Designing a microbial fermentation-functionalized alginate microsphere for targeted release of 5-ASA using nano dietary fiber carrier for inflammatory bowel disease treatment.

Patients with inflammatory bowel disease (IBD) always suffer from severe abdominal pain and appear to be at high risk for colorectal cancer. Recently, the co-delivery of targeted drugs and gut microbiota has developed into an attractive strategy. A new strategy using gut microbiota fermentation to overcome the interspace diffuse resistance from the mucus layer to control drug release in inflammatory bowel sites (IBS sites) has not yet been available. Here, we designed an alginate hydrogel microsphere encapsulating bifidobacterium (Bac) and drug-modified nanoscale dietary fibers (NDFs). The hydrogel microsphere is responsible for protecting drugs from acidic and multi-enzymatic environments and delivering drugs to the colorectum. Subsequently, the fermentation of Bac by digesting NDFs and proteins as carbon and nitrogen sources can promote drug release and play a probiotic role in the gut microbiota. In vitro evidence indicated that small-sized NDF (NDF-1) could significantly promote short-chain fatty acid (SCFA) expression. Notably, NDF-1 hydrogel microspheres showed a boost release of 5-ASA in the IBS sites, resulting in the amelioration of gut inflammation and remodeling of gut microbiota in chronic colitis mice. This study developed a controlled release system based on microbial fermentation for the treatment of IBD.

Adjuvant-free cellulose nanofiber vaccine induces permanent humoral immune response in mouse.

Vaccines have become one of the most effective strategies to deal with various infectious diseases and chronic noninfectious diseases, such as SARS virus, Novel Coronavirus, cancer, etc. However, recent studies have found that the neutralizing antibody titers induced by vaccines would drop to half level or even lower after vaccination. In this study, we designed a novel small-sized positively charged nanofiber-1 (PEI-CNF-1) as a vaccine carrier, which can induce a high long-term humoral immune response by controlled release of antigen. Further studies showed that PEI-CNF-1 could significantly induce the release of immune response factor IL-1ßand bone marrow-derived cell (BMDC) maturation. Moreover, compare to other cellulose nanofibers (CNFs), PEI-CNF-1 combined antigen (ovalbumin, OVA) induced and maintained the highest and longest antibody titers after vaccination. Interestingly, the antibody titers have no significant difference between at 21 and 90 d. Mechanically, we found that PEI-NCF-1 not only could control the slow-release of antigen, but also could be more easily swallowed by macrophages and metabolized by the bodies, thus presenting antigen more effectively. In conclusion, we believe that PEI-CNF-1 have a very high application prospect in inducing long-term humoral immune response, so as to achieve efficient prevention effect to epidemic viruses.

Engineering Fe-N Doped Graphene to Mimic Biological Functions of NADPH Oxidase in Cells.

NADPH oxidase (NOX) as a transmembrane enzyme complex controls the generation of superoxide that plays important roles in immune signaling pathway. NOX inactivation may elicit immunodeficiency and cause chronic granulomatous disease (CGD). Biocompatible synthetic materials with NOX-like activities would therefore be interesting as curative and/or preventive approaches in case of NOX deficiency. Herein, we synthesized a Fe-N doped graphene (FeNGR) nanomaterial that could mimic the activity of NOX by efficiently catalyzing the conversion of NADPH into NADP+ and triggering the generation of oxygen radicals. The resulting FeNGR nanozyme had similar cellular distribution to NOX and is able to mimic the enzyme function in NOX-deficient cells by catalyzing the generation of superoxide and retrieving the immune activity, evidenced by TNF-α, IL-1ß, and IL-6 production in response to Alum exposure. Overall, our study discovered a synthetic material (FeNGR) to mimic NOX and demonstrated its biological function in immune activation of NOX-deficient cells.

Engineering the Protein Corona Structure on Gold Nanoclusters Enables Red-Shifted Emissions in the Second Near-infrared Window for Gastrointestinal Imaging.

