Integrated analysis of ncRNA in hepatocellular carcinoma with CTNNB1 mutations reveals miR-205-5p and miR-3940-3p Axes.

BACKGROUND: Catenin beta 1 (CTNNB1) mutations are one of the most common mutations involved in hepatocellular carcinoma (HCC) progression. However, the association between CTNNB1 mutations and HCC remains controversial. METHODS: Five tumor samples with wild-type CTNNB1 and three tumor samples with CTNNB1 mutations were collected from patients with HCC for whole transcriptome sequencing. Selected ncRNAs and mRNAs were validated by qPCR in 48 HCC tumors. Selected ncRNA regulatory axes were verified in HCC cells by transfecting mimics and inhibitors of miRNA. RESULTS: A network of differentially expressed (DE) lncRNA/circRNA-miRNA-mRNA was constructed to explore the effects of CTNNB1 mutations on ncRNA regulation. TXNRD1, CES1, MATN2, SERPINA5, lncRNA STAT4-210, hsa_circ_0007824, hsa_circ_0008234, hsa-miR-205-5p and hsa-miR-199a-5p were verified at the RNA expression level to validate the sequencing results. The down-up-down axes GLIS3-209/circ_0085440-miR-205-5p-GHRHR and WNK2-213-miR-3940-3p-LY6E were verified at the expression level, and proved to inhibit and promote cell proliferation, respectively. CONCLUSION: This study demonstrated CTNNB1 mutations associated ncRNA regulatory axes playing different roles in HCC cell proliferation, providing novel insights into the controversial role of CTNNB1 in HCC.

Targeting TNF/IL-17/MAPK pathway in hE2A-PBX1 leukemia: effects of OUL35, KJ-Pyr-9, and CID44216842.

t(1;19)(q23;p13) is one of the most common translocation genes in childhood acute lymphoblastic leukemia (ALL) and is also present in acute myeloid leukemia (AML) and mixed-phenotype acute leukemia (MPAL). This translocation results in the formation of the oncogenic E2A-PBX1 fusion protein, which contains a trans-activating domain from E2A and a DNA-binding homologous domain from PBX1. Despite its clear oncogenic potential, the pathogenesis of E2A-PBX1 fusion protein is not fully understood (especially in leukemias other than ALL), and effective targeted clinical therapies have not been developed. To address this, we established a stable and heritable zebrafish line expressing human E2A-PBX1 (hE2A-PBX1) for high-throughput drug screening. Blood phenotype analysis showed that hE2A-PBX1 expression induced myeloid hyperplasia by increasing myeloid differentiation propensity of hematopoietic stem cells (HSPC) and myeloid proliferation in larvae, and progressed to AML in adults. Mechanistic studies revealed that hE2A-PBX1 activated the TNF/IL-17/MAPK signaling pathway in blood cells and induced myeloid hyperplasia by upregulating the expression of runx1. Interestingly, through high-throughput drug screening, three small molecules targeting the TNF/IL-17/MAPK signaling pathway were identified, including OUL35, KJ-Pyr-9, and CID44216842, which not only alleviated the hE2A-PBX1-induced myeloid hyperplasia in zebrafish but also inhibited the growth and oncogenicity of human pre-B ALL cells with E2A-PBX1. Overall, this study provides a novel hE2APBX1 transgenic zebrafish leukemia model and identifies potential targeted therapeutic drugs, which may offer new insights into the treatment of E2A-PBX1 leukemia.

A NIR-II Photoacoustic/NIR-IIa Fluorescent Probe for Targeted Imaging of Glioma under NIR-II Excitation.

Fluorescence and photoacoustic (PA) imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has garnered massive interest owing to high maximum permissible exposure of light, reduced autofluorescence, and improved deep penetration. However, active targeted NIR-II photoacoustic/NIR-IIa fluorescence imaging of glioma under NIR-II excitation has been seldom reported, which is partly ascribable to the lack of suitable materials. In this study, a small-molecule-based αvß3-targeted NIR-II photoacoustic/NIR-IIa fluorescent probe IR-32p was generated and subsequently evaluated in U87MG tumor-bearing mice excited with NIR-I and NIR-II light. Exceptional dual-modal imaging properties such as good tumor uptake, high targeting specificity, and high tumor contrast were achieved in an orthotopic glioma model under 1020/1064 nm excitation, exhibiting a superior imaging depth of glioma through the skull. Our study introduces an outstanding dual-modal contrast agent with NIR-II absorption and confirms the superiority of NIR-II excitation over NIR-I in in vivo NIR-II/PA imaging.

