Bioorthogonal "Click and Release" Reaction-Triggered Aggregation of Gold Nanoparticles Combined with Released Lonidamine for Enhanced Cancer Photothermal Therapy.

Cancer has been the most deadly disease, and 13 million cancer casualties are estimated to occur each year by 2030. Gold nanoparticles (AuNPs)-based photothermal therapy (PTT) has attracted great interest due to its high spatiotemporal controllability and noninvasiveness. Due to the trade-off between particle size and photothermal efficiency of AuNPs, rational design is needed to realize aggregation of AuNPs into larger particles with desirable NIR adsorption in tumor site. Exploiting the bioorthogonal "Click and Release" (BCR) reaction between iminosydnone and cycloalkyne, aggregation of AuNPs can be achieved and attractively accompanied by the release of chemotherapeutic drug purposed to photothermal synergizing. We synthesize iminosydnone-lonidamine (ImLND) as a prodrug and choose dibenzocyclooctyne (DBCO) as the trigger of BCR reaction. A PEGylated AuNPs-based two-component nanoplatform consisting of prodrug-loaded AuNPs-ImLND and tumor-targeting peptide RGD-conjugated AuNPs-DBCO-RGD is designed. In the therapeutic regimen, AuNPs-DBCO-RGD are intravenously injected first for tumor-specific enrichment and retention. Once the arrival of AuNPs-ImLND injected later at tumor site, highly photothermally active nanoaggregates of AuNPs are formed via the BCR reaction between ImLND and DBCO. The simultaneous release of lonidamine further enhanced the therapeutic performance by sensitizing cancer cells to PTT.

A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-Mediated Synergistic Antitumor Metabolic and Immune Therapy.

Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) are constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibits glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells causes self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which has the effects of converting enemies into friends. Meanwhile, PMIR exactly offsets the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together cause immunogenic cell death of tumor cells and relieve PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposes a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments.

Engineering metal-based hydrogel-mediated tertiary lymphoid structure formation via activation of the STING pathway for enhanced immunotherapy.

Tertiary lymphoid structures (TLSs) primarily constructed by multiple immune cells can effectively enhance tumor immune responses, but expediting the formation of TLSs is still an enormous challenge. Herein, a stimulator of interferon gene (STING)-activating hydrogel (ZCCG) was elaborately developed by coordinating Zn2+ with 4,5-imidazole dicarboxylic acid, and simultaneously integrating chitosan (a stimulant of STING pathway activation) and CpG (an agonist of toll-like receptor 9, TLR9) for initiating and activating cGAS-STING and TLR9 pathway-mediated immunotherapy. Moreover, the dual-pathway activation could effectively enhance the infiltration of immune cells and the expression of lymphocyte-recruiting chemokines in the tumor microenvironment (TME), thereby promoting the formation of TLSs and further strengthening tumoricidal immunity. Local administration of the hydrogel could prime systemic immune responses and long-term immune memory and improve the therapeutic effects of programmed death-1 antibody (αPD-1) to inhibit tumor progression, metastasis and recurrence. The engineered hydrogel lays the foundation for tumor immunotherapy strategies based on the enhanced formation of TLSs via the activation of the cGAS-STING and TLR9 pathways.

Hybrid Vesicles Based on Autologous Tumor Cell Membrane and Bacterial Outer Membrane To Enhance Innate Immune Response and Personalized Tumor Immunotherapy.

Tumor heterogeneity, often leading to metastasis, limits the development of tumor therapy. Personalized therapy is promising to address tumor heterogeneity. Here, a vesicle system was designed to enhance innate immune response and amplify personalized immunotherapy. Briefly, the bacterial outer membrane vesicle (OMV) was hybridized with the cell membrane originated from the tumor (mT) to form new functional vesicles (mTOMV). In vitro experiments revealed that the mTOMV strengthened the activation of innate immune cells and increased the specific lysis ability of T cells in homogeneous tumors. In vivo experiments showed that the mTOMV effectively accumulated in inguinal lymph nodes, then inhibited lung metastasis. Besides, the mTOMV evoked adaptive immune response in homologous tumor rather than the heterogeneous tumor, reversibly demonstrating the effects of personalized immunotherapy. The functions to inhibit tumor growth and metastasis accompanying good biocompatibility and simple preparation procedure of mTOMV provide their great potential for clinical applications.

Non-depleting reformation of immunosuppressive myeloid cells to broaden the application of anti-PD therapy.

Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and presenting obstacles in immunotherapy. Herein, we report a nano-educator (NE) that when loaded with all trans retinoic acid (ATRA) and anti-PD-1 antibodies (aPD-1) instructs myeloid cells to assist T cells towards revitalizing anti-PD-1 therapy. In vivo, ATRA converts myeloid-derived suppressor cells (MDSCs) into dendritic cells (DCs), which are essential for anti-PD-1 therapy, while intervening in the polarization of macrophages. Furthermore, aPD-1-armed T cells reboot anti-tumor immunity after suppression relief, which exposes tumor-specific antigens and in turn promotes the maturation of transformed DCs. The nano-platform provides shelter for vulnerable immunomodulatory agents and durable drug release to stimulate intensive immune modulation. We established three types of tumor-bearing mice models with different myeloid cell contents to show the spatiotemporal complementarity of ATRA and aPD-1. The NE re-educates the tumor's guard to assist T cells in enhanced immunotherapy, broadening the application of aPD-1 in the treatment of anti-PD-1-resistant tumors.

The Outlook of the Development of Innovative Products from Biocompatible Natural Spider Silk in the Beauty Thread-Lifting Industry.

Embedding thread lift rhytidectomy, also known as "thread lifting" in China, with the natures of simple operation, less trauma and quick recovery, is progressively used in clinical practice as a new technology of face lifting. Herewith, a brief introduction of the previous advances of thread lifting techniques and materials in the facial beauty industry, combined with the discussion on various types of sutures, common complications, and the site of actions were provided. The main limitations of present thread lifting material include: (1) the use of non-absorbable sutures is liable to cause allergies and a series of complications; (2) the absorbable sutures are easily degradation, and people need to reshape in a relatively short period. Therefore, the high biocompatible spider silk was proposed as a novel material of thread lifting suture and related devices, the advantages and preliminary achievements on spider silk were also addressed.

Multifunctional peptides for tumor therapy.

Controlled nano-systems for drug delivery are designed to deliver therapeutical drugs to desirable sites on demand. Due to the diverse physiological functions of peptides, it is reasonable to introduce peptides into anti-tumor nano-system. The integration of peptides into nanomaterials has complementary advantages, which not only avoids the rapid degradation of peptides in vivo, but also improves the intelligence and functionality of the nano-system. We summarized the functional peptides with targeting and stimulus-responsive properties, and the present review outlined the most relevant and recent developed peptide-based multifunctional nanomaterials for tumor therapy.

Near-Infrared Light Responsive Nanoreactor for Simultaneous Tumor Photothermal Therapy and Carbon Monoxide-Mediated Anti-Inflammation.

Photothermal therapy (PTT) is an effective treatment modality with high selectivity for tumor suppression. However, the inflammatory responses caused by PTT may lead to adverse reactions including tumor recurrence and therapeutic resistance, which are regarded as major problems for PTT. Here, a near-infrared (NIR) light-responsive nanoreactor (P@DW/BC) is fabricated to simultaneously realize tumor PTT and carbon monoxide (CO)-mediated anti-inflammatory therapy. Defective tungsten oxide (WO3) nanosheets (DW NSs) are decorated with bicarbonate (BC) via ferric ion-mediated coordination and then modified with polyethylene glycol (PEG) on the surface to fabricate PEG@DW/BC or P@DW/BC nanosheets. Upon 808 nm NIR laser irradiation, the DW content in P@DW/BC can serve as not only a photothermal agent to realize photothermal conversion but also a photocatalyst to convert carbon dioxide (CO2) to CO. In particular, the generated heat can also trigger the decomposition of BC to produce CO2 near the NSs, thus enhancing the photocatalytic CO generation. Benefiting from the efficient hyperthermia and CO generation under single NIR laser irradiation, P@DW/BC can realize effective thermal ablation of tumor and simultaneous inhibition of PTT-induced inflammation.

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors.

Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)-camouflaged hollow MnO2 (HMnO2 ) catalytic nanosystem embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long-circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O2 , which can be produced during the decomposition of endogenous H2 O2 catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti-PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.

A Versatile Carbon Monoxide Nanogenerator for Enhanced Tumor Therapy and Anti-Inflammation.

