Oral Administration Properties Evaluation of Three Milk-Derived Extracellular Vesicles Based on Ultracentrifugation Extraction Methods.

Milk-derived extracellular vesicles (M-EVs) are low-cost, can be prepared in large quantities, and can cross the gastrointestinal barrier for oral administration. However, the composition of milk is complex, and M-EVs obtained by different extraction methods may affect their oral delivery. Based on this, a new method for extracting M-EVs based on cryogenic freezing treatment (Cryo-M-EVs) is proposed and compared with the previously reported acetic acid treatment (Acid-M-EVs) method and the conventional ultracentrifugation method (Ulltr-M-EVs). The new method simplifies the pretreatment step and achieves 25-fold and twofold higher yields than Acid-M-EVs and Ulltr-M-EVs. And it is interesting to note that Cryo-M-EVs and Acid-M-EVs have higher cellular uptake efficiency, and Cryo-M-EVs present the best transepithelial transport effect. After oral administration of the three M-EVs extracted by three methods in mice, Cryo-M-EVs effectively successfully cross the gastrointestinal barrier and achieve hepatic accumulation, whereas Acid-M-EVs and Ultr-M-EVs mostly reside in the intestine. The M-EVs obtained by the three extraction methods show a favorable safety profile at the cellular as well as animal level. Therefore, when M-EVs obtained by different extraction methods are used for oral drug delivery, their accumulation properties at different sites can be utilized to better deal with different diseases.

Oxygen-Bridged Cu Binuclear Sites for Efficient Electrocatalytic CO2 Reduction to Ethanol at Ultralow Overpotential.

Electrocatalytic CO2 reduction (CO2RR) to alcohols offers a promising strategy for converting waste CO2 into valuable fuels/chemicals but usually requires large overpotentials. Herein, we report a catalyst comprising unique oxygen-bridged Cu binuclear sites (CuOCu-N4) with a Cu···Cu distance of 3.0-3.1 Å and concomitant conventional Cu-N4 mononuclear sites on hierarchical nitrogen-doped carbon nanocages (hNCNCs). The catalyst exhibits a state-of-the-art low overpotential of 0.19 V (versus reversible hydrogen electrode) for ethanol and an outstanding ethanol Faradaic efficiency of 56.3% at an ultralow potential of -0.30 V, with high-stable Cu active-site structures during the CO2RR as confirmed by operando X-ray adsorption fine structure characterization. Theoretical simulations reveal that CuOCu-N4 binuclear sites greatly enhance the C-C coupling at low potentials, while Cu-N4 mononuclear sites and the hNCNC support increase the local CO concentration and ethanol production on CuOCu-N4. This study provides a convenient approach to advanced Cu binuclear site catalysts for CO2RR to ethanol with a deep understanding of the mechanism.

Constructing Gold Single-Atom Catalysts on Hierarchical Nitrogen-Doped Carbon Nanocages for Carbon Dioxide Electroreduction to Syngas.

Precious-metal single-atom catalysts (SACs), featured by high metal utilization and unique coordination structure for catalysis, demonstrate distinctive performances in the fields of heterogeneous and electrochemical catalysis. Herein, gold SACs are constructed on hierarchical nitrogen-doped carbon nanocages (hNCNC) via a simple impregnation-drying process and first exploited for electrocatalytic carbon dioxide reduction reaction (CO2RR) to produce syngas. The as-constructed Au SAC exhibits the high mass activity of 3319 A g-1 Au at -1.0 V (vs reversible hydrogen electrode, RHE), much superior to the Au nanoparticles supported on hNCNC. The ratio of H2/CO can be conveniently regulated in the range of 0.4-2.2 by changing the applied potential. Theoretical study indicates such a potential-dependent H2/CO ratio is attributed to the different responses of HER and CO2RR on Au single-atom sites coordinating with one N atom at the edges of micropores across the nanocage shells. The catalytic mechanism of the Au active sites is associated with the smooth switch between twofold and fourfold coordination during CO2RR, which much decreases the free energy changes of the rate-determining steps and promotes the reaction activity.

Hierarchical Dual Single-Atom Catalysts with Coupled CoN4 and NiN4 Moieties for Industrial-Level CO2 Electroreduction to Syngas.