Electrocatalytic Activity of CO2 Reduction to CO on Cadmium Sulfide Enhanced by Chloride Anion Doping.

The electrocatalytic CO2 reduction (ECR) to produce valuable fuel is a promising process for addressing atmospheric CO2 emissions and energy shortages. In this study, Cl-anion doped cadmium sulfide structures were directly fabricated on a nickel foam surface (Cl/CdS-NF) using an in situ hydrothermal method. The Cl-anion doping could significantly improve ECR activity for CO production in ionic liquid and acetonitrile mixed solution, compared to pristine CdS. The highest Faradaic efficiency of CO is 98.1 % on a Cl/CdS-NF-2 cathode with an excellent current density of 137.0 mA cm-2 at -2.25 V versus ferrocene/ferrocenium (Fc/Fc+ , all potentials are versus Fc/Fc+ in this study). In particular, CO Faradaic efficiencies remained above 80 % in a wide potential range of -2.05 V to -2.45 V and a maximum partial current density (192.6 mA cm-2 ) was achieved at -2.35 V. The Cl/CdS-NF-2, with appropriate Cl anions, displayed abundant active sites and a suitable electronic structure, resulting in outstanding ECR activity. Density functional theory calculations further demonstrated that Cl/CdS is beneficial for increasing the adsorption capacities of *COOH and *H, which can enhance the activity of the ECR toward CO and suppress the hydrogen evolution reaction.

Dual-Recognition Triggered Proximity Ligation Combined with a Rolling Circle Amplification Strategy for Analysis of Exosomal Protein-Specific Glycosylation.

Exosomal surface glycan reveals the biological function and molecular information on the protein, especially in indicating the pathogenesis of certain diseases through monitoring of specific protein glycosylation accurately. However, in situ and nondestructive measurement techniques for certain Exosomal glycoproteins are still lacking. In this work, combined with on-chip purification, we designed a proximity ligation assay-induced rolling circle amplification (RCA) strategy for highly sensitive identification of Exosomal protein-specific glycosylation based on a couple of proximity probes to target Exosomal protein and the protein-specific glycosylation site. Benefiting from efficient separation, scalable dual-recognition, and proximity-triggered RCA amplification, the proposed strategy could convert different protein-specific glycan levels to prominent changes in absorbance signals, resulting in accurate quantification of specific glycosylated Exosomal protein. When detecting the glycosylated PD-L1 on MDA-MB-231 exosomes and glycosylated PTK7 on HepG2 exosomes, the detection limits were calculated to be as low as 1.04 × 104 and 2.759 × 103 particles/mL, respectively. In addition, we further expand the dual-recognition site to investigate the potential correlation of Exosomal glycosylation with polarization of THP-1 cells toward the tumor-suppressive M1 phenotype. Overall, this strategy provides a universal tool for multiple analyses of diverse protein-specific glycosylated exosomes, exhibiting enormous potential to explore exosome function and search for new early diagnosis markers.

Functional, antioxidant, and sensory properties of mixed-fruit (pitaya, watermelon, and mint) and pitaya wines.

Fermentation of fruits offers a diverse range of flavors, smells, and colors. Colored fruits are rich in naturally occurring pigments, such as betacyanin. Hence, they are considered to possess powerful antioxidant activities. However, in wine production, such pigments often diversify the flavor and color of the wine. The objective of this study was to compare the quality of two types of wines: a single-fruit (pitaya) wine and a mixed-fruit wine that contains watermelon (Citrullus lanatus), mint (Mintha spicata), and pitaya (Hylocereus costaricensis). In this study, fresh pitaya, watermelon, and mint leaves were fermented using Saccharomyces cerevisiae. Juice extracts underwent fermentation at room temperature for 7 days under dark conditions. Physicochemical changes, such as pH, sugar content, specific gravity, and alcohol content, were observed daily. The antioxidant activities were measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the ferric reducing antioxidant power (FRAP) assay, and total phenolic contents (TPCs). After 14 days of fermentation, the alcohol contents of mixed and pitaya wine were 11.22% (v/v) and 11.25%, respectively. The total sugar content of the mixed wine was 8.0 °Brix, while that of pitaya wine was 7.0 °Brix. Moreover, pitaya wine exhibited a higher TPC (22.7 mg GAE/100 g D.W.), and better FRAP (3578 µmole/L) and DPPH scavenging ability (80.2%) compared to the mixed wine with a TPC of 21.4 mg GAE/100 g D.W., FRAP of 2528 µmole/L, and DPPH of 75.6%., while the addition of watermelon and mint did not change the alcohol percentage contents of wine.