Carbon monoxide (CO) is regarded as a potential therapeutic agent with multiple beneficial functions for biomedical applications. In this study, a versatile CO nanogenerator (designated as PPOSD) was fabricated and developed for tumor therapy and anti-inflammation. Partially oxidized tin disulfide (SnS2) nanosheets (POS NSs) were decorated with a tumor-targeting polymer (polyethylene glycol-cyclo(Asp-d-Phe-Lys-Arg-Gly), PEG-cRGD), followed by the loading of chemotherapeutic drug doxorubicin (DOX) to prepare polymer@POS@DOX, or PPOSD. After injected intravenously, PPOSD could selectively accumulate in tumor tissue via the cRGD-mediated tumor recognition. Upon 561 nm laser irradiation, the POS moiety in PPOSD can photoreduce CO2 to CO, which significantly sensitized the chemotherapeutic effect of DOX. The POS in PPOSD can also act as a photothermal agent for effective photothermal therapy (PTT) of the tumor upon 808 nm laser irradiation. Furthermore, the generated CO can simultaneously decrease the inflammatory reaction caused by PTT. Blood analysis and hematoxylin-eosin staining of major organs showed that no obvious systemic toxicity was induced after the treatment, suggesting good biosafety of PPOSD. This versatile CO nanogenerator will find great potential for both enhanced tumor inhibition and anti-inflammation.

Artificial Super Neutrophils for Inflammation Targeting and HClO Generation against Tumors and Infections.

Neutrophils are powerful effector leukocytes that play an important role in innate immune systems for opposing tumor progression and ameliorating pathogen infections. Inspired by their distinct functions against tumors and infections, the artificial "super neutrophils" are proposed with excellent inflammation targeting and hypochlorous acid (HClO) generation characteristics for targeting and eliminating malignant tumor cells and pathogens. The "super neutrophils" are fabricated by embedding glucose oxidase (GOx) and chloroperoxidase (CPO) into zeolitic imidazolate framework-8 (ZIF-8) for HClO generation via enzymatic cascades, and then encapsulating them with the neutrophil membrane (NM) for inflammation targeting. In vitro and in vivo results indicate that these artificial "super neutrophils" can generate seven times higher reactive HClO than the natural neutrophils for eradicating tumors and infections. The "super neutrophils" demonstrated here with easy fabrication and good neutrophil-mimicking property exhibit great potential for biomedical applications.

A modular theranostic platform for tumor therapy and its metabolic studies.

Theranostic systems are able to detect and treat diseases with only one procedure, thus greatly lessening the pain of patients. Since each patient's disease can be considered as a new clinical subtype, it is essential to develop theranostic nanomaterials with changeable functions for personal treatment. In this work, a novel modular theranostic platform was designed to control the stimuli-responsive drug release. As a patch board, mesoporous silica nanoparticles (MSNs) were functionalized with a linear pH-responsive benzimidazole (Bz)-polyethylene glycol (PEG) chain containing a redox-responsive ferrocene (Fc) oxide stopper at the end. As the plug, the ß-CD ring was initially located at the Bz position. In an acidic tumor microenvironment, the pH sensitive Bz was protonated and the complex formation constant between Bz and ß-CD decreased. At the same time, the complex formation constant between Fc and ß-CD increased remarkably. As a result, the ß-CD ring would depart from the nanoparticle surface to the Fc position at pH 6.2 & 10 mM GSH, physically causing an "And" logic gate type drug release. Herein, a "plug and play" method was used to achieve changeable functions with only one platform. By plugging modified ß-CD into the patch board, theranostic systems with changeable functions can be achieved easily.

Diblock Polymer Brush (PHEAA- b-PFMA): Microphase Separation Behavior and Anti-Protein Adsorption Performance.

In this paper, a series of amphiphilic diblock polymers of poly(hydroxyethylacrylamide)- b-poly(1H,1H-pentafluoropropyl methacrylate) (PHEAA- b-PFMA) were grafted from silicon wafer via surface-initiated atom transfer radical polymerization (SI-ATRP). Surface wettability and chemical compositions of the modified surfaces were characterized by contact angle goniometer and X-ray photoelectron spectroscopy (XPS) respectively. Molecular weight and polydispersity of each block were measured using gel permeation chromatography (GPC). The topography and the microphase separation behavior of PHEAA- b-PFMA surfaces were investigated by atomic force microscope (AFM). The results show that only when the grafting density (σ) and thickness of PHEAA brush were in the range of 0.9-1.3 (chain/nm2) and 6.6-15.1 nm, respectively, and the ratio of PFMA/PHEAA varied from 89/42 to 89/94, could the diblock copolymer phase separate into nanostructures. Further, the antiprotein adsorption performance of the modified surfaces against BSA, fibrinogen, and lysozyme was studied. The results indicated the modified surfaces could reduce the protein adsorption compared to the pristine silicon wafer. For Fibrinogen, the antiadsorption effect of PHEAA- b-PFMA-modified surfaces with microphase segregation was better than that of corresponding PHEAA modified surfaces. The results provide further evidence that surface composition and microphase segregation of fluorinated moieties of block copolymer brushes significantly impact protein adsorption behaviors.