Renewable-driven electrochemical CO2 reduction reaction (CO2RR) to syngas is an encouraging alternative strategy to traditional fossil fuel-based syngas production, and the development of industrial-level electrocatalysts is vital. Herein, based on theoretical optimization of metal species, hierarchical CoxNi1-x-N-C dual single-atom catalyst (DSAC) with individual NiN4 (CO preferential) and CoN4 (H2 preferential) moieties was constructed by a two-step pyrolysis route. The Co0.5Ni0.5-N-C exhibits a stable CO Faradaic efficiency of 50 ± 5% and an industrial-level current density of 101-365 mA cm-2 in an ultrawide potential window of -0.5 to -1.1 V. The CO/H2 ratio of syngas can be conveniently tuned by regulating the Co/Ni ratio. The coupled effect of NiN4 and CoN4 moieties under a local high-pH microenvironment is responsible for the regulation of the CO/H2 selectivity and yield for the CoxNi1-x-N-C catalyst, which is not present in the mixed Co-N-C and Ni-N-C catalyst. This study provides a promising DSAC strategy for achieving industrial-level syngas production via CO2RR.

High-Dispersive Pd Nanoparticles on Hierarchical N-Doped Carbon Nanocages to Boost Electrochemical CO2 Reduction to Formate at Low Potential.

Electrochemical CO2 reduction reaction (CO2 RR) to value-added chemicals/fuels is an effective strategy to achieve the carbon neutral. Palladium is the only metal to selectively produce formate via CO2 RR at near-zero potentials. To reduce cost and improve activity, the high-dispersive Pd nanoparticles on hierarchical N-doped carbon nanocages (Pd/hNCNCs) are constructed by regulating pH in microwave-assisted ethylene glycol reduction. The optimal catalyst exhibits high formate Faradaic efficiency of >95% within -0.05-0.30 V and delivers an ultrahigh formate partial current density of 10.3 mA cm-2 at the low potential of -0.25 V. The high performance of Pd/hNCNCs is attributed to the small size of uniform Pd nanoparticles, the optimized intermediates adsorption/desorption on modified Pd by N-doped support, and the promoted mass/charge transfer kinetics arising from the hierarchical structure of hNCNCs. This study sheds light on the rational design of high-efficient electrocatalysts for advanced energy conversion.

Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery.

Nanoparticle-based therapeutics represent potential strategies for treating atherosclerosis; however, the complex plaque microenvironment poses a barrier for nanoparticles to target the dysfunctional cells. Here, we report reactive oxygen species (ROS)-responsive and size-reducible nanoassemblies, formed by multivalent host-guest interactions between ß-cyclodextrins (ß-CD)-anchored discoidal recombinant high-density lipoprotein (NP3 ST) and hyaluronic acid-ferrocene (HA-Fc) conjugates. The HA-Fc/NP3 ST nanoassemblies have extended blood circulation time, specifically accumulate in atherosclerotic plaque mediated by the HA receptors CD44 highly expressed in injured endothelium, rapidly disassemble in response to excess ROS in the intimal and release smaller NP3 ST, allowing for further plaque penetration, macrophage-targeted cholesterol efflux and drug delivery. In vivo pharmacodynamicses in atherosclerotic mice shows that HA-Fc/NP3 ST reduces plaque size by 53%, plaque lipid deposition by 63%, plaque macrophage content by 62% and local inflammatory factor level by 64% compared to the saline group. Meanwhile, HA-Fc/NP3 ST alleviates systemic inflammation characterized by reduced serum inflammatory factor levels. Collectively, HA-Fc/NP3 ST nanoassemblies with ROS-responsive and size-reducible properties exhibit a deeper penetration in atherosclerotic plaque and enhanced macrophage targeting ability, thus exerting effective cholesterol efflux and drug delivery for atherosclerosis therapy.

Lipid-Based Intelligent Vehicle Capabilitized with Physical and Physiological Activation.

Intelligent drug delivery system based on "stimulus-response" mode emerging a promising perspective in next generation lipid-based nanoparticle. Here, we classify signal sources into physical and physiological stimulation according to their origin. The physical signals include temperature, ultrasound, and electromagnetic wave, while physiological signals involve pH, redox condition, and associated proteins. We first summarize external physical response from three main points about efficiency, particle state, and on-demand release. Afterwards, we describe how to design drug delivery using the physiological environment in vivo and present different current application methods. Lastly, we draw a vision of possible future development.

Anchoring ß-CD on simvastatin-loaded rHDL for selective cholesterol crystals dissolution and enhanced anti-inflammatory effects in macrophage/foam cells.