A Native Drug-Free Macromolecular Therapeutic to Trigger Mutual Reinforcing of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction for Cancer Treatment.

Drug-free macromolecular therapeutics are promising alternatives to traditional drugs. Nanomedicines with multiple organelles targeting can potentially increase the efficacy. Herein, a drug-free macromolecular therapeutic was designed to formulate endoplasmic reticulum (ER) and mitochondria dual-targeting nanoparticles (EMT-NPs), which can synergistically elicit ER stress and mitochondrial dysfunction. In vitro experiments indicated that EMT-NPs could effectively enter ER and mitochondria at an approximate ratio of 2 to 3. Subsequently, EMT-NPs could upregulate ER stress-related protein expression (IRE1α, CHOP), boosting calcium ion (Ca2+) efflux and activating the caspase-12 signaling cascade in cancer cells. In addition, EMT-NPs induced direct oxidative stress in mitochondria; some mitochondrial-related apoptotic events such as decreased mitochondrial membrane potential (MMP), upregulation of Bax, cytochrome c release, and caspase-3 activation were also observed for tumor cells upon incubation with EMT-NPs. Furthermore, the leaked Ca2+ from ER could induce mitochondrial Ca2+ overloading to further augment cancer cell apoptosis. In brief, mitochondrial and ER signaling networks collaborated well to promote cancer cell death. Extended photoacoustic and fluorescence imaging served well for the treatment of in vivo patient-derived xenografts cancer model. This drug-free macromolecular strategy with multiple subcellular targeting provides a potential paradigm for cancer theranostics in precision nanomedicine.

Centralized Excited States and Fast Radiation Transitions Reduce Laser Threshold in Carbon Dots.

As a new type of solution-processed nano-laser material, carbon dots (CDs) have shown considerable potential in optical communication, laser displays, micro/nano processing, and biomedicine. Reducing the laser threshold of the gain material is of considerable significance for further development of CDs' applications in the field of micro/nano lasers. A series of blue-emissive CDs (B-CDs) are synthesized by changing the molar ratios of the precursors (citric acid (CA): L-Cysteine (L-Cys)). B-CDs have a structure of carbon nanoparticles with their surface being modified with 5-oxo-3,5-dihydro-2Hthiazolo [3,2-a]pyridine-7-carboxylic acid (TPCA). The laser can only be generated when the molar ratio of the precursors is between 1:1 and 2:1. With an increase in this ratio, the laser threshold decreases from 341.6 to 165.5 mJ cm-2 . The decrease in the laser threshold is attributed to the increase in the radiation transition rate and centralized sp3 -related excited state levels, which are favorable for light amplification and population inversion. These results will be instructional for the reasonably design of CDs-based laser materials and prompt their potential use in practical photonics.

