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Repurposing the RNA‐guided endonuclease Cas9 to develop artificial CRISPR molecular machines represents a new direction toward synthetic molecular information processing. The operation of CRISPR‐Cas9‐based machines, nevertheless, relies on the molecular recognition of freely diffused sgRNA/Cas9, making it practically challenging to perform spatially regulated localized searching or navigation. Here, we develop a DNA origami‐based single‐molecule CRISPR machine that can perform spatially resolved DNA cleavage via either free or localized searching modes. When triggered at a specific site on the DNA origami with nanoscale accuracy, the free searching mode leads to searching activity that gradually decays with the distance, whereas the localized mode generates spatially‐confined searching activity. Our work expands the function of CRISPR molecular machines and lays foundations to develop integrated molecular circuits and high‐throughput nucleic acid detection. [ABSTRACT FROM AUTHOR]

Repurposing the RNA‐guided endonuclease Cas9 to develop artificial CRISPR molecular machines represents a new direction toward synthetic molecular information processing. The operation of CRISPR‐Cas9‐based machines, nevertheless, relies on the molecular recognition of freely diffused sgRNA/Cas9, making it practically challenging to perform spatially regulated localized searching or navigation. Here, we develop a DNA origami‐based single‐molecule CRISPR machine that can perform spatially resolved DNA cleavage via either free or localized searching modes. When triggered at a specific site on the DNA origami with nanoscale accuracy, the free searching mode leads to searching activity that gradually decays with the distance, whereas the localized mode generates spatially‐confined searching activity. Our work expands the function of CRISPR molecular machines and lays foundations to develop integrated molecular circuits and high‐throughput nucleic acid detection. [ABSTRACT FROM AUTHOR]

Abstract: CRISPR/Cas9 technology enables targeted gene editing; yet, the efficiency and specificity remain unsatisfactory, particularly for the nonvirally delivered, plasmid‐based CRISPR/Cas9 system. To tackle this, a self‐assembled micelle is developed and evaluated for human papillomavirus (HPV) E7 oncogene disruption. The optimized micelle enables effective delivery of Cas9 plasmid with a transient transgene expression profile, benefiting the specificity of Cas9 recognition. Furthermore, the feasibility of using the micelle is explored for another nucleic acid‐guided nuclease system, Natronobacterium gregoryi Argonaute (NgAgo). Both systems are tested in vitro and in vivo to evaluate their therapeutic potential. Cas9‐mediated E7 knockout leads to significant inhibition of HPV‐induced cancerous activity both in vitro and in vivo, while NgAgo does not show significant E7 inhibition on the xenograft mouse model. Collectively, this micelle represents an efficient delivery system for nonviral gene editing, adding to the armamentarium of gene editing tools to advance safe and effective precision medicine‐based therapeutics. [ABSTRACT FROM AUTHOR]

Membrane curvature reflects physical forces operating on the lipid membrane, which plays important roles in cellular processes. Here, we design a mechanosensitive DNA (MSD) nanomachine that mimics natural mechanosensitive PIEZO channels to convert the membrane tension changes of lipid vesicles with different sizes into fluorescence signals in real time. The MSD nanomachine consists of an archetypical six‐helix‐bundle DNA nanopore, cholesterol‐based membrane anchors, and a solvatochromic fluorophore, spiropyran (SP). We find that the DNA nanopore effectively amplifies subtle variations of the membrane tension, which effectively induces the isomerization of weakly emissive SP into highly emissive merocyanine isomers for visualizing membrane tension changes. By measuring the membrane tension via the fluorescence of MSD nanomachine, we establish the correlation between the membrane tension and the curvature that follows the Young‐Laplace equation. This DNA nanotechnology‐enabled strategy opens new routes to studying membrane mechanics in physiological and pathological settings. [ABSTRACT FROM AUTHOR]

Membrane curvature reflects physical forces operating on the lipid membrane, which plays important roles in cellular processes. Here, we design a mechanosensitive DNA (MSD) nanomachine that mimics natural mechanosensitive PIEZO channels to convert the membrane tension changes of lipid vesicles with different sizes into fluorescence signals in real time. The MSD nanomachine consists of an archetypical six‐helix‐bundle DNA nanopore, cholesterol‐based membrane anchors, and a solvatochromic fluorophore, spiropyran (SP). We find that the DNA nanopore effectively amplifies subtle variations of the membrane tension, which effectively induces the isomerization of weakly emissive SP into highly emissive merocyanine isomers for visualizing membrane tension changes. By measuring the membrane tension via the fluorescence of MSD nanomachine, we establish the correlation between the membrane tension and the curvature that follows the Young‐Laplace equation. This DNA nanotechnology‐enabled strategy opens new routes to studying membrane mechanics in physiological and pathological settings. [ABSTRACT FROM AUTHOR]