Macrophage/foam cells and cholesterol crystals (CCs) have been regarded as the central triggers of maladaptive inflammation in atherosclerotic plaque. Despite the tremendous progress of recombinant high-density lipoprotein (rHDL) serving for targeted drug delivery to alleviate inflammation in macrophage/foam cells, the active attempt to modulate/improve its CCs dissolution capacity remains poorly explored. The untreated CCs can seriously aggravate inflammation and threaten plaque stability. Based on the superb ability of ß-cyclodextrin (ß-CD) to bind CCs and promote cholesterol efflux, simvastatin-loaded discoidal-rHDL (ST-d-rHDL) anchored with ß-CD (ßCD-ST-d-rHDL) was constructed. We verified that ßCD-ST-d-rHDL specifically bound and dissolved CCs extracellularly and intracellularly. Furthermore, anchoring ß-CD onto the surface of ST-d-rHDL enhanced its cholesterol removal ability in RAW 264.7 cell-derived foam cells characterized by accelerated cholesterol efflux, reduced intracellular lipid deposition, and improved cell membrane fluidity/permeability. Finally, ßCD-ST-d-rHDL exerted efficient drug delivery and effective anti-inflammatory effects in macrophage/foam cells. Collectively, anchoring ß-CD onto the surface of ST-d-rHDL for selective CCs dissolution, accelerated cholesterol efflux, and improved drug delivery represents an effective strategy to enhance anti-inflammatory effects for the therapy of atherosclerosis.

A Fibrin Site-Specific Nanoprobe for Imaging Fibrin-Rich Thrombi and Preventing Thrombus Formation in Venous Vessels.

Venous thromboembolism (VTE) is a prevalent public health issue worldwide. Before treatment, spatiotemporally accurate thrombus detection is essential. However, with the currently available imaging technologies, this is challenging. Herein, the development of a novel fibrin-specific nanoprobe (NP) based on the conjugation of poly(lactic-co-glycolic acid) with the pentapeptide Cys-Arg-Glu-Lys-Ala (CREKA) for selective and semiquantitative imaging in vivo is presented. By integrating Fe3 O4 and NIR fluorochrome (IR780), the NP can function as a highly sensitive sensor for the direct analysis of thrombi in vivo. The fibrin-specific NP distinguishes fibrin-rich thrombi from collagen-rich or erythrocyte-rich thrombi, which can be beneficial for future individually tailored therapeutic strategy. Furthermore, loading NPs with the ketotifen fumarate results in mast cell degranulation inhibition, and hence, NPs can prevent thrombosis without the risk of excessive bleeding. Thus, the use of fibrin-specific NPs may serve as a safe alternative approach for the detection and prevention of VTEs in susceptible populations in the future.

Correction: Supramolecular copolymer modified statin-loaded discoidal rHDLs for atherosclerotic anti-inflammatory therapy by cholesterol efflux and M2 macrophage polarization.

Correction for 'Supramolecular copolymer modified statin-loaded discoidal rHDLs for atherosclerotic anti-inflammatory therapy by cholesterol efflux and M2 macrophage polarization' by Qiqi Zhang et al., Biomater. Sci., 2021, 9, 6153-6168, DOI: 10.1039/D1BM00610J.

Nanomaterials with changeable physicochemical property for boosting cancer immunotherapy.

The past decade has witnessed a great progress in cancer immunotherapy with the sequential approvals of therapeutic cancer vaccine, immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapy. However, some hurdles still remain to the wide implementation of cancer immunotherapy, including low immune response, complex tumor heterogeneity, off-target immunotoxicity, poor solid tumor infiltration, and immune evasion-induced treatment tolerance. Owing to changeable physicochemical properties in response to endogenous or exogenous stimuli, nanomaterials hold the remarkable potential in incorporation of multiple agents, efficient biological barrier penetration, precise immunomodulator delivery, and controllable content release for boosting cancer immunotherapy. Herein, we review the recent advances in nanomaterials with changeable physicochemical property (NCPP) to develop cancer vaccine, remold tumor microenvironment and evoke direct T cell activation. Besides, we provide our outlook on this emerging field at the intersection of NCPP design and cancer immunotherapy.

Supramolecular copolymer modified statin-loaded discoidal rHDLs for atherosclerotic anti-inflammatory therapy by cholesterol efflux and M2 macrophage polarization.