A modified surgical method for the treatment of ONFH: quadratus femoris muscle pedicle bone grafting with preservation of the posterior superior retinacular artery.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) can lead to pain and loss of function of the hip joint, which places a great burden on patients and society. Surgery is the main treatment for osteonecrosis of the femoral head, and quadratus femoris muscle pedicle bone grafting has a definite therapeutic effect as one method of surgery for the treatment of ONFH. However, the posterior superior retinacular artery is often injured during quadratus femoris muscle pedicle bone graft surgery. There is evidence that this artery is extremely important to the femoral head, as injury to this artery will seriously affect the blood supply of the femoral head. Therefore, this situation restricts the clinical application of quadratus femoris muscle pedicle bone grafts. We aimed to explore a new surgical method of quadratus femoris muscle pedicle bone grafting that can preserve the integrity of the posterior superior retinacular artery. METHODS: We modified the traditional quadratus femoris muscle pedicle bone graft and preserved the integrity of the posterior superior retinacular artery. To explore the safety and feasibility of the operation, we simulated the operation on 6 fresh frozen cadavers (12 hips) and measured the related data. We also tried this modified surgical method in the clinic and collected detailed data from the patients. RESULTS: By simulating the modified quadratus femoris muscle pedicle bone graft on the hip joints of fresh frozen cadavers, we found that the posterior superior retinacular artery existed in all cadaver specimens and that the sources may be different (MFCA or IGA). In the modified operation, the joint capsule did not need to be cut during the operation; therefore, the integrity of the posterior superior retinacular artery was preserved. The quadratus femoris muscle was exposed via the posterior approach of the hip joint, and then the quadratus femoris muscle pedicle bone flap was chiseled. After the pedicle of the quadratus femoris muscle was loosened properly, the migration distance of the quadratus femoris muscle pedicle bone flap reached 5.89 ± 0.45 (χ ± s) cm. The bone flap was trimmed properly and placed on one side. Next, we drilled a bone tunnel from the external intertrochanteric aspect of the capsule of the hip joint, and the bone tunnel broke through the sclerosing zone and proceeded straight to the necrotic area of the femoral head. Next, the necrotic bone was removed with a ring saw and arc bone knife, autogenous bone or allogeneic bone was filled into the bone groove according to the situation, and the cancellous bone in the bone groove was tamped by percussion. Then, the bone flap was inserted into the bone groove, and appropriate pressurization was performed. The depth of the bone groove was determined by the location of ONFH. We found that the furthest distance between the bone groove and the femoral head was 4.76 ± 0.07 (χ ± s) cm and that the length of the bone flap was (4.91 ± 0.23) (χ ± s) cm. This means that when the depth of the bone groove reached the area of ONFH, the quadratus femoris muscle pedicle bone flap had a sufficient length and migration distance to be embedded in the area of ONFH and firmly fixed, and the quadratus femoris did not have much tension. The closest distance between the posterior superior retinacular artery and the bone groove was (1.11 ± 0.96) (χ ± s) cm. When the bone groove was created in this area, the edge of the bone groove had a safe distance of at least 1 cm from the posterior superior retinacular artery of the femoral head. We attempted to implement this modified operation clinically. During the procedure, the quadratus femoris muscle pedicle bone flap was embedded into the drilled bone groove and fixed with a magnesium nail. There was no sliding of the bone flap after the operation, and the posterior superior retinacular artery was intact. We followed the patient for 3 months and found that the patient recovered well with no weight-bearing by the affected limb. The duration of the modified operation was shorter than that of the traditional quadratus femoris muscle pedicle bone graft, the amount of bleeding was significantly reduced, the postoperative pain was lessened, and no special discomfort was reported. Postoperative imaging examination showed that the collapse of the femoral head had been partially corrected and that the bone flap had gradually fused with the surrounding bone. CONCLUSIONS: Through this experimental study, we confirmed the feasibility of the modified method for quadratus femoris muscle pedicle bone grafting with preservation of the posterior superior retinacular artery. This modified operation not only retains the integrity of the posterior superior retinacular artery of the femoral head but also reduces the difficulty of the operation and shortens the surgical time, which is of great clinical significance.

Simultaneous Sensing of H2S and ATP with a Two-Photon Fluorescent Probe in Alzheimer's Disease: toward Understanding Why H2S Regulates Glutamate-Induced ATP Dysregulation.

Energy deprivation and reduced levels of hydrogen sulfide (H2S) in the brain is closely associated with Alzheimer's disease (AD). However, there is currently no fluorescent probe for precise exploration of both H2S and adenosine triphosphate (ATP) to directly demonstrate their relationship and their dynamic pattern changes. Herein, we developed a two-photon fluorescent probe, named AD-3, to simultaneously image endogenous H2S and ATP from two emission channels of fluorescent signals in live rat brains with AD. The probe achieved excellent selectivity and good detection linearity for H2S in the 0-100 µM concentration range and ATP in the 2-5 mM concentration range, respectively, with a detection limit of 0.19 µM for H2S and 0.01 mM for ATP. Fluorescence imaging in live cells reveals that such probe could successfully apply for simultaneous imaging and accurate quantification of H2S and ATP in neuronal cells. Further using real-time quantitative polymerase chain reaction and Western blots, we confirmed that H2S regulates ATP synthesis by acting on cytochrome C, cytochrome oxidase subunit 3 of complex IV, and protein 6 of complex I in the mitochondrial respiratory chain. Subsequently, we constructed a high-throughput screening platform based on AD-3 probe to rapidly screen the potential anti-AD drugs to control glutamate-stimulated oxidative stress associated with abnormal H2S and ATP levels. Significantly, AD-3 probe was found capable of imaging of H2S and ATP in APP/PS1 mice, and the concentration of H2S and ATP in the AD mouse brain was found to be lower than that in wild-type mice.

