Investigation of the mucin-nanoparticle interactions via real-time monitoring by microbalance and kinetic model simulation.

Interactions between nanoparticles and the mucus layer are crucial to understand the behaviours in biological environments and design drug delivery systems. In this study, we developed a kinetic deposition model for the dynamic mucin-nanoparticle interactions using quartz crystal microbalance with dissipation (QCM-D). We investigated the effects of the physiochemical properties of several nanoparticles (including size, charge, and shape) and the physiological conditions on the mucin-nanoparticle interaction. Interestingly, layered double hydroxide (LDH) nanoparticles showed stronger interactions with the mucus layer compared to other types of nanoparticles due to their unique plate-like morphology. In specific for sheet-like LDH nanoparticles, our model found that their equilibrium adsorption capacity (Qe) followed the Langmuir adsorption isotherm, and the adsorption rate (k1) increased proportionally with the nanoparticle concentration. In addition, the particle size and thickness affected Qe and the surface coverage. Furthermore, bovine serum albumin (BSA) coating dramatically increased k1 of LDH nanoparticles. We proposed a novel mechanism to elucidate mucin-nanoparticle interactions, shedding light on the synergistic roles of drag force (Fd), repulsive force (Fr), and adsorptive force (Fa). These findings offer valuable insights into the complex mucin-nanoparticle interactions and provide guidance for the design of drug delivery systems.

Isomorphic Insertion of Ce(III)/Ce(IV) Centers into Layered Double Hydroxide as a Heterogeneous Multifunctional Catalyst for Efficient Meerwein-Ponndorf-Verley Reduction.

The development of highly active acid-base catalysts for transfer hydrogenations of biomass derived carbonyl compounds is a pressing challenge. Solid frustrated Lewis pairs (FLP) catalysis is possibly a solution, but the development of this concept is still at a very early stage. Herein, stable, phase-pure, crystalline hydrotalcite-like compounds were synthesized by incorporating cerium cations into layered double hydroxide (MgAlCe-LDH). Besides the insertion of well-isolated cerium centers surrounded by hydroxyl groups, the formation of hydroxyl vacancies near the aluminum centers, which were formed by the insertion of cerium centers into the layered double hydroxides (LDH) lattice, was also identified. Depending on the initial cerium concentration, LDHs with different Ce(III)/Ce(IV) ratios were produced, which had Lewis acidic and basic characters, respectively. However, the acid-base character of these LDHs was related to the actual Ce(III)/Ce(IV) molar ratios, resulting in significant differences in their catalytic performance. The as-prepared structures enabled varying degrees of transfer hydrogenation (Meerwein-Ponndorf-Verley MPV reduction) of biomass-derived carbonyl compounds to the corresponding alcohols without the collapse of the original lamellar structure of the LDH. The catalytic markers through the test reactions were changed as a function of the amount of Ce(III) centers, indicating the active role of Ce(III)-OH units. However, the cooperative interplay between the active sites of Ce(III)-containing specimens and the hydroxyl vacancies was necessary to maximize catalytic efficiency, pointing out that Ce-containing LDH is a potentially commercial solid FLP catalysts. Furthermore, the crucial role of the surface hydroxyl groups in the MPV reactions and the negative impact of the interlamellar water molecules on the catalytic activity of MgAlCe-LDH were demonstrated. These solid FLP-like catalysts exhibited excellent catalytic performance (cyclohexanol yield of 45%; furfuryl alcohol yield of 51%), which is competitive to the benchmark Sn- and Zr-containing zeolite catalysts, under mild reaction conditions, especially at low temperature (T = 65 °C).

Enhancing plant biotechnology by nanoparticle delivery of nucleic acids.

