Autonomously Assembled Living Capsules by Microbial Coculture for Enhanced Bacteriotherapy of Inflammatory Bowel Disease.

Microorganism-mediated self-assembling of living formulations holds great promise for disease therapy. Here, we constructed a prebiotic-probiotic living capsule (PPLC) by coculturing probiotics (EcN) with Gluconacetobacter xylinus (G. xylinus) in a prebiotic-containing fermentation broth. Through shaking the culture, G. xylinus secretes cellulose fibrils that can spontaneously encapsulate EcN to form microcapsules under shear forces. Additionally, the prebiotic present in the fermentation broth is incorporated into the bacterial cellulose network through van der Waals forces and hydrogen bonding. Afterward, the microcapsules were transferred to a selective LB medium, which facilitated the colonization of dense probiotic colonies within them. The in vivo study demonstrated that PPLC-containing dense colonies of EcN can antagonize intestinal pathogens and restore microbiota homeostasis by showing excellent therapeutic performance in treating enteritis mice. The in situ self-assembly of probiotics and prebiotics-based living materials provides a promising platform for the treatment of inflammatory bowel disease.

Customized materials-assisted microorganisms in tumor therapeutics.

Microorganisms have been extensively applied as active biotherapeutic agents or drug delivery vehicles for antitumor treatment because of their unparalleled bio-functionalities. Taking advantage of the living attributes of microorganisms, a new avenue has been opened in anticancer research. The integration of customized functional materials with living microorganisms has demonstrated unprecedented potential in solving existing questions and even conferring microorganisms with updated antitumor abilities and has also provided an innovative train of thought for enhancing the efficacy of microorganism-based tumor therapy. In this review, we have summarized the emerging development of customized materials-assisted microorganisms (MAMO) (including bacteria, viruses, fungi, microalgae, as well as their components) in tumor therapeutics with an emphasis on the rational utilization of chosen microorganisms and tailored materials, the ingenious design of biohybrid systems, and the efficacious antitumor mechanisms. The future perspectives and challenges in this field are also discussed.

Intelligent testing strategy and analytical techniques for the safety assessment of nanomaterials.

Nanomaterials (NMs) are widely used in various areas because of their unique and useful physicochemical properties. However, they may pose toxicity risks to human health after exposure. Applicable and reliable approaches are needed for risk assessment of NMs. Herein, an intelligent analytical strategy for safety assessment of NMs is proposed that focuses on toxicity assessment using an in vitro cell model. The toxicity assessment by testing on the adverse outcome pathway in a cell culture system was defined by application of a tiered testing approach. To provide an overview of the applicable approach for risk assessment of NMs, we discuss the most commonly used techniques and analytical methods, including computational toxicology methods in dosimetry assessment, high-throughput screening for toxicity testing with high efficiency, and omics-based toxicology assessment methods. The final section focuses on the route map for an integrated approach to a testing and assessment strategy on how to extrapolate the in vitro NM toxicity testing data to in vivo risk assessment of NMs. The intelligent analytical strategy, having evolved step-by-step, could contribute to better applications for safety evaluation and risk assessment of NMs in reality.

Integrated cascade catalysis of microalgal bioenzyme and inorganic nanozyme for anti-inflammation therapy.

Combinations of multiple enzymes for cascade catalysis have been widely applied in biomedicine, but the integration of a natural bioenzyme with an inorganic nanozyme is less developed. Inspired by the abundant content of superoxide dismutase (SOD) in Spirulina platensis (SP), we establish an integrated cascade catalysis for anti-inflammation therapy by decorating catalase (CAT)-biomimetic ceria nanoparticles (CeO2) onto the SP surface via electrostatic interaction to build microalgae-based biohybrids. The biohybrids exhibit combined catalytical competence for preferentially transforming superoxide anion radicals (O2˙-) to hydrogen peroxide (H2O2), and subsequently catalyzing H2O2 disproportionation to water and oxygen. In ulcerative colitis and Crohn's disease, the biohybrids reveal a satisfactory therapeutic effect owing to the synergistic reactive oxygen species (ROS)-scavenging capacity, suggesting a new train of thought for enzyme-based biomedical application.

Polymeric nano-system for macrophage reprogramming and intracellular MRSA eradication.