The application of NIR-II emitters for gastrointestinal (GI) tract imaging remains challenging due to fluorescence quenching in the digestive microenvironment. Herein, we report that red-shifting of the fluorescence emission of Au nanoclusters (AuNCs) into NIR-II region with improved quantum yields (QY) could be achieved by engineering a protein corona structure consisting of a ribonuclease-A (RNase-A) on the particle surfaces. RNase-A-encapsulated AuNCs (RNase-A@AuNCs) displayed emissions at 1050 nm with a 1.9 % QY. Compared to rare earth and silver-based NIR-II emitters, RNase-A@AuNCs had excellent biocompatibility, showing >50-fold higher sensitivity in GI tract, and migrated homogenously during gastrointestinal peristalsis to allow visualization of the detailed structures of the GI tract. RNase-A@AuNCs could successfully examine intestinal tumor mice from healthy mice, indicating a potential utility for early diagnosis of intestinal tumors.

Exploring the interactions between engineered nanomaterials and immune cells at 3D nano-bio interfaces to discover potent nano-adjuvants.

Engineered nanomaterials (ENMs) as adjuvants can potentiate the adaptive immune responses to antigens by activating immune cells in three dimensional (3D) matrixes of tissues. However, few reports explored the interactions of nano-adjuvants and immune cells at 3D nano-bio interfaces. Herein we designed an alginate-calcium microsphere of macrophage cells to explore the interactions. By an extensive comparison of ENM-induced cytokines in 2D and 3D cultured cells, IL-1ß released in 3D microspheres was found to be a predictive biomarker to assess ENM-induced immune responses in vivo. Among nine representative ENMs, La2O3 boosts the highest adaptive humoral immune response, even stronger than clinically used Alum adjuvant. It could be attributed to the biotransformation of La2O3 from spherical particles into urchin-like LaPO4, resulting in strong biopersistence and NLRP3 inflammasome activation. These findings could be potentially used for the high throughput screening of nano-adjuvants from increasingly invented ENMs to speed up their clinical uses.

Development of Small HN Linked Radionuclide Iodine-125 for Nanocarrier Image Tracing in Mouse Model.

Background: Radionuclides have important roles in clinical tumor radiotherapy as they are used to kill tumor cells or as imaging agents for drug tracing. The application of radionuclides has been developing as an increasing number of nanomaterials are used to deliver radionuclides to tumor areas to kill tumor cells. However, promoting the efficient combination of radionuclides and nanocarriers (NCs), enhancing radionuclide loading efficiency, and avoiding environmental pollution caused by radionuclide overuse are important challenges that hinder their further development. Methods: In the present study, a new small molecule compound (3-[[(2S)-2-hydroxy-3-(4-hydroxyphenyl)-1-carbonyl] amino]-alanine, abbreviation: HN, molecular formula: C12H16N2O5) was synthesized as a linker between radionuclide iodine-125 (125I) and NCs to enable a more efficient binding between NCs and radionuclides. Results: In vitro evidence indicated that the linker was able to bind 125I with higher efficiency (labeling efficiency >80%) than that of tyrosine, as well as various NCs, such as cellulose nanofibers, metal oxide NCs, and graphene oxide. Single-photon emission computed tomography/computed tomography imaging demonstrated the biological distribution of 125I-labeled NCs in different organs/tissues after administration in mice. Conclusion: These results showed an improvement in radionuclide labeling efficiency for nanocarriers and provided an approach for nanocarrier image tracing.

Antibiotic-Like Activity of Atomic Layer Boron Nitride for Combating Resistant Bacteria.

The global rise of antimicrobial resistance (AMR) that increasingly invalidates conventional antibiotics has become a huge threat to human health. Although nanosized antibacterial agents have been extensively explored, they cannot sufficiently discriminate between microbes and mammals, which necessitates the exploration of other antibiotic-like candidates for clinical uses. Herein, two-dimensional boron nitride (BN) nanosheets are reported to exhibit antibiotic-like activity to AMR bacteria. Interestingly, BN nanosheets had AMR-independent antibacterial activity without triggering secondary resistance in long-term use and displayed excellent biocompatibility in mammals. They could target key surface proteins (e.g., FtsP, EnvC, TolB) in cell division, resulting in impairment of Z-ring constriction for inhibition of bacteria growth. Notably, BN nanosheets had potent antibacterial effects in a lung infection model by P. aeruginosa (AMR), displaying a 2-fold increment of survival rate. Overall, these results suggested that BN nanosheets could be a promising nano-antibiotic to combat resistant bacteria and prevent AMR evolution.