Plant biotechnology plays a crucial role in developing modern agriculture and plant science research. However, the delivery of exogenous genetic material into plants has been a long-standing obstacle. Nanoparticle-based delivery systems are being established to address this limitation and are proving to be a feasible, versatile, and efficient approach to facilitate the internalization of functional RNA and DNA by plants. The nanoparticle-based delivery systems can also be designed for subcellular delivery and controlled release of the biomolecular cargo. In this review, we provide a concise overview of the recent advances in nanocarriers for the delivery of biomolecules into plants, with a specific focus on applications to enhance RNA interference, foreign gene transfer, and genome editing in plants.

Development of polysaccharide-coated layered double hydroxide nanocomposites for enhanced oral insulin delivery.

Oral insulin (INS) is predicted to have the most therapeutic advantages in treating diabetes to repress hepatic glucose production through its potential to mimic the endogenous insulin pathway. Many oral insulin delivery systems have been investigated. Layered double hydroxide (LDH) as an inorganic material has been widely used in drug delivery thanks to its appealing features such as good biocompatibility, low toxicity, and excellent loading capability. However, when used in oral drug delivery, the effectiveness of LDH is limited due to the acidic degradation in the stomach. In this study, to overcome these challenges, chitosan (Chi) and alginate (Alg) dual-coated LDH nanocomposites with the loading of insulin (Alg-Chi-LDH@INS) were developed by the layered-by-layered method for oral insulin delivery with dynamic size of ~ 350.8 nm, negative charge of ~ - 13.0 mV, and dispersity index 0.228. The insulin release profile was evaluated by ultraviolet-visible spectroscopy. The drug release profiles evidenced that alginate and chitosan coating partially protect insulin release from a burst release in acidic conditions. The analysis using flow cytometry showed that chitosan coating significantly enhanced the uptake of LDH@INS by Caco-2 cells compared to unmodified LDH and free insulin. Further in the in vivo study in streptozocin-induced diabetic mice, a significant hypoglycemic effect was maintained following oral administration with great biocompatibility (~ 50% blood glucose level reduction at 4 h). This research has thus provided a potential nanocomposite system for oral delivery of insulin.

Reduction of intracellular oxidative stress with a copper-incorporated layered double hydroxide.

Biocompatible Cu(II)-doped layered double hydroxide (CMA) nanoparticles were developed to combat reactive oxygen species. The 2-dimensional nanozymes showed both superoxide dismutase- and catalase-like activities in chemical assays, while proving as efficient antioxidants in the reduction of intracellular oxidative stress. The results indicate the great promise of CMA in antioxidant therapies.

Enhancing Cancer Chemo-Immunotherapy: Innovative Approaches for Overcoming Immunosuppression by Functional Nanomaterials.

Chemotherapy is a critical modality in cancer therapy to combat malignant cell proliferation by directly attacking cancer cells and inducing immunogenic cell death, serving as a vital component of multi-modal treatment strategies for enhanced therapeutic outcomes. However, chemotherapy may inadvertently contribute to the immunosuppression of the tumor microenvironment (TME), inducing the suppression of antitumor immune responses, which can ultimately affect therapeutic efficacy. Chemo-immunotherapy, combining chemotherapy and immunotherapy in cancer treatment, has emerged as a ground-breaking approach to target and eliminate malignant tumors and revolutionize the treatment landscape, offering promising, durable responses for various malignancies. Notably, functional nanomaterials have substantially contributed to chemo-immunotherapy by co-delivering chemo-immunotherapeutic agents and modulating TME. In this review, recent advancements in chemo-immunotherapy are thus summarized to enhance treatment effectiveness, achieved by reversing the immunosuppressive TME (ITME) through the exploitation of immunotherapeutic drugs, or immunoregulatory nanomaterials. The effects of two-way immunomodulation and the causes of immunoaugmentation and suppression during chemotherapy are illustrated. The current strategies of chemo-immunotherapy to surmount the ITME and the functional materials to target and regulate the ITME are discussed and compared. The perspective on tumor immunosuppression reversal strategy is finally proposed.

Simultaneous Light-Triggered Release of Nitric Oxide and Carbon Monoxide from a Lipid-Coated Upconversion Nanosystem Inhibits Colon Tumor Growth.

