Ultrasound Trigger Ce-Based MOF Nanoenzyme For Efficient Thrombolytic Therapy.

The inflammatory damage caused by thrombus formation and dissolution can increase the risk of thrombotic complications on top of cell death and organ dysfunction caused by thrombus itself. Therefore, a rapid and precise thrombolytic therapy strategy is in urgent need to effectively dissolve thrombus and resist oxidation simultaneously. In this study, Ce-UiO-66, a cerium-based metal-organic framework (Ce-MOF) with reactive oxygen species (ROS) scavenging properties, encapsulated by low-immunogenic mesenchymal stem cell membrane with inflammation-targeting properties, is used to construct a targeted nanomedicine Ce-UiO-CM. Ce-UiO-CM is applied in combination with external ultrasound stimulation for thrombolytic therapy in rat femoral artery. Ce-UiO-66 has abundant Ce (III)/Ce (IV) coupling sites that react with hydrogen peroxide (H2O2) to produce oxygen, exhibiting catalase (CAT) activity. The multi-cavity structure of Ce-UiO-66 can generate electron holes, and its pore channels can act as micro-reactors to further enhance its ROS scavenging capacity. Additionally, the porous structure of Ce-UiO-66 and the oxygen produced by its reaction with H2O2 may enhance the cavitation effects of ultrasound, thereby improving thrombolysis efficacy.

Correction: Self-quenched ferrocenyl diketopyrrolopyrrole organic nanoparticles with amplifying photothermal effect for cancer therapy.

[This corrects the article DOI: 10.1039/C7SC03351F.].

A Smart DNA-Based Nanosystem Containing Ribosome-Regulating siRNA for Enhanced mRNA Transfection.

Messenger RNA (mRNA) transfection is the prerequisite for the application of mRNA-based therapeutics. In hard-to-transfect cells, such as macrophages, the effective transfection of mRNA remains a long-standing challenge. Herein, a smart DNA-based nanosystem is reported containing ribosome biogenesis-promoting siRNA, realizing efficient mRNA transfection in macrophages. Four monomers are copolymerized to form a nanoframework (NF), including N-isopropylacrylamide (NIPAM) as the skeleton and acrydite-DNA as the initiator to trigger the cascade assembly of DNA hairpins (H1-polyT and H2-siRNA). By virtue of the phase transition characteristic of polymeric NIPAM, below the lower critical solution temperature (LCST, ≈34 °C), the NF swells to expose polyT sequences to hybridize with the polyA tail of mRNA. Above the LCST, the NF deswells to encapsulate mRNA. The disulfide bond in the NF responds to glutathione, triggering the disassembly of the nanosystem; the siRNA and mRNA are released in response to triphosadenine and RNase H. The siRNA down-regulates the expression of heat shock protein 27, which up-regulates the expression of phosphorylated ribosomal protein S6. The nanosystem shows satisfactory mRNA transfection and translation efficiency in a mouse model. It is envisioned that the DNA-based nanosystem will provide a promising carrier to deliver mRNA in hard-to-transfect cells and promote the development of mRNA-based therapeutics.

Correction: FDPP-HA as a theranostic agent for cancer-targeted fluorescence imaging and photodynamic therapy.

[This corrects the article DOI: 10.1039/C7RA06551E.].

Framework-Hotspot Enhanced Trans Cleavage of CRISPR-Cas12a for Clinical Samples Detection.

The trans-cleavage property of CRISPR-Cas12a system makes it an excellent tool for disease diagnosis. Nevertheless, most methods based on CRISPR-Cas system still require pre-amplification of the target to achieve the desired detection sensitivity. Here we generate Framework-Hotspot reporters (FHRs) with different local densities to investigate their effect on trans-cleavage activity of Cas12a. We find that the cleavage efficiency increases and the cleavage rate accelerates with increasing reporter density. We further construct a modular sensing platform with CRISPR-Cas12a-based target recognition and FHR-based signal transduction. Encouragingly, this modular platform enables sensitive (100 fM) and rapid (<15 min) detection of pathogen nucleic acids without pre-amplification, as well as detection of tumor protein markers in clinical samples. The design provides a facile strategy for enhanced trans cleavage of Cas12a, which accelerates and broadens its applications in biosensing.

