanomaterials (INMs) have exhibited a series of attractive applications in biomedical fields. Biological barriers prevent successful delivery of nanomedicine in living systems that limits the development of nanomedicine especially for sufficient delivery of drugs and effective therapy. Numerous researches have focused on overcoming these biological barriers and homogeneity of organisms to enhance therapeutic efficacy, however, most of these strategies fail to resolve these challenges. In this review, we present the latest progress about how INMs interact with biological barriers and penetrate these barriers. We also summarize that both native structure and components of biological barriers and physicochemical properties of INMs contributed to the penetration capacity. Knowledge about the relationship between INMs structure and penetration capacity will guide the design and application of functional and efficient nanomedicine in the future.
... To date, several lines of evidence have confirmed that the safety risks of nanomaterials to the intestine are not insubstantial [6,7]. Apart from nano safety concerns, therapeutic systems based on nanomaterials have shown great potential for applications in intestine-related diseases, since such formulations can easily enter the target organ [8,9]. From the perspective of toxicology and nanomedicine, there is an urgent need to understand nano-intestine interactions and their underlying mechanisms, to both avoid the risks and broaden the application of nanomaterials. ...
With research burgeoning in nanoscience and nanotechnology, there is an urgent need to develop new biological models that can simulate native structure, function, and genetic properties of tissues to evaluate the adverse or beneficial effects of nanomaterials on a host. Among the current biological models, three-dimensional (3D) organoids have developed as powerful tools in the study of nanomaterial-biology (nano-bio) interactions, since these models can overcome many of the limitations of cell and animal models. A deep understanding of organoid techniques will facilitate the development of more efficient nanomedicines and further the fields of tissue engineering and personalized medicine. Herein, we summarize the recent progress in intestinal organoids culture systems with a focus on our understanding of the nature and influencing factors of intestinal organoid growth. We also discuss biomimetic extracellular matrices (ECMs) coupled with nanotechnology. In particular, we analyze the application prospects for intestinal organoids in investigating nano-intestine interactions. By integrating nanotechnology and organoid technology, this recently developed model will fill the gaps left due to the deficiencies of traditional cell and animal models, thus accelerating both our understanding of intestine-related nanotoxicity and the development of nanomedicines.