Gas therapy has gained noteworthy attention in biomedical research, with the rise of gas-releasing molecules enhancing their therapeutic potential, especially when integrated into nano-based drug delivery systems. Herein, we present a lipid-coated gas delivery system to simultaneously shuttle two gas-releasing molecules carrying nitric oxide (NO) and carbon monoxide (CO), respectively. Upconversion nanoparticles (UCNPs) are designed to generate photons at 360 nm upon 808 nm of near-infrared (NIR) irradiation. These in situ-generated UV photons trigger simultaneous NO and CO release from S-nitrosoglutathione (GSNO) and the CO-releasing molecule (CORM), respectively, which are coloaded into lipid-coated UCNP/GSNO/CORM/FA nanoparticles (LUGCF). LUGCF with a GSNO/CORM mass ratio of 2:1 is determined to be optimal in terms of synergistically instigating apoptosis in HCT116 and CT26 colon cancer cells, where both NO/CO are released and subsequent production of ROS are detected. This CO/NO combination nanoplatform exhibits a very effective inhibition of colon tumor growth in vivo at relatively low doses upon a mild 808 nm irradiation. Overall, we effectively integrated two therapeutic gas-releasing molecules in one NIR-responsive nanosystem, presenting a promising therapeutic strategy for future biomedical applications in dual-gas cancer therapy.

A dendritic/tumor fusion cell vaccine enhances efficacy of nanobody-based CAR-T cells against solid tumor.

Background: Chimeric antigen receptor (CAR) T-cell therapy is practical in treating cancers of hematopoietic origin, but of that in solid tumors compromises efficacy for the loss of the antigen recognized by the CAR. However, dendritic cell (DC)/tumor fusion vaccines present a spectrum of known or unknown tumor antigens to stimulate T cell expansion and enhanced T cell response. Developing a new strategy of enhanced nanobody-based CAR-T (Nb-CAR-T) cells antitumor activity by DC/tumor fusion vaccines stimulation would provide guidance for more effective CAR-T cell therapies. Methods: Considering the therapeutic potential of nanobody (Nb), we first screened EGFRvIII Nb, then constructed and verified the function of EGFRvIII Nb-CAR-T cells in vitro and in vivo. We further combined DC/tumor fusion vaccines to boost EGFRvIII Nb-CAR-T cells antitumor effect, which was evaluated in vitro Nb-CAR-T cell function and in the tumor-bearing xenograft mouse models. Results: We had for the first time successfully selected EGFRvIII Nb for the generation of the novel EGFRvIII Nb-CAR-T cells. Importantly, our results suggested that DC/tumor fusion vaccines stimulate Nb-CAR-T cells response not only in improving T cell proliferation, T cell activation, cytokine secretion and tumor-specific cytotoxicity in vitro, but also significantly reducing tumor burden, prolonging survival and improving Nb-CAR-T cells infiltration. Conclusions: We have innovatively shown that DC/tumor fusion vaccines significantly enhance the efficacy of Nb-CAR-T cells against solid tumors. This new strategy has provided a promising therapeutic platform for promoting the clinical treatment of CAR-T cells therapy.

2D Ultrathin Iron Doped Bismuth Oxychloride Nanosheets with Rich Oxygen Vacancies for Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) combines ultrasound and sonosensitizers to produce toxic reactive oxygen species (ROS) for cancer cell killing. Due to the high penetration depth of ultrasound (US), SDT breaks the depth penetration barrier of conventional photodynamic therapy for the treatment of deeply seated tumors. A key point to enhance the therapeutic efficiency of SDT is the development of novel sonosensitizers with promoted ability for ROS production. Herein, ultrathin Fe-doped bismuth oxychloride nanosheets with rich oxygen vacancies and bovine serum albumin coating on surface are designed as piezoelectric sonosensitizers (BOC-Fe NSs) for enhanced SDT. The oxygen vacancies of BOC-Fe NSs provide electron trapping sites to promote the separation of e- -h+ from the band structure, which facilitates the ROS production under the ultrasonic waves. The piezoelectric BOC-Fe NSs create a built-in field and the bending bands, further accelerating the ROS generation with US irradiation. Furthermore, BOC-Fe NSs can induce ROS generation by a Fenton reaction catalyzed by Fe ion with endogenous H2 O2 in tumor tissues for chemodynamic therapy. The as-prepared BOC-Fe NSs efficiently inhibited breast cancer cell growth in both in vitro and in vivo tests. The successfully development of BOC-Fe NSs provides a new nano-sonosensitiser option for enhanced SDT for cancer therapy.