In vivo hitchhiking of immune cells by intracellular self-assembly of bacteria-mimetic nanomedicine for targeted therapy of melanoma.

Cell-based drug carriers are mostly prepared in vitro, which may negatively affect the physiological functions of cells, and induce possible immune rejections when applied to different individuals. In addition, the immunosuppressive tumor microenvironment limits immune cell-mediated delivery. Here, we report an in vivo strategy to construct cell-based nanomedicine carriers, where bacteria-mimetic gold nanoparticles (GNPs) are intravenously injected, selectively phagocytosed by phagocytic immune cells, and subsequently self-assemble into sizable intracellular aggregates via host-guest interactions. The intracellular aggregates minimize exocytosis of GNPs from immune cells and activate the photothermal property via plasmonic coupling effects. Phagocytic immune cells carry the intracellular GNP aggregates to melanoma tissue via inflammatory tropism. Moreover, an initial photothermal treatment (PTT) of the tumor induces tumor damage that subsequently provides positive feedback to recruit more immune cell-based carriers for enhanced targeting efficiency. The optimized secondary PTT notably improves antitumor immunotherapy, further strengthened by immune checkpoint blockade.

A single-molecular ruthenium(II) complex-based NIR-II fluorophore for enhanced chemo-photothermal therapy.

Novel NIR-II Ru(II) polypyridyl fluorophore Ru-1 dots for synergistic chemo-photothermal therapy against 4T1 tumors were designed and synthesized. Guided by in vivo NIR-II fluorescence imaging, the synergistic therapeutic efficacy, intracellular delivery, and biodistribution of the Ru-1 dots were precisely tracked in real-time.

Carbon Dots as a Potential Therapeutic Agent for the Treatment of Cancer-Related Anemia.

Due to the adverse effects of erythropoietin (EPO) on cancer patient survival, it is necessary to develop new agents that can be used to efficiently manage and treat cancer-related anemia. In this study, novel distinctive carbon dots, J-CDs, derived from jujube are designed, synthesized, and characterized. Based on the obtained results, this material comprises sp2 and sp3 carbon atoms, as well as oxygen/nitrogen-based groups, and it specifically promotes the proliferation of erythroid cells by stimulating the self-renewal of erythroid progenitor cells in vitro and in vivo. Moreover, J-CDs have no discernible effects on tumor proliferation and metastasis, unlike EPO. Transcriptome profiling suggests that J-CDs upregulate the molecules involved in hypoxia response, and they also significantly increase the phosphorylation levels of STAT5, the major transducer of signals for erythroid progenitor cell proliferation. Overall, this study demonstrates that J-CDs effectively promote erythrocyte production without affecting tumor proliferation and metastasis; thus, they may be promising agents for the treatment of cancer-related anemia.

Rationally Driven Drug Nonradiative Decay via a Label-Free Polyprodrug Strategy to Renew Tumor Cascade Photothermal-Chemotherapy.

Drugs are frequently used for only chemotherapy that ignores their photophysical properties that potentially endow them with other therapeutic potency. Additionally, current photothermal-chemotherapy replies on the codelivery of drugs and photothermal agents, but their spatiotemporal delivery and precise release is unsatisfactory. Herein, label-free doxorubicin (DOX) polyprodrug nanoparticles (DPNs) are formulated from disulfide bonds-tethered DOX polyprodrug amphiphiles (PDMA-b-PDOXM). Benefiting from boosted nonradiative decay of high-density DOX, significant fluorescence quenching and photothermal effects are observed for DPNs without common photothermal agents. Upon cellular uptake and laser irradiation, the heat can promote lysosomal escape of DPNs into reductive cytosol, whereupon free DOX is released to activate chemotherapy and fluorescence, achieving rational cascade photothermal-chemotherapy. The current label-free polyprodrug strategy can make full use of drugs; it provides an alternative insight to extend the therapeutic domain of drugs.

Versatile Types of Inorganic/Organic NIR-IIa/IIb Fluorophores: From Strategic Design toward Molecular Imaging and Theranostics.