A huge amount of coal with high content of Na and K in ash was found in Xinjiang Province, China. However, the most serious ash fouling/slagging problems of that kind of coal usually cause the increasing of operating costs and energy consumption in a power plant. In order to clarify the mechanism of the effect on ash deposition behavior on different material surfaces, the experimental study, as well as quantum chemistry calculation, was used in this study. The results show that the nickel-based material can significantly alleviate the ash deposition of high-alkali coal. The adsorption energy between Na atom and NiO is much higher than that between Na atom and Fe2O3. The much lower system energy between Na atom and Fe2O3 will cause more stable system of Na-Fe2O3. However, for nickel-based material, the electrons of Na-NiO system are being at a higher energy status, which will cause the system to stay at a relative unstable status. The quantum chemistry calculation results can well explain the phenomena of the experimental result. Furthermore, the interaction mechanisms between Na and Al-based materials were also calculated to predict the effect of Al-based material on preventing ash fouling and slagging. Copyright © 2016 Curtin University of Technology and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Dynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we constructed a super DNA‐enzymes molecule (SDEM) that comprises at least two cascade enzymes and multiple linked DNA strands to control and detect metabolism. We found that the programmable SDEM, which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP), has a 20‐fold lower detection limit and a 1.6‐fold higher reaction rate than free enzymes. An SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from an SDEM with GOx and HRP cascades to an SDEM with sarcosine oxidase (SOX) and HRP cascades in over six orders of magnitude less time than without the catassembly to detect different metabolisms (GO and sarcosine) on demand. [ABSTRACT FROM AUTHOR]

Dynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we constructed a super DNA‐enzymes molecule (SDEM) that comprises at least two cascade enzymes and multiple linked DNA strands to control and detect metabolism. We found that the programmable SDEM, which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP), has a 20‐fold lower detection limit and a 1.6‐fold higher reaction rate than free enzymes. An SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from an SDEM with GOx and HRP cascades to an SDEM with sarcosine oxidase (SOX) and HRP cascades in over six orders of magnitude less time than without the catassembly to detect different metabolisms (GO and sarcosine) on demand. [ABSTRACT FROM AUTHOR]

The emerging stem cell‐derived hepatocyte‐like cells (HLCs) are the alternative cell sources of hepatocytes for treatment of highly lethal acute liver failure (ALF). However, the hostile local environment and the immature cell differentiation may compromise their therapeutic efficacy. To this end, human adipose‐derived mesenchymal stromal/stem cells (hASCs) are engineered into different‐sized multicellular spheroids and co‐cultured with 3D coaxially and hexagonally patterned human umbilical vein endothelial cells (HUVECs) in a liver lobule‐like manner to enhance their hepatic differentiation efficiency. It is found that small‐sized hASC spheroids, with a diameter of ≈50 µm, show superior pro‐angiogenic effects and hepatic differentiation compared to the other counterparts. The size‐dependent functional enhancements are mediated by the Wnt signaling pathway. Meanwhile, co‐culture of hASCs with HUVECs, at a HUVECs/hASCs seeding density ratio of 2:1, distinctly promotes hepatic differentiation and vascularization both in vitro and in vivo, especially when endothelial cells are patterned into hollow hexagons. After subcutaneous implantation, the mini‐liver, consisting of HLC spheroids and 3D‐printed interconnected vasculatures, can effectively improve liver regeneration in two ALF animal models through amelioration of local oxidative stress and inflammation, reduction of liver necrosis, as well as increase of cell proliferation, thereby showing great promise for clinical translation. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) involves extensive necrosis of liver cells and severe impairment of liver function. Hepatocyte transplantation holds promise for treating ALF by swiftly supporting liver functions and promoting liver regeneration. However, the scarcity of suitable cell sources requires strategies to obtain enough functional hepatocyte‐like cells (HLCs) and optimize their in vivo transplantation efficiency. A DNA hexahedral nanostructure (DHN) is developed loaded with microRNA‐122 to efficiently induce hepatic differentiation of human adipose‐derived mesenchymal stem cells into HLCs. These HLCs can serve as alternative hepatocyte sources, as confirmed by expression of liver‐specific genes and proteins, and the restoration of liver functions. To enhance in vivo survival efficiency of HLCs, a versatile scaffold is also created by 3D printing the calcium‐cross‐linked mixture bioink composed of sodium alginate, gelatin, and silk fibroin with excellent ROS scavenging capabilities. The scaffold is infused with chitosan‐DHN hydrogel containing HLCs for tissue engineering orthotopic transplantation in CCl4‐induced ALF mice. The transplanted composite scaffold‐HLCs successfully repair tissue necrosis in the liver injury area of mice and regulate expressions of genes and proteins associated with inflammation, oxidative stress, and hepatocyte function. Collectively, this study offers a novel approach and strategy for identifying alternative hepatocyte sources and treating ALF. [ABSTRACT FROM AUTHOR]