Engineering nano-cellulose bio-composites to improve protein delivery for oral vaccination.

Oral vaccine is a non-invasive, ideal way to protect communities from infectious diseases. Effective vaccine delivery systems are required to enhance vaccine absorption in the small intestine and its cellular uptake by immune cells. Here, we constructed alginate/chitosan-coated cellulose nanocrystal (Alg-Chi-CNC) and nanofibril (Alg-Chi-CNF) nanocomposites to enhance ovalbumin (OVA) delivery in the intestine. In vitro mucosal permeation and diffusion and cellular uptake demonstrated that Chi-CNC exhibited better cellular uptake in epithelial and antigen-presenting cells (APCs). In vivo results revealed that alginate/chitosan-coated nanocellulose nanocomposites generated strong systemic and mucosal immune responses. Though the features of functional nano-cellulose composites affected mucus permeation and APC uptakes, in vivo specific-OVA immune responses have not shown significant differences due to the complexity of the small intestine.

The adjacent effect between Gd(III) and Cu(II) in layered double hydroxide nanoparticles synergistically enhances T1-weighted magnetic resonance imaging contrast.

Magnetic resonance imaging (MRI) is one key technology in modern diagnostic medicine. However, the development of high-relaxivity contrast agents with favorable properties for imaging applications remains a challenging task. In this work, dual Gd(III) and Cu(II) doped-layered double hydroxide (GdCu-LDH) nanoparticles show significantly higher longitudinal relaxivity compared with sole-metal-based LDH (Gd-LDH and Cu-LDH) nanoparticles. This relaxation enhancement in GdCu-LDH is also much greater than the simple addition of the relaxivity rate of the two paramagnetic ions in Gd-LDH and Cu-LDH, presumably attributed to synergistic T1 shortening between adjacent Gd(III) and Cu(II) in the LDH host layers (adjacent effect). Moreover, our GdCu-LDH nanoparticles exhibit a pH-ultrasensitive property in MRI performance and show much clearer MR imaging for tumor tissues in mice than Gd-LDH and Cu-LDH at the equivalent doses. Thus, these novel Gd/Cu-co-doped LDH nanoparticles provide higher potential for accurate cancer diagnosis in clinic application. To the best of our knowledge, this is the first report that two paramagnetic metal ions in one nanoparticle synergistically improve the T1-MRI contrast.

"Trojan horse" nanoparticle-delivered cancer cell membrane vaccines to enhance cancer immunotherapy by overcoming immune-escape.

Cancer cell membranes (CCMs) have emerged as advanced cancer treatment vaccines to boost the immune response against cancer and have shown great potential in cancer immunotherapy. However, the CCM vaccine confronts the challenges of a weak and short immune response, ascribed to the immune escape and low accumulation of the CCM in antigen presentation cells (APCs). To overcome these shortcomings, we devised a "Trojan horse" CCM nano-vaccine delivered by layered double hydroxide (LDH) nanoparticles with mannose targeting and bovine serum albumin (BSA) coating to overcome the immune escape challenge, efficiently boosting the immune response to cancer cells. This "Trojan horse" CCM nano-vaccine, named LGCMB, is constructed by assembling the CCM antigen on CpG-LDH (LG), followed by mannose-BSA coating for the APC target and BSA coating to mask immune-escape protein on the CCM. The in vitro cellular uptake and maturation data have clearly shown that the BSA coating strategy with mannose as a "Trojan horse" efficiently targeted APCs (macrophages and DCs) and effectively inhibited the immune escape of the CCM, competently stimulating the APC maturation. Moreover, LGCMB can migrate to the draining lymph nodes (LNs) and trigger tumor-specific CD8+ T cell responses in vivo. As expected, the LGCMB nano-vaccine significantly suppressed tumor growth in vivo, showing great potential as a precision cancer vaccine.