Editing flagellin derivatives for exploration of potent radioprotective agents.

Exploration of medical radiation countermeasures (MRCs) has great implications in protection of mammals from radiation damages. While flagellin has been recently reported to show radioprotective effects, the relationships between flagellin structure and radioprotective activity are rarely explored. Herein, we deliberately edited the amino acid sequence of flagellin in its binding domain with toll-like receptor 5 (TLR5) for exploration of potent flagellin derivatives (Fds). An in vitro screening paradigm was developed to examine the radioprotective effects of six engineered Fds. Notably, mutation of 103 threonine on flagellin into asparagine resulted in a potent MRC candidate (Fd-T103N) displaying 1.28-fold increment of interactions with TLR5. Fd-T103N was able to further activate NF-κB pathway, induce immune protective cytokine (e.g. G-CSF) release, and significantly ameliorate γ-irradiation induced cell death. The protection effects of Fd-T103N were further validated in mice exposed to 10 Gy γ-irradiations. Compared to parent flagellin, Fd-T103N treatment showed higher G-CSF release in mouse blood, lower intestine damages, and 13% increments of mouse survival rates. In short, the established predictive paradigm could greatly reduce the labor-, time- and animal-costs in exploration of MRC candidates. Fd-T103N is a promising candidate of investigational new drug for radioprotection.

Vacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death.

Sustainable developments of nanotechnology necessitate the exploration of structure-activity relationships (SARs) at nano-bio interfaces. While ferroptosis may contribute in the developments of some severe diseases (e.g., Parkinson's disease, stroke and tumors), the cellular pathways and nano-SARs are rarely explored in diseases elicited by nano-sized ferroptosis inducers. Here we find that WS2 and MoS2 nanosheets induce an iron-dependent cell death, ferroptosis in epithelial (BEAS-2B) and macrophage (THP-1) cells, evidenced by the suppression of glutathione peroxidase 4 (GPX4), oxygen radical generation and lipid peroxidation. Notably, nano-SAR analysis of 20 transition metal dichalcogenides (TMDs) disclosures the decisive role of surface vacancy in ferroptosis. We therefore develop methanol and sulfide passivation as safe design approaches for TMD nanosheets. These findings are validated in animal lungs by oropharyngeal aspiration of TMD nanosheets. Overall, our study highlights the key cellular events as well as nano-SARs in TMD-induced ferroptosis, which may facilitate the safe design of nanoproducts.

Antibacterial applications of graphene oxides: structure-activity relationships, molecular initiating events and biosafety.

Bacterial infections may lead to diverse acute or chronic diseases (e.g., inflammation, sepsis and cancer). New antibiotics against bacteria are rarely discovered in recent years, which necessitates the exploration of new antibacterial agents. Engineered nanomaterials (ENMs) have been extensively studied for antibacterial use because of their long lasting killing effects in wide spectra of bacteria. Graphene oxide (GO) is one of the most widely studied ENMs and exhibit strong bactericidal effects. The physicochemical properties of GO play important roles in bacterial killing by triggering a cascade of toxic events. Many studies have explored the signaling pathways of GO in bacteria. Although molecular initiating events (MIEs) of GO in bacteria dominate its killing efficiency as well as toxicity mechanisms, they have been rarely reviewed. In this report, we discussed the structure-activity relationships (SARs) involved in GO-induced bacterial killing and the MIEs including redox reaction with biomolecules, mechanical destruction of membranes and catalysis of extracellular metabolites. Furthermore, we summarized the clinical or commercial applications of GO-based antibacterial products and discussed their biosafety in mammal. Finally, we reviewed the remaining challenges in GO for antibacterial applications, which may offer new insights for the development of nano antibacterial studies.