DNA Nanoclusters Combined with One-Shot Radiotherapy Augment Cancer Immunotherapy Efficiency.

Immunotherapy shows immense promise for improving cancer treatment. Combining immunotherapy with radiotherapy provides a conspicuous advantage due to its enhanced abscopal effect. However, established immune tolerance mechanisms in the tumor microenvironment can hamper the generation of a sufficient abscopal effect. Herein, a type of DNA nanocluster (DNAnc) that is self-assembled by a CpG-ODNs-loaded Y-shaped double-stranded DNA vector based on the unique complementary base-pairing rules is designed. The unique structure of DNAnc makes it load more than ≈8125.5 ± 822.5 copies of CpG ODNs within one single nanostructure, which effectively increases resistance to nuclease degradation and elevates the efficiency of repolarizing macrophages to an M1-like phenotype. Mechanistic studies reveal that more DNAncs are endocytosed by macrophages in the cancer tissue and repolarized macrophages to elicit a robust abscopal effect with the accumulation of macrophages induced by radiotherapy, generating potent, long-term, and durable antitumor immunity for the inhibition of tumor metastasis and the prevention of tumor recurrence, which provides a novel strategy to boost cancer immunotherapy.

A DNA/DMXAA/Metal-Organic Framework Activator of Innate Immunity for Boosting Anticancer Immunity.

Immunotherapy has achieved revolutionary success in clinics, but it remains challenging for treating hepatocellular carcinoma (HCC) characterized by high vascularization. Here, it is reported that metal-organic framework-801 (MOF-801) can be employed as a stimulator of interferon genes (STING) through Toll-like receptor 4 (TLR4) not just as a drug delivery carrier. Notably, cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) and 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) STING agonist with vascular disrupting function coordinates with MOF-801 to self-assemble into a nanoparticle (MOF-CpG-DMXAA) that effectively delivers CpG ODNs and DMXAA to cells for synergistically improving the tumor microenvironment by reprogramming tumor-associated macrophages (TAMs), promoting dendritic cells (DCs) maturation, as well as destroying tumor blood vessels. In HCC-bearing mouse models, it is demonstrated that MOF-CpG-DMXAA triggers systemic immune activation and stimulates robust tumoricidal immunity, resulting in a superior immunotherapeutic efficiency in orthotopic and recurrent HCC.

Ultrasensitive DNA-Biomacromolecule Sensor for the Detection Application of Clinical Cancer Samples.

Diagnostic testing of biological macromolecules is of great significance for early warning of disease and cancer. Nevertheless, restricted by limited surface area and large steric hindrance, sensitive detection of macromolecules with interface-based sensing method remains challenging. Here, a "biphasic replacement" electrochemical aptamer-based (BRE-AB) sensing strategy which placed capture reaction of the biomacromolecule in a homogeneous solution phase and replaced with a small diameter of single-stranded DNA to attach to the interface is introduced. Using the BRE-AB sensor, the ultrasensitive detection of luteinizing hormone (LH) with the detection limit of 10 × 10-12 m is demonstrated. Molecular Dynamics simulations are utilized to explore the binding mechanism of aptamer and target LH. Moreover, it is confirmed that the BRE-AB sensor has excellent sensing performance in whole blood and undiluted plasma. Using the BRE-AB sensor, the LH concentrations in 40 clinical samples are successfully quantified and it is found that LH is higher expressed in breast cancer patients. Furthermore, the sensor enables simple, low-cost, and easy to regenerate and reuse, indicating potentially applicable for point-of-care biological macromolecules diagnostics.

Nonplanar Helicene Benzo[4]Helicenium for the Precise Treatment of Renal cell Carcinoma.