A New Sono-Chemo Sensitizer Overcoming Tumor Hypoxia for Augmented Sono/Chemo-Dynamic Therapy and Robust Immune-Activating Response.

Novel sonosensitizers with intrinsic characteristics for tumor diagnosis, efficient therapy, and tumor microenvironment regulation are appealing in current sonodynamic therapy. Herein, a manganese (Mn)-layered double hydroxide-based defect-rich nanoplatform is presented as a new type of sono-chemo sensitizer, which allows ultrasound to efficiently trigger reactive oxygen species generation for enhanced sono/chemo-dynamic therapy. Moreover, such a nanoplatform is able to relieve tumor hypoxia and achieve augmented singlet oxygen production via catalyzing endogenous H2 O2 into O2 . On top of these actions, the released Mn2+ ions and immune-modulating agent significantly intensify immune activation and reverse the immunosuppressive tumor microenvironment to the immunocompetent one. Consequently, this nanoplatform exhibits excellent anti-tumor efficacy and effectively suppresses both primary and distant tumor growth, demonstrating a new strategy to functionalize nanoparticles as sono-chemo sensitizers for synergistic combination cancer therapy.

Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions.

Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio-nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio-nano interactions and pave the way forward in the development of more effective cancer nanomedicines.

Synthesis and activity-detection of photoswitchable ligands with fipronil to insect.

BACKGROUND: Ionotropic γ-aminobutyric acid (GABA) receptor (GABAR) in an insect is the major inhibitory receptor and is one of the most important targets for insecticides. Due to the high spatiotemporal resolution of GABAR, the photopharmacological ligands acting on it in vertebrates but not insect have been developed. RESULTS: In this study, two types of photochromic ligands (PCLs) including DTFIPs (DTFIP1 and DTFIP2) and ABFIPs (p-, m-, and o-ABFIP) were synthesized by incorporating photoswitch azobenzene or dithienylethene into fipronil (FIP), which is the antagonist of insect GABAR. Their photomodulation was measured by mosquito larval behavior, and their potential action mechanism was explored by the two-electrode voltage clamp (TEVC) technique in vitro. DTFIP1 and m-ABFIP exhibited the most significant difference of insecticidal activity by about 90- and 5-fold to mosquito larvae between non-irradiated and irradiated formation, respectively, and allowed for optical control of mosquito swimming activity. TEVC assay results indicated that m-ABFIP and DTFIP1 enable optical control over the homomeric LsRDL-type GABAR, which is achieved by regulating the chloride channel of resistance to dieldrin (RDL)-type GABAR by photoisomerization. CONCLUSION: Our results suggested that PCLs synthesized from fipronil provide an alternative and precise tool for studying insect ionotropic GABARs and GABA-dependent behavior. © 2022 Society of Chemical Industry.

Progress in oral insulin delivery by PLGA nanoparticles for the management of diabetes.

Currently, the only practical way to treat type 1 and advanced insulin-dependent type 2 diabetes mellitus (T1/2DM) is the frequent subcutaneous injection of insulin, which is significantly different physiologically from endogenous insulin secretion from pancreatic islets and can lead to hyperinsulinemia, pain, and infection in patients with poor compliance. Hence, oral insulin delivery has been actively pursued to revolutionize the treatment of insulin-dependent diabetes. In this review, we provide an overview of recent progress in developing poly(lactic co-glycolic acid) (PLGA) nanoparticles (NPs) for oral insulin delivery. Different strategies for insulin-loaded PLGA NPs to achieve normoglycemic effects are discussed. Finally, challenges and future perspectives of PLGA NPs for oral insulin delivery are put forward.