A highly efficient bactericidal surface based on the co-capture function and photodynamic sterilization.

Bacterial infection is posing a great threat to human life, and constructing a platform to capture or kill the bacteria attached on a material surface is of particular significance. Herein, a nano-topographic material surface (SiNW-p-ppix@CDm) has been successfully synthesized based on silicon nanowire (SiNW) arrays modified with a random copolymer, which was decorated with photosensitive protoporphyrin IX (ppix) and ß-CD-mannose7 (CDm). The as-prepared surface exhibits a highly efficient bacterial capture, which is based on the co-capture function between the SiNW topographic surface and the bacterial attachment molecule CDm, and sterilization of ppix under irradiation by 630 nm light. The Gram-negative bacterium Escherichia coli (E. coli) was adopted to evaluate the surface bactericidal efficiency. Finally, the killing efficiency can be proved to be 96.7% from fluorescence microscopy after staining with the live/dead bacterial viability kit. The reason for sterilization is that the bacterial cell wall had been split by the reactive oxygen species (ROS), which could be demonstrated via scanning electronic microscopy (SEM). This functional substrate could be used for bacterial enrichment apparatus such as used in water quality monitoring, and even in constructing clinical antibacterial materials.

Water-soluble photoluminescent fullerene capped mesoporous silica for pH-responsive drug delivery and bioimaging.

In this paper, a biocompatible and water-soluble fluorescent fullerene (C60-TEG-COOH) coated mesoporous silica nanoparticle (MSN) was successfully fabricated for pH-sensitive drug release and fluorescent cell imaging. The MSN was first reacted with 3-aminopropyltriethoxysilane to obtain an amino-modified MSN, and then the water-soluble C60 with a carboxyl group was used to cover the surface of the MSN through electrostatic interaction with the amino group in PBS solution (pH = 7.4). The release of doxorubicin hydrochloride (DOX) could be triggered under a mild acidic environment (lysosome, pH = 5.0) due to the protonation of C60-TEG-COO-, which induced the dissociation of the C60-TEG-COOH modified MSN (MSN@C60). Furthermore, the uptake of nanoparticles by cells could be tracked because of the green fluorescent property of the C60-modified MSN. In an in vitro study, the prepared materials showed excellent biocompatibility and the DOX-loaded nanocarrier exhibited efficient anticancer ability. This work offered a simple method for designing a simultaneous pH-responsive drug delivery and bioimaging system.

PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment.

This work presented a sustained release system of simvastatin (SIM) based on the mesoporous hydroxyapatite (MHA) capped with poly(N-isopropylacrylamide) (PNIPAAM). The MHA was prepared by using cetyltrimethylammonium bromide (CTAB) as a template and the modified PNIPAAM layer on the surface of MHA was fabricated through surface-initiated atom transfer radical polymerization (SI-ATRP). The SIM loaded MHA-PNIPAAM showed a sustained release of SIM at 37 °C over 16 days. The bone marrow mesenchymal stem cell (BMSC) proliferation was assessed by cell counting kit-8 (CCK-8) assay, and the osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity and Alizarin Red staining. The release profile showed that the release of SIM from MHA-SIM-PNIPAAM lasted 16 days and the cumulative amount of released SIM was almost seven-fold than MHA-SIM. Besides, SIM loaded MHA-PNIPAAM exhibited better performance on cell proliferation, ALP activity, and calcium deposition than pure MHA due to the sustained release of SIM. The quantity of ALP in MHA-SIM-PNIPAAM group was more than two fold than pure MHA group at 7 days. Compared to pure MHA, better BMSC attachment on PNIPAAM modified MHA was observed using fluorescent microscopy, indicating the better biocompatibility of MHA-PNIPAAM.

The DnaJ-like zinc finger domain protein ORANGE localizes to the nucleus in etiolated cotyledons of Arabidopsis thaliana.