In vivo imaging in the second near-infrared window (NIR-II, 1000-1700 nm), which enables us to look deeply into living subjects, is producing marvelous opportunities for biomedical research and clinical applications. Very recently, there has been an upsurge of interdisciplinary studies focusing on developing versatile types of inorganic/organic fluorophores that can be used for noninvasive NIR-IIa/IIb imaging (NIR-IIa, 1300-1400 nm; NIR-IIb, 1500-1700 nm) with near-zero tissue autofluorescence and deeper tissue penetration. This review provides an overview of the reports published to date on the design, properties, molecular imaging, and theranostics of inorganic/organic NIR-IIa/IIb fluorophores. First, we summarize the design concepts of the up-to-date functional NIR-IIa/IIb biomaterials, in the order of single-walled carbon nanotubes (SWCNTs), quantum dots (QDs), rare-earth-doped nanoparticles (RENPs), and organic fluorophores (OFs). Then, these novel imaging modalities and versatile biomedical applications brought by these superior fluorescent properties are reviewed. Finally, challenges and perspectives for future clinical translation, aiming at boosting the clinical application progress of NIR-IIa and NIR-IIb imaging technology are highlighted.

Rapid FRET-based homogeneous immunoassay of procalcitonin using matched carbon dots labels.

A novel method for the detection of procalcitonin in a homogeneous system by matched carbon dots (CDs) labeled immunoprobes was proposed based on the principle of FRET and double antibody sandwich method. Blue-emitting carbon dots with a strong fluorescence emission range of 400-550 nm and red-emitting carbon dots with the best excitation range of 410-550 nm were prepared before they reacted with procalcitonin protoclone antibody pairs to form immunoprobes. According to the principles of FRET, blue-emitting carbon dots were selected as the energy donor and red-emitting carbon dots as the energy receptor. The external light source excitation (310 nm) could only cause weak luminescence of CDs. However, once procalcitonin was added, procalcitonin and antibodies would be combined with each other quickly (≤20 min). Here, blue-emitting carbon dots acquired energy could be transferred to red-emitting carbon dots efficiently, causing the emitted fluorescence enhancement of red-emitting carbon dots. The fluorescence detection results in PBS buffer solution and diluted rabbit blood serum showed that the fluorescence intensity variation was linear with the concentration of procalcitonin. There was a good linear relationship betweenF/F0 and procalcitonin concentrations in PBS buffer solution that ranged from 0 to 100 ng ml-1, and the linear equation wasF/F0 = 0.004 *Cpct + 0.98359. Detection in the diluted rabbit serum led to the results that were linear in two concentration ranges, including 0-40 ng ml-1and 40-100 ng ml-1, and the detection limit based on 3σK-1was 0.52 ng ml-1. It is likely that this matched CDs labeled immunoprobes system can provide a new mode for rapid homogeneous detection of disease markers.

NIR II Light-Response Au Nanoframes: Amplification of a Pressure- and Temperature-Sensing Strategy for Portable Detection and Photothermal Therapy of Cancer Cells.

Quantitative detection of cancer cells using portable devices is promising for the development of simple, fast, and point-of-care cancer diagnostic techniques. However, how to further amplify the detection signal to improve the sensitivity and accuracy of detecting cancer cells by portable devices remains a challenge. To solve the problem, we, for the first time, synthesized folic-acid-conjugated Au nanoframes (FA-Au NFs) with amplification of pressure and temperature signals for highly sensitive and accurate detection of cancer cells by portable pressure meters and thermometers. The resulting Au NFs exhibit excellent near-infrared (NIR) photothermal performance and catalase activity, which can promote the decomposition of NH4HCO3 and H2O2 to generate corresponding gases (CO2, NH3, and O2), thereby synergistically amplifying pressure signals in a closed reaction vessel. At the same time, Au NFs with excellent peroxidase-like activity can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to produce TMB oxide (oxTMB) with a strong photothermal effect, thereby cooperating with Au NFs to amplify the photothermal signal. In the presence of cancer cells with overexpressing folate receptors (FRs), the molecular recognition signals between FA and FR can be converted into amplified pressure and temperature signals, which can be easily read by portable pressure meters and thermometers, respectively. The detection limits for cancer cells using pressure meters and thermometers are 6 and 5 cells/mL, respectively, which are better than other reported methods. Moreover, such Au NFs can improve tumor hypoxia by catalyzing the decomposition of H2O2 to produce O2 and perform photothermal therapy of cancer. Together, our work provides new insight into the application of Au NFs to develop a dual-signal sensing platform with amplification of pressure and temperature signals for portable and ultrasensitive detection of cancer cells as well as personalized cancer therapy.