Intracellular Methicillin-Resistant Staphylococcus aureus (MRSA) remains a major factor of refractory and recurrent infections, which cannot be well addressed by antibiotic therapy. Here, we design a cellular infectious microenvironment-activatable polymeric nano-system to mediate targeted intracellular drug delivery for macrophage reprogramming and intracellular MRSA eradication. The polymeric nano-system is composed of a ferrocene-decorated polymeric nanovesicle formulated from poly(ferrocenemethyl methacrylate)-block-poly(2-methacryloyloxyethyl phosphorylcholine) (PFMMA-b-PMPC) copolymer with co-encapsulation of clofazimine (CFZ) and interferon-γ (IFN-γ). The cellular-targeting PMPC motifs render specific internalization by macrophages and allow efficient intracellular accumulation. Following the internalization, the ferrocene-derived polymer backbone sequentially undergoes hydrophobic-to-hydrophilic transition, charge reversal and Fe release in response to intracellular hydrogen peroxide over-produced upon infection, eventually triggering endosomal escape and on-site cytosolic drug delivery. The released IFN-γ reverses the immunosuppressive status of infected macrophages by reprogramming anti-inflammatory M2 to pro-inflammatory M1 phenotype. Meanwhile, intracellular Fe2+-mediated Fenton reaction together with antibiotic CFZ contributes to increased intracellular hydroxyl radical (•OH) generation. Ultimately, the nano-system achieves robust potency in ablating intracellular MRSA and antibiotic-tolerant persisters by synchronous immune modulation and efficient •OH killing, providing an innovative train of thought for intracellular MRSA control.

An orally delivered bacteria-based coacervate antidote for alcohol detoxification.

Alcohol intoxication causes serious diseases, whereas current treatments are mostly supportive and unable to convert alcohol into nontoxic products in the digestive tract. To address this issue, an oral intestinal-coating coacervate antidote containing acetic acid bacteria (AAB) and sodium alginate (SA) mixture was constructed. After oral administration, SA reduces absorption of ethanol and promotes the proliferation of AAB, and AAB converts ethanol to acetic acid or carbon dioxide and water by two sequential catalytic reactions in the presence of membrane-bound alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). In vivo study shows that the bacteria-based coacervate antidote can significantly reduce the blood alcohol concentration (BAC) and effectively alleviates alcoholic liver injury in mice. Given the convenience and effectiveness of oral administration, AAB/SA can be used as a promising candidate antidote for relieving alcohol-induced acute liver injury.

Colon-targeted bacterial hydrogel for tumor vascular normalization and improved chemotherapy.

The endogenous H2S plays an important role in the occurrence and development of colon cancer, and is related to the abnormal blood vessels. Here, we reported on a sulfhydryl hyaluronid-based hydrogel (HA-SH) synthesized by amide reaction and further obtained a bacterial hydrogel by loading Thiobacillus denitrificans to the hydrogel for targeting adhesion to the colon. It was found that the loaded bacteria in HA-SH hydrogel can scavenge excess H2S in colon cancer, then promote tumor vascular normalization and improve the delivery of chemotherapy drug CPT to inhibit tumor progression. Both in vivo and in vitro experiments show that the self-crosslinked bacterial hydrogel has satisfactory effects in inhibiting tumor progression and promoting tumor vascular normalization in colon cancer. This study presents an efficient method to target the colon and consume overexpressed H2S in colon cancer to inhabit tumor progression, providing a new way for oral drug treatment of colon cancer.

A Microbial Community Cultured in Gradient Hydrogel for Investigating Gut Microbiome-Drug Interaction and Guiding Therapeutic Decisions.

Despite the recognition that the gut microbiota acts a clinically significant role in cancer chemotherapy, both mechanistic understanding and translational research are still limited. Maximizing drug efficacy requires an in-depth understanding of how the microbiota contributes to therapeutic responses, while microbiota modulation is hindered by the complexity of the human body. To address this issue, a 3D experimental model named engineered microbiota (EM) is reported for bridging microbiota-drug interaction research and therapeutic decision-making. EM can be manipulated in vitro and faithfully recapitulate the human gut microbiota at the genus/species level while allowing co-culture with cells, organoids, and isolated tissues for testing drug responses. Examination of various clinical and experimental drugs by EM reveales that the gut microbiota affects drug efficacy through three pathways: immunological effects, bioaccumulation, and drug metabolism. Guided by discovered mechanisms, custom-tailored strategies are adopted to maximize the therapeutic efficacy of drugs on orthotopic tumor models with patient-derived gut microbiota. These strategies include immune synergy, nanoparticle encapsulation, and host-guest complex formation, respectively. Given the important role of the gut microbiota in influencing drug efficacy, EM will likely become an indispensable tool to guide drug translation and clinical decision-making.