Vitamin A deficiency (VAD) is a worldwide health problem. Overexpression of the DnaJ-like zinc finger domain protein ORANGE (OR) is a novel strategy for the biofortification of pro-vitamin A carotenoids in different staple crops to alleviate VAD. In plants, OR triggers the differentiation from non-pigmented plastids into carotenoid-accumulating plastids. There are different reports on the subcellular localization of this protein in either chloroplasts or the nucleus, both of which were supported by confocal observation and protein-protein interaction results. In this work, we studied the subcellular localization of OR in the cotyledons of germinating seedlings whose plastids were transitioning from non-pigmented proplastids into carotenoid-accumulating etioplasts in the dark, and then into chloroplasts upon illumination. Our Western blot analysis identified two bands of the Arabidopsis OR protein (AtOR) from the chloroplast fraction of the mature leaves (i.e., a 34-kDa form corresponding to the full-length peptide and a 30-kDa form suggesting the removal of the N-terminal chloroplast transit peptide). We found that the full-length AtOR was predominantly localized in the nucleus in etiolated cotyledons, although its abundance decreased upon illumination. Our bioinformatics analysis indicated a nuclear localization signal (NLS) after the N-terminal chloroplast transit peptide. When we substituted different N-terminal regions of AtOR with the green fluorescent protein, our confocal observations demonstrated that this NLS was sufficient to target AtOR to the nucleus. Our results demonstrate that AtOR is a dual-targeted protein that mainly localizes in the nucleus in etiolated cotyledons.

Glucose- and pH-responsive nanogated ensemble based on polymeric network capped mesoporous silica.

In this paper, a glucose and pH-responsive release system based on polymeric network capped mesoporous silica nanoparticles (MSN) has been presented. The poly(acrylic acid) (PAA) brush on MSN was obtained through the surface-initiated atom transfer radical polymerization (SI-ATRP) of t-butyl acrylate and the subsequent hydrolysis of the ester bond. Then the PAA was glycosylated with glucosamine to obtain P(AA-AGA). To block the pore of silica, the P(AA-AGA) chains were cross-linked through the formation of boronate esters between 4,4-(ethylenedicarbamoyl)phenylboronic acid (EPBA) and the hydroxyl groups of P(AA-AGA). The boronate esters disassociated in the presence of glucose or in acidic conditions, which lead to opening of the mesoporous channels and the release of loaded guest molecules. The rate of release could be tuned by varying the pH or the concentration of glucose in the environment. The combination of two stimuli exhibited an obvious enhanced release capacity in mild acidic conditions (pH 6.0).

Highly efficient antibacterial surface grafted with a triclosan-decorated poly(N-hydroxyethylacrylamide) brush.

This work presented a highly efficient antibacterial Ti-surface which was grafted with poly(N-hydroxyethylacrylamide) (PHEAA) brush and further decorated with triclosan (TCS). The modified surfaces were characterized using contact angle measurements, X-ray photoelectron spectroscopy, and attenuated total reflectance Fourier transform infrared. The antibacterial performance of the modified surfaces was evaluated using the Streptococcus mutans and Actinomyces naeslundii attachment test. The Ti surface with PHEAA brush (Ti-PHEAA) was able to resist the adhesion of the bacteria, while the TCS-decorated Ti surface (Ti-TCS) showed the capability of killing the bacteria adhered on the surface. As we coupled the TCS to the PHEAA brush, the surface showed highly efficient antibacterial performance due to the combination of the resistance to the bacteria adhesion and its activity of killing bacteria.

[Research on Improving the Measurement Speed of THz-TDS Instruments].

The measurement speed is an important parameter of terahertz time-domain spectroscopy (THz-TDS) instruments. To improve the measurement speed of the spectrometer we need to increase the scanning speed of the delay line. In this paper, we study the influence of the scanning speed, the time constant of lock-in amplifier and the sampling rate on the signal quality. The results show that, when the time constant equal to 10 ms, increasing the scanning speed does not cause significant changes in the amplitude of the signal. But when the time constant equal to 30, 100 and 300 ms, with the increasing of the scanning speed the signal amplitude decreases rapidly. Therefore, the time constant should be set as small as possible to avoid deterioration of signal quality. On the other hand, higher the scanning speed is, fewer data points are collected with a same time-domain length. Therefore, when the scanning speed increase, not only the time constant should be reduced, but also the sampling rate should be increased to avoid the distortion of signal waveform caused by the number reduction of data points. The conclusions can provide a reference for improving the measurement speed of THz-TDS instrument.