Foam cells with the pro-inflammatory macrophage phenotype (M1) play an essential role in atherosclerosis progression. Either cellular cholesterol removal or drug intervention was reported to polarize M1 into the anti-inflammatory phenotype (M2) for atherosclerosis regression. These might be realized simultaneously by drug-loaded discoidal reconstituted high-density lipoproteins (d-rHDLs) with the functions of cellular cholesterol efflux and targeted drug delivery on macrophages. However, cholesterol reception can drive the remodelling of d-rHDLs, which serves to release drugs specifically in the atherosclerotic plaque but might incur premature drug leakage in blood circulation. Given that, the proposed strategy is to inhibit the remodelling behaviour of the carrier in blood circulation and responsively accelerate it under the atherosclerotic microenvironmental stimulus. Herein, atorvastatin calcium-loaded d-rHDL was modified by a PEGylated ferrocene/ß-cyclodextrin supramolecular copolymer (PF/TC) to construct ROS-responsive PF/TC-AT-d-rHDL, which is expected to possess plasma stability and biosafety as well as triggered drug release by cholesterol efflux promotion. As a result, PF/TC-AT-d-rHDL could responsively dissemble into ß-cyclodextrin modified AT-d-rHDL under the ROS-triggered dissociation of PF/TC, therefore exhibiting increased cholesterol efflux from the cholesterol donor and drug release through the remodelling behaviour of the carrier in vitro. Moreover, PF/TC-AT-d-rHDL enhanced cellular cholesterol removal in foam cells after response to ROS, inhibiting intracellular lipid deposition compared with other d-rHDL carriers. Interestingly, cellular drug uptake was significantly promoted upon cellular cholesterol removal by restoring the permeability and fluidity of foam cell membranes as indicated by flow cytometry and fluorescence polarization analysis, respectively. Importantly, compared with untreated foam cells, PF/TC-AT-d-rHDL obviously increased the ratio of M2/M1 by 6.3-fold, which was even higher than the effect of PF/TC-d-rHDL (3.4-fold) and free drugs (1.9-fold), revealing that PF/TC-AT-d-rHDL synergistically promoted the M2 polarization of macrophages. Accordingly, PF/TC-AT-d-rHDL boosted the secretion of anti-inflammatory cytokines and inhibited that of inflammatory cytokines. Collectively, PF/TC-AT-d-rHDL exerted synergistic M2 polarization effects on foam cells for atherosclerotic immunomodulatory therapy via responsively mediating cholesterol efflux and delivering drugs.

PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells.

Glioblastoma (GBM) is the most common type of primary central nervous system tumor in adults, which has high mortality and morbidity rates, and short survival time, namely <15 months after the diagnosis and application of standard therapy, which includes surgery, radiation therapy and chemotherapy; thus, novel therapeutic strategies are imperative. The activation of the PI3K/AKT signaling pathway plays an important role in GBM. In the present study, U87 and U251 GBM cells were treated with the PI3K/mTORC1/2 inhibitor PQR309, and its effect on glioma cells was investigated. Cell Counting Kit­8 assay, 5­ethynyl­2'­deoxyuridine and colony formation assays revealed dose­ and time­dependent cytotoxicity in glioma cells that were treated with PQR309. Flow cytometry and western blotting revealed that PQR309 can significantly induce tumor cell apoptosis and arrest the cell cycle in the G1 phase. Furthermore, the expression levels of AKT, phosphorylated (p)­AKT, Bcl­2, Bcl­xL, Bad, Bax, cyclin D1, cleaved caspase­3, MMP­9 and MMP­2 were altered. In addition, the migration and invasion of glioma cells, as detected by wound healing, migration and Transwell invasion assays, exhibited a marked suppression after treating the cells with PQR309. These results indicated that PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells. The present study provides evidence supportive of further development of PQR309 for adjuvant therapy of GBM.

Correlation of photocatalytic bactericidal effect and organic matter degradation of TiO2. Part I: observation of phenomena.

This study aims to investigate the correlation of the photocatalytic oxidation effect of decomposing organic matter and inactivating bacteria using two different TiO2 materials: a Degussa P25 powder film and a commercial TiO2 thin film. The destructed organic matter was formaldehyde and the test bacterium was E. coli (JM 109 strain). The decomposition tests and the bactericidal tests were carried out in a plate reactor and on the TiO2 surface, respectively. Observations indicate that there exists an apparent correlation between the two photocatalytic processes of decomposing formaldehyde and inactivating E. coli. However, it is essential to distinguish the exact driver for microbe inactivation, in which both UV light irradiation and reactive oxygen species reaction are directfactors of disinfection, and for organic matter, in which only reactive oxygen species reaction contributes to degradation. Observations from this study would make it possible to use analogy as a potential method to evaluate the antimicrobial effect based on the organic compound degradation effect, whereby the latter is much easier to measure quantitatively.