Although epitaxial strain imparted by lattice mismatch between a film and the underlying substrate has led to distinct structures and emergent functionalities, the discrete lattice parameters of limited substrates, combined with strain relaxations driven by film thickness, result in severe obstructions to subtly regulate electro‐elastic coupling properties in perovskite ferroelectric films. Here a practical and universal method to achieve highly strained phases with large tetragonal distortions in Pb‐based ferroelectric films through synergetic effects of moderately (≈1.0%) misfit strains and laser fluences during pulsed laser deposition process is demonstrated. The phase possesses unexpectedly large Poisson's ratio and negative thermal expansion, and concomitant enhancements of spontaneous polarization (≈100 µC cm−2) and Curie temperature (≈800 °C), 40% and 75% larger than that of bulk counterparts, respectively. This strategy efficiently circumvents the long‐standing issue of limited numbers of discrete substrates and enables continuous regulations of exploitable lattice states in functional oxide films with tightly elastic coupled performances beyond their present levels. [ABSTRACT FROM AUTHOR]

As a currently common strategy to treat cancer, surgical resection may cause tumor recurrence and metastasis due to residual postoperative tumors. Herein, an implantable sandwich‐structured dual‐drug depot is developed to trigger a self‐intensified starvation therapy and hypoxia‐induced chemotherapy sequentially. The two outer layers are 3D‐printed using a calcium‐crosslinked mixture ink containing soy protein isolate, polyvinyl alcohol, sodium alginate, and combretastatin A4 phosphate (CA4P). The inner layer is one patch of poly (lactic‐co‐glycolic acid)‐based electrospun fibers loaded with tirapazamine (TPZ). The preferentially released CA4P destroys the preexisting blood vessels and prevents neovascularization, which obstructs the external energy supply to cancer cells but aggravates hypoxic condition. The subsequently released TPZ is bioreduced to cytotoxic benzotriazinyl under hypoxia, further damaging DNA, generating reactive oxygen species, disrupting mitochondria, and downregulating hypoxia‐inducible factor 1α, vascular endothelial growth factor, and matrix metalloproteinase 9. Together these processes induce apoptosis, block the intracellular energy supply, counteract the disadvantage of CA4P in favoring intratumor angiogenesis, and suppress tumor metastasis. The in vivo and in vitro results and the transcriptome analysis demonstrate that the postsurgical adjuvant treatment with the dual‐drug‐loaded sandwich‐like implants efficiently inhibits tumor recurrence and metastasis, showing great potential for clinical translation. [ABSTRACT FROM AUTHOR]

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Resolving inflammation and promoting intestinal tissue regeneration are critical for inflammatory bowel disease (IBD) treatment. Bioactive glass (BG) is a clinically approved bone graft material and has been shown to modulate inflammatory response, but it is unknown whether BG can be applied to treat IBD. Here, it is reported that BG attenuates pro‐inflammatory response of lipopolysaccharide (LPS)‐stimulated macrophages and hence reduces inflammatory damage to intestinal organoids in vitro. In addition, zein/sodium alginate‐based core–shell microspheres (Zein/SA/BG) are developed for oral delivery of BG, which helps prevent premature dissolution of BG in the stomach. The results show that Zein/SA/BG protects BG from a gastric‐simulated environment while dissolved in an intestinal‐simulated environment. When administered to acute and chronic colitis mice model, Zein/SA/BG significantly reduces intestinal inflammation, promotes epithelial tissue regeneration, and partially restores microbiota homeostasis. These findings are the first to reveal the therapeutic efficacy of BG against IBD, which may provide a new therapeutic approach at low cost for effective IBD treatment. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a leading cause of drug‐induced liver injury and acute liver failure, while the detection, prognosis prediction, and therapy for APAP‐induced liver injury (AILI) remain improved. Here, it is determined that the temporal pattern of circulating cell‐free DNA (cfDNA) is strongly associated with damage and inflammation parameters in AILI. CfDNA is comparable to alanine aminotransferase (ALT) in predicting mortality and outperformed ALT when combined with ALT in AILI. The depletion of cfDNA or neutrophils alleviates liver damage, while the addition of cfDNA or adoptive transfer of neutrophils exacerbates the damage. The combination of DNase I and N‐acetylcysteine attenuates AILI significantly. This study establishes that cfDNA is a mechanistic biomarker to predict mortality in AILI mice. The combination of scavenging cfDNA and reducing oxidative damage provides a promising treatment for AILI. [ABSTRACT FROM AUTHOR]