Orally administered Bi2S3@SiO2 core-shell nanomaterials as gastrointestinal contrast agents and their influence on gut microbiota.

Effective and safe contrast agents for X-ray computed tomography (CT) imaging of the gastrointestinal (GI) tract are quite desirable for realizing high diagnostic accuracy and low toxicity in the clinic. Herein, we synthesize a series of silica-coated bismuth sulfide core-shell nanomaterials (Bi2S3@SiO2) of various sizes and systematically study their GI CT contrast performance and potential toxic effects in comparison with those of barium sulfate (BaSO4) in mice. The in vivo experimental results suggest that these Bi2S3@SiO2 core-shell nanomaterials display superior CT contrast performance and higher elimination efficacy than BaSO4 by single-dose exposure manner (10 â€‹mg/kg Bi element/b.w. for Bi2S3@SiO2 versus 30 â€‹mg/kg Ba element/b.w. for BaSO4). Furthermore, 28 days after exposure, Bi2S3@SiO2 core-shell nanomaterials show minimal toxic effects in vivo and nonsignificant influences on the structure and function of the gut microbiota in mice. This demonstrates that no adverse effects on the gut homeostasis are induced by Bi2S3@SiO2 core-shell nanomaterials and, thus, suggests that they can act as excellent and safe CT contrast agents for GI tract imaging.

Perturbation of gut microbiota plays an important role in micro/nanoplastics-induced gut barrier dysfunction.

The widespread occurrence of microplastics (MPLs) and nanoplastics (NPLs), collectively abbreviated as M/NPLs, has markedly affected the ecosystem and has become a global threat to human health. Multiple investigations have shown that the chronic ingestion of M/NPLs negatively affects gut barrier function but the mechanism remains unclear. Herein, this research has investigated the toxic effects of pristine polystyrene (PS) M/NPLs, negatively charged carboxylated polystyrene M/NPLs (PS-COOH) and positively charged aminated polystyrene M/NPLs (PS-NH2) of two sizes (70 nm and 5 µm in diameter) in mice. Gavage of these PS M/NPLs for 28 days caused obvious injuries to the gut tract, leading to the decreased expression of tight junction proteins. The toxicity of the M/NPLs was ranked as PS-NH2 > PS-COOH > pristine PS. Oral administration of these M/NPLs resulted in marked gut microbiota dysbiosis. The M/NPLs-enriched genera generally contained opportunistic pathogens which are accompanied by a deteriorated intestinal barrier function, while most M/NPLs-decreased bacteria were beneficial microbes with known tight junction-promoting functions, implicating an important indirect toxic effect of gut microbiota dysbiosis in M/NPLs-induced gut barrier dysfunction. In conclusion, this research highlights the importance of gut microbiota in the toxicity of M/NPLs exposure on gut barrier function, providing novel insights into the adverse effects of M/NPLs exposure on human health.

Complex to simple: In vitro exposure of particulate matter simulated at the air-liquid interface discloses the health impacts of major air pollutants.

Particulate matter (PM) exposure poses many adverse effects on human health. However, it is challenging to clearly differentiate between the contributions of individual pollutants on toxicity from complex mixtures of ambient air pollutants. The aim of this study is to generate aerosols constituted by silica nanoparticles (NPs) and bisulfate to serve as simulators of particle-associated high-sulfur air pollution. Then, the health impacts of sulfur dioxide were evaluated at the cellular level using an air-liquid interface (ALI) exposure chamber. BEAS-2B cells were exposed to either nano-silica or bisulfite aerosol individually or bisulfate-coated silica (SiO2-NH2@HSO3) for 3 h using the ALI. The cellular toxicities were carefully compared based on the exposure dosages. The ALI exposure of SiO2 NPs alone did not produce any apparent cytotoxicity in cells, but the aerosol exposure of SiO2-NH2@HSO3 significantly decreased the cell viability and enhanced the production of cellular reactive oxygen species in a dose-dependent manner. Consequently, the excessive oxidative stress resulted in mitochondrial damage as well as cellular apoptosis. ALI exposure can possibly reflect the realistic physiological exposure condition of the human respiratory system. As a derivative of the sulfur dioxide component of air pollution, sulfate exacerbates the toxic effects of inhalable PMs. This result may be due to the large surface area of the nanoparticles, with the possibility of carrying more sulfite to the target cells during aerosol exposure. The sulfate levels offer a meaningful complement to the present PM2.5 index of air pollution for achieving better human health protection.