Nitrogen-Doped Chiral CuO/CoO Nanofibers: An Enhanced Electrochemiluminescence Sensing Strategy for Detection of 3,4-Dihydroxy-Phenylalanine Enantiomers.

l-3,4-Dihydroxy-phenylalanine (l-DOPA) is the most effective drug for the treatment of Parkinson's disease, which plays a very important role in clinical and neurochemistry. However, how to achieve high-sensitivity recognition of l-DOPA still faces challenges. Here, a facile strategy is presented to construct nitrogen-doped chiral CuO/CoO nanofibers (N-CuO/CoO NFs) with nanozyme activity and electrochemiluminescence property, in which CuO/CoO NFs are used as the catalytic activity center and chiral cysteine (Cys) is used as the inducer of chiral recognition, for enantioselective catalysis and sensitive recognition of DOPA enantiomers. Notably, N doping not only enhances the enzyme-mimic activity of CuO/CoO NFs but also amplifies their electrochemiluminescence (ECL) signals in the presence of luminol. More importantly, in the presence of DOPA enantiomers, the d-cysteine (d-Cys)-modified N-CuO/CoO NFs exhibit different ECL performances; thus, d-Cys@N-CuO/CoO NFs could selectively distinguish and sensitively detect l-DOPA through ECL signals, and the detection limit is 0.29 nM for l-DOPA. In addition, it also showed good sensing performance for the determination of l-DOPA in fetal bovine serum. This is the first report on the detection of DOPA enantiomers based on an enhanced ECL strategy, providing a robust pathway for chiral discrimination and detection of chiral molecules.

Polyamine-Responsive Morphological Transformation of a Supramolecular Peptide for Specific Drug Accumulation and Retention in Cancer Cells.

The precise accumulation and extended retention of nanomedicines in the tumor tissue has been highly desired for cancer therapy. Here a novel supramolecular-peptide derived nanodrug (SPN) that can be transformed to microfibers in response to intracellular polyamine in cancer cells for significantly enhanced tumor specific accumulation and retention is developed. The supramolecular-peptide is constructed via the non-covalent interactions between cucurbit[7]uril (CB[7]) and Phe on Phe-Phe-Val-Leu-Lys-camptothecin conjugates (FFVLK-CPT, PC). The resultant amphiphilic supramolecular complex subsequently self-assembles into nanoparticles with a hydrodynamic diameter of 164.2 ± 3.7 nm. Upon internalization into spermine-overexpressed cancer cells, the CB[7]-Phe host-guest pairs can be competitively dissociated by spermine and can release free PC, which immediately form ß-sheet structures and subsequently reorganize into microfibers, leading to dramatically improved accumulation, retention, and sustained release of CPT in tumor cells for highly effective cancer therapy. Accordingly, this SPN exhibit rather low toxicity against non-cancerous cells due to the morphological stability and fast exocytosis of the nanodrugs in those cells without abundant spermine. This study reports the first supramolecular peptide capable of polyamine-responsive "nanoparticle-to-microfiber" transformation for specific tumor therapy with minimal side effects. This work also offers novel insights to the design and development of stimuli-responsive nanomaterials as precision medicine.

Synthesis of an AIEgen functionalized cucurbit[7]uril for subcellular bioimaging and synergistic photodynamic therapy and supramolecular chemotherapy.

Aggregation-induced emission (AIE) based fluorophores (AIEgens) have attracted increasing attention for biomedical applications due to their unique optical properties. Here we report an AIE photosensitizer functionalized CB[7], namely AIECB[7], which could spontaneously self-assemble into nanoaggregates in aqueous solutions. Interestingly, the carbonyl-lace of CB[7] may potentially act as a proton acceptor in an acidic environment to fine-tune the fluorescence and singlet oxygen generation of AIECB[7] nanoaggregates by regulating the inner stacking of AIEgens. Additionally, benefiting from the guest-binding properties of CB[7], oxaliplatin was included into AIECB[7] nanoaggregates for combined photodynamic therapy and supramolecular chemotherapy. To show the modular versatility of this supramolecular system, a hypoxia-activatable prodrug banoxantrone (AQ4N) was loaded into AIECB[7] nanoaggregates, which exhibited synergistic antitumor effects on a multicellular tumor spheroid model (MCTS). This work not only provides AIECB[7] for versatile theranostic applications, but also offers important new insights into the design and development of macrocycle-conjugated AIE materials for diverse biomedical applications.