O2-Supplying Nanozymes Alleviate Hypoxia and Deplete Lactate to Eliminate Tumors and Activate Antitumor Immunity.

Direct hypoxia alleviation and lactate depletion in the tumor microenvironment (TME) are promising for effective cancer therapy but still very challenging. To address this challenge, the current research directly reshapes the TME for inhibiting tumor growth and activating the antitumor immunity using a drug-free nanozyme. Herein, the acid-sensitive nanozymes were constructed based on peroxidized layered double hydroxide nanoparticles for O2 self-supply and self-boosted lactate depletion. The coloading of partially cross-linked catalase and lactate oxidase enabled the acid-sensitive nanozymes to promote three reactions, that is, (1) H2O2 generation from MgO2 hydrolysis (30% at pH 7.4 vs 63% at pH 6.0 in 8 h); (2) O2 generation from H2O2 (12% at pH 7.4 vs 21% at pH 6.0 in 2 h); and (3) lactate depletion by in situ generated O2 (50% under hypoxia vs 75% under normoxia in 24 h in vitro) in parallel or tandem. These promoted reactions together efficiently induced colon cancer cell apoptosis under the hypoxic conditions, significantly inhibited tumor growth (>95%), and suppressed distant tumor growth upon seven administrations in every 3 days and moreover transformed the immunosuppressive tumor into "hot" one in the colon tumor-bearing mouse model. This is the first example for a nanozyme that supplies sufficient O2 for hypoxia relief and lactate depletion, thus providing a new insight into drug-free nanomaterial-mediated TME-targeted cancer therapy.

Inhibition of colon cancer K-RasG13D mutation reduces cancer cell proliferation but promotes stemness and inflammation via RAS/ERK pathway.

K-Ras is a well-studied oncogene, and its mutation is frequently found in epithelial cancers like pancreas, lung, and colorectal cancers. Cancer cells harboring K-Ras mutations are difficult to treat due to the drug resistance and metastasis properties. Cancer stem cells (CSCs) are believed the major cause of chemotherapeutic resistance and responsible for tumor recurrence and metastasis. But how K-Ras mutation affects CSCs and inflammation is not clear. Here, we compared two colon cancer cell lines, HCT-116 and HT-29, with the former being K-RasG13D mutant and the latter being wildtype. We found that HCT-116 cells treated with a K-Ras mutation inhibitor S7333 formed significantly more tumor spheroids than the untreated control, while the wild type of HT-29 cells remained unchanged. However, the size of tumor spheroids was smaller than the untreated controls, indicating their proliferation was suppressed after S7333 treatment. Consistent with this, the expressions of stem genes Lgr5 and CD133 significantly increased and the expression of self-renewal gene TGF-ß1 also increased. The flow cytometry analysis indicated that the expression of stem surface marker CD133 increased in the treated HCT-116 cells. To understand the pathway through which the G13D mutation induced the effects, we studied both RAS/ERK and PI3K/Akt pathways using specific inhibitors SCH772984 and BEZ235. The results indicated that RAS/ERK rather than PI3K/Akt pathway was involved. As CSCs play the initial role in cancer development and the inflammation is a vital step during tumor initiation, we analyzed the correlation between increased stemness and inflammation. We found a close correlation of increased Lgr5 and CD133 with proinflammatory factors like IL-17, IL-22, and IL-23. Together, our findings suggest that K-RasG13D mutation promotes cancer cell growth but decreases cancer stemness and inflammation thus tumorigenesis and metastasis potential in colon cancer. Inhibition of this mutation reverses the process. Therefore, care needs be taken when employing targeted therapies to K-RasG13D mutations in clinics.