Immune and targeted therapy are becoming the first-line treatment for renal cell carcinoma (RCC). However, therapeutic outcomes are limited due to the low efficiency and side effect. Here, it is found that helicenes are able to exhibit an anticancer capability through changing the molecular structure from planar to nonplanar. Furthermore, the cytotoxicity in vitro and cancer inhibition ability of nonplanar helicenes increase with its aromatic rings' number. It is further demonstrated that benzo[4]helicenium shows the specific killing efficiency against the RCC cancer as compared to normal kidney cells. This is majorly originated from a more selective damage of benzo[4]helicenium for mitochondria and DNA in RCC cancer cells, not the normal kidney. The selective killing ability of benzo[4]helicenium makes it have potential to be used as a targeted drug for the precise treatment of RCC.

Nanoassemblies with Effective Serum Tolerance Capability Achieving Robust Gene Silencing Efficacy for Breast Cancer Gene Therapy.

The transfection efficiency of siRNA mediated by cationic polymers is limited due to the instability of polymers/siRNA complexes in the presence of serum. Poly(ethylene glycol) (PEG) is usually applied to modify cationic polymers, so as to reduce protein and cell adsorption and then to improve siRNA transfection efficiency. However, the polymers' modification with PEG mostly consumes the free amino of the polymers, which can, in turn, reduce the charge density and limit their siRNA transfection efficacy. Here, a new PEG modification strategy that need not consume the surface aminos of polymers is proposed. Catechol-PEG polymers are coated on the surface of phenylboronic acid (PBA)-modified Generation 5 (G5) poly(amidoamine) dendrimers (G5PBA) via reversible boronate esters to establish PEG-modified dendrimer/siRNA nanoassemblies for efficient siRNA delivery. The PEG/G5PBA/siRNA nanoassemblies have positive charge and show excellent gene silencing efficacy in the absence of serum in vitro. More importantly, the PEG/G5PBA/siRNA nanoassemblies also exhibit excellent serum resistance and gene silencing efficacy in serum-containing medium. Furthermore, the effective antiserum and gene silencing efficacy elicited by these nanoassemblies lead to excellent antitumor effects in vivo. This proposed strategy constitutes an important approach to reach an excellent gene silencing efficacy in the presence of serum.

Iron Oxide Nanoparticles as Autophagy Intervention Agents Suppress Hepatoma Growth by Enhancing Tumoricidal Autophagy.

The combined treatment with nanoparticles and autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), is extensively explored for cancer therapy. However, the toxicity of autophagy inhibitors and their unselective for tumoricidal autophagy have seriously hindered the application of the combined treatment. In this study, a carboxy-functional iron oxide nanoparticle (Fe2O3@DMSA) is designed and identified to significantly exert an antitumor effect without adding CQ or HCQ. Further investigation indicates that the effective inhibition effect of Fe2O3@DMSA alone on hepatoma growth is triggered by inhibiting the fusion of autophagosomes and lysosomes to enhance tumoricidal autophagy, which is induced by intracellular iron-retention-induced sustained reactive oxygen species (ROS) production. Furthermore, in two hepatoma-bearing mouse models, Fe2O3@DMSA alone effectively suppresses the growth of tumors without obvious toxic side effects. These studies offer a promising strategy for cancer therapy.

Meta-analysis: Resistance Training Improves Cognition in Mild Cognitive Impairment.

This study investigated the benefits of resistance training on cognition in patients with mild cognitive impairment. We searched the PubMed, Embase and Cochrane Library databases, and seven randomized controlled trials were reviewed. We evaluated the risk of bias using the Cochrane Collaboration's bias assessment tool. Standard mean differences with 95% confidence intervals were calculated for statistical analysis. This meta-analysis assessed three variables: general cognitive function, executive function and working memory. The results indicate that general cognitive function improved significantly (standardized mean difference: 0.53, P=0.04), and further subgroup analyses on frequency and duration per session showed that the subgroups 'twice a week' (P=0.01) and 'duration per session >60 min' (P=0.0006) exhibited better performance than the subgroups 'three time a week' (P=0.47) and 'duration per session <60 min' (P=0.53). Additionally, a moderate effect size was found in executive function (standardized mean difference: 0.50, P=0.0003), and there was non-significant effect in working memory (P=0.14). In summary, resistance training may mitigate mild cognitive impairment by improving cognition. Larger-scale studies are recommended to demonstrate the relationship between resistance training and cognition in mild cognitive impairment.