Hyaluronic acid modified MPEG-b-PAE block copolymer aqueous micelles for efficient ophthalmic drug delivery of hydrophobic genistein.

The ophthalmic drug delivery is a challenge in the clinical treatment of ocular diseases. The traditional drug administration usually shows apparent limitations, such as the low bioavailability from the reason of low penetration of the cornea and the short survival time of drug in the eyes. To overcome these shortcomings, we propose an amphiphilic polymer micelle modified with hyaluronic acid (HA) for high efficient ophthalmic delivery of genistein, a widely used hydrophobic drug for treatment of ocular angiogenesis. The MPEG-b-PAE copolymer was synthesized by the Michael addition reaction, and the final drug carrier MPEG-b-PAE-g-HA was obtained by the process of esterification. Then, genistein was packaged in this drug carrier, getting the final micelles with size of about 84.5 nm. The cell viability tests showed that the micelles take no obvious cytotoxicity to the human cornea epithelium cells. The functionalities of drug slow release and cornea penetration ability were demonstrated in a series ex vivo experiments. Further, the vascular inhibition test illustrated that the micelles could significantly inhibit the angiogenesis of human umbilical vein endothelial cells. These results indicate that the constructed polymer has high feasibility to be used as drug carrier in the treatment of ocular diseases.

Numerical simulation of the fracture process in ceramic FPD frameworks caused by oblique loading.

Using a newly developed three-dimensional (3D) numerical modeling code, an analysis was performed of the fracture behavior in a three-unit ceramic-based fixed partial denture (FPD) framework subjected to oblique loading. All the materials in the study were treated heterogeneously; Weibull׳s distribution law was applied to the description of the heterogeneity. The Mohr-Coulomb failure criterion with tensile strength cut-off was utilized in judging whether the material was in an elastic or failed state. The simulated loading area was placed either on the buccal or the lingual cusp of a premolar-shaped pontic with the loading direction at 30°, 45°, 60°, 75° or 90° angles to the occlusal surface. The stress distribution, fracture initiation and propagation in the framework during the loading and fracture process were analyzed. This numerical simulation allowed the cause of the framework fracture to be identified as tensile stress failure. The decisive fracture was initiated in the gingival embrasure of the pontic, regardless of whether the buccal or lingual cusp of the pontic was loaded. The stress distribution and fracture propagation process of the framework could be followed step by step from beginning to end. The bearing capacity and the rigidity of the framework vary with the loading position and direction. The framework loaded with 90° towards the occlusal surface has the highest bearing capacity and the greatest rigidity. The framework loaded with 30° towards the occlusal surface has the least rigidity indicating that oblique loading has a major impact on the fracture of ceramic frameworks.

A 3D numerical simulation of stress distribution and fracture process in a zirconia-based FPD framework.

In this study, a numerical approach to the fracture behavior in a three-unit zirconia-based fixed partial denture (FPD) framework was made under mechanical loading using a newly developed three-dimensional (3D) numerical modeling code. All the materials studied were treated heterogeneously and Weibull distribution law was applied to describe the heterogeneity. The Mohr-Coulomb failure criterion with tensile strength cut-off was utilized to judge whether the material was in an elastic or failed state. For validation, the fracture pattern obtained from the numerical modeling was compared with a laboratory test; they largely correlated with each other. Similar fracture initiation sites were detected both in the numerical simulation and in an earlier fractographic analysis. The numerical simulation applied in this study clearly described the stress distribution and fracture process of zirconia-based FPD frameworks, information that could not be gained from the laboratory tests alone. Thus, the newly developed 3D numerical modeling code seems to be an efficient tool for prediction of the fracture process in ceramic FPD frameworks.