Tai Chi is Effective in Delaying Cognitive Decline in Older Adults with Mild Cognitive Impairment: Evidence from a Systematic Review and Meta-Analysis.

To determine whether Tai Chi (TC) is effective in slowing cognitive decline in older populations with mild cognitive impairment (MCI), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) on Tai Chi and MCI. We searched eight electronic databases (PubMed, PsycINFO, Wanfang, Web of Science, MEDLINE, CNKI, EBSCO, and the Cochrane Central Register of Controlled Trials) for appropriate RCTs published up to August 2019. For those studies included, the data were extracted, methodological quality was evaluated, and then meta-analysis was performed using Review Manager software (version 5.3). A total of 11 of the studies were available for systematic review, which together included 1061 participants, met the inclusion criteria, and ten of these were included in the meta-analysis. For most RCTs, the methodological quality was moderate. The meta-analysis revealed that Tai Chi could significantly improve global cognitive function; memory and learning; mental speed and attention; ideas, abstraction, figural creations, and mental flexibility; and visuospatial perception. The present review adds to the evidence showing that Tai Chi is potentially beneficial in improving cognitive functions among elderly people with MCI. However, strictly designed and well-reported RCTs are required.

Potent anti-tumor immunostimulatory biocompatible nanohydrogel made from DNA.

Unmethylated CpG oligodeoxynucleotides are potent immunostimulatory motifs in activating both innate and acquired immune system by inducing Th1 type antigen-specific T cell responses, but their instability in serum greatly influences their immunostimulant efficiency. Here, we constructed a novel immuno-DNA nanohydrogels consisting of tandem repeat sequences of CpG units named CpG-MCA nanohydrogels through multi-primed chain amplification. CpG-MCA nanohydrogels were proved to resist degradation and increase the proliferation and migration of murine macrophage-like RAW264.7 cells. Furthermore, CpG-MCA nanohydrogels effectively induced high expression of tumor necrosis factor-α and interleukin-6, and remarkably inhibited the proliferation of U251 cells, suggesting that CpG-MCA nanohydrogels are expected to be employed as the potent anti-cancer immunostimulant.

Hydrangea-structured tumor microenvironment responsive degradable nanoplatform for hypoxic tumor multimodal imaging and therapy.

Developing new strategies to alleviate tumor hypoxia and enhance the therapeutic efficacy towards solid tumors is of great significance to tumor therapy. Herein, to overcome tumor hypoxia, specifically designed aza-BODIPY photosensitizer is co-loaded with anti-cancer drug (doxorubicin, DOX) onto the hydrangea-structured MnO2 nanoparticles, and a tumor microenvironment (TME) responsive degradable nanoplatform (MDSP NP) is established. MDSP NPs (∼54 nm), with near infrared absorption (∼853 nm), can be rapidly dissociated to generate oxygen in response to TME, whereby improving tumor hypoxia, in favor of effective drugs release and enhanced chemo/photodynamic therapy. Revealed by in vivo fluorescence and photoaccoustic imaging, MDSP NPs are preferential accumulated at tumor site. Confirmed by photothermal imaging, MDSP NPs can induce hyperthermia to relieve hypoxia, promote the uptake of therapeutic nanoparticles, and further reduce the resistance and improve the therapeutic efficiency. As a result, a remarkable synergistic tumor chemo/photodynamic/photothermal therapy with hydrangea-structured TME responsive oxygen-self-generation nanoplatform is confirmed by both in vitro and in vivo studies, testifying its great potential for hypoxic tumor treatment in clinical application.

Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer's Disease: A Meta-Analysis of a Case-Control Study.

Objectives: Blood lipid profiles have been ambiguously reported as biomarkers of AD in recent years. This study was conducted to evaluate the correlation between blood lipid levels and AD in later-life and to explore the effectiveness and reliability of blood lipid profiles as biomarkers of AD. Methods: Database searching was conducted using PubMed, the Cochrane Library, EMBASE, and Medline. This study was designed following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria. Review Manager 5.3 (RevMan 5.3) software was adopted to perform meta-analysis evaluating the standard mean difference (SMD) with its 95% confidence intervals (CI). Results: A total of 5,286 participants were enrolled from 27 case-control studies in this meta-analysis. The pooled results demonstrated that total cholesterol (TC) level was significantly associated with AD in late-life (SMD = 0.17, 95% CI: [0.01, 0.32], P = 0.03), especially in the subgroup under 70 years old (SMD: 0.45, 95% CI: [0.11, 0.79], P = 0.01) and the subgroup of Western population (SMD: 0.29, 95% CI: [0.04, 0.53], P = 0.02). In the subgroup under 70 years old, the high-density lipoprotein cholesterol (HDL-C) level (SMD = -0.50, 95% CI: [-0.76, -0.25], P = 0.0001) and the low-density lipoprotein cholesterol (LDL-C) level (SMD = 0.59, 95% CI: [0.02, 1.16], P = 0.04) in the AD group were significantly lower and higher than in the control group, respectively. In the subgroup with a sample size larger than 100 subjects, the LDL-C level was significantly higher in AD patients than in the control elderly group (SMD = 0.31, 95% CI: [0.05, 0.56], P = 0.02). There was no significant association between triglyceride (TG) levels and AD in later-life (SMD = -0.00, 95% CI: [-0.12, 0.12], P = 1.00). Conclusion: TC can be a new predictive biomarker of AD or cognitive decline in later-life. Increased TC levels are found to be associated with an elevated risk of AD. Decreased HDL-C levels and increased LDL-C levels may relate to an elevated risk of AD in subjects aged 60-70. Further comprehensive researches will be necessary in the future.

Tumor-Targeting Nanoparticles of Small-Molecule Diketopyrrolopyrrole Derivative for Photothermal Therapy.

Herein, an small-molecule organic nanoparticles, BNTP NPs, has been synthesized. Due to its strong and broad absorption spectra and tumor targeting, BNTP NPs is used as a photothermal agent with photothermal conversion efficiency of 23.2%. BNTP NPs can target tumors, realize tumor diagnosis and suppress the growth of tumor effectively both in vitro and in vivo. Xenon lamp instead of laser is used as light source of BNTP NPs to make PTT safer. No obvious toxicity reaction is observed from histologic analysis and body weight of mice. The results confirm that BNTP NPs have potential for clinical application of PTT.

pH-Responsive PEG-Doxorubicin-Encapsulated Aza-BODIPY Nanotheranostic Agent for Imaging-Guided Synergistic Cancer Therapy.

Synergistic cancer therapy is of great interest for multiple advantages, such as excellent targeting accuracy, low side effects, and enhanced therapeutic efficiency. Herein, a near-infrared photosensitizer aza-BODIPY (AB) with high singlet oxygen quantum yield (ΦΔ = 82%) is designed and synthesized. With Schiff's base obtained from condensation reaction between doxorubicin (DOX) and polyethylene glycol-benzaldehyde (PEG-CHO) as the polymer matrix, aza-BODIPY is encapsulated to afford hydrophilic nanoparticles (DAB NPs). The DAB NPs exhibit high reactive oxygen species (ROS) generation rate and outstanding photothermal conversion efficiency (η = 38.3%) under irradiation. In vivo fluorescence- and photothermal-imaging (PTI) results demonstrate that DAB NPs can specifically accumulate at tumor sites and serve as dual-modal imaging probe for cancer diagnosis. Particularly, triggered by acidic tumor microenvironment, the HCN bond of Schiff's base would be broken simultaneously, resulting in the efficient release of DOX from DAB NPs at tumor sites as well as enhancing the targeting performance of chemotherapeutics. Compared with free DOX and aza-BODIPY nanoparticles, DAB NPs can inhibit tumor growth more effectively through pH-responsive photodynamic/photothermal/chemo synergistic therapy. This report may also present a practicable strategy to develop a pH-responsive nanotheranostic agent for tumor targeting, imaging, and therapy.