Abstract: Osteosarcoma is one of the most serious bone malignancies with rapid speed of deterioration and low survival rate in children and teenagers. Chemotherapy is an important treatment for osteosarcoma, while the conventional small‐molecule therapeutics exhibit low efficacies and severe side effects in the clinic. Drug‐delivery platforms based on nanotechnology, particularly for self‐stabilized delivery platforms with prolonged blood circulation, enhanced intratumoral accumulation, improved antitumor efficacy, and diminished side effects, may break the deadlock on osteosarcoma chemotherapy. Here, a cisplatin (CDDP)‐crosslinked hyaluronic acid (HA) nanogel (CDDPHANG) is prepared for effective delivery of doxorubicin (DOX) to treat osteosarcoma. Importantly, both DOX and CDDP have led clinically used antitumor drugs, and CDDP acts as a crosslinker and ancillary anticarcinogen to prevent the premature release of DOX and to achieve synergistic therapeutic performance. Because of the enhanced stability of the nanogel, this CDDP‐crosslinked DOX‐loaded nanomedicine (CDDPHANG/DOX) exhibits an obviously prolonged circulation time compared to free drugs. Moreover, after valid tumor accumulation, DOX and CDDP are synergistically delivered into the tumor cells and synchronously released into the intracellular acidic environment. Based on the synergistic apoptosis‐inducing effects of DOX and CDDP, CDDPHANG/DOX reveals an evidently enhanced antitumor efficacy compared to free drugs and their combination, indicating its great prospects for the chemotherapy of osteosarcoma. [ABSTRACT FROM AUTHOR]

Insulin, a main medication to control glycemia of type 1 and advanced type 2 diabetes, faces problems of a short half‐life and poor stability during its clinical use. Zwitterionic polymer shows unique properties of antifouling and low immunogenicity. Here, we have synthesized a new insulin‐zwitterionic polymer conjugate (INS‐PMPC) through grafting‐from strategy by controlled radical polymerization. Apart from showing excellent stability upon mechanical agitation, the resulting INS‐PMPC conjugate provided over 20 h of glycemic control due to improved pharmacokinetics in diabetic mice with one single subcutaneous injection. Most importantly, this insulin‐zwitterionic polymer conjugate significantly decreases the incidence of hypoglycemia. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B infection remains incurable due to the stable presence of various forms of hepatitis B virus (HBV) genome, especially the HBV covalently closed circular DNA (cccDNA). The emergence of clustered regularly interspaced short palindromic repeat (CRISPR) technology provides a new opportunity to potentially cure the HBV infection. However, the efficiency and specificity remain unsatisfactory, especially for nonviral CRISPR/Cas9 delivery. To tackle these, a liver‐specific CRISPR/Cas9 magnetic nanosystem FMNPpAG333/sgXPP is constructed based on fluorinated polyethylenimine‐coated magnetic nanoparticles and liver‐specific ApoE.HCR.hAAT promoter‐driven Cas9‐T2A‐EGFP plasmid with dual sgRNAs. The elaborate system enables magnetic field‐induced spatially specific distribution and hepatocyte‐specific promoter‐driven liver‐specific gene editing. Moreover, this CRISPR/Cas9 magnetic nanosystem is designed to disrupt the two conserved sites in X opening reading frame and Pol opening reading frame of the HBV genome, thereby significantly inactivating the HBV genome without showing off‐target effects. Treatment with FMNPpAG333/sgXPP for 7 days reduces serum HBsAg levels by 76% with a total editing efficiency of ≈20% in the two conserved sites. Collectively, this study demonstrates spatiotemporal liver genome editing as well as the feasibility of applying a nonviral CRISPR/Cas9 vector for HBV treatment, which may open up a new application for CRISPR therapeutics. [ABSTRACT FROM AUTHOR]

In the article "3D Printing of a Vascularized Mini-Liver," the authors discuss the development of a vascularized mini-liver using 3D bioprinting. The researchers found that human mesenchymal stromal/stem cell spheroids had superior hepatic differentiation and pro-angiogenic effects. Additionally, the coculture of these cells with hexagonally and coaxially patterned endothelial cells resulted in the production of hepatocyte-like cells. The fabrication of a vascularized hepatic lobule-like mini-liver showed promise in effectively treating acute liver failure. [Extracted from the article]

Freestanding oxide nanomembranes have promising applications because of their novel electronic states and flexible crystalline structures. Several materials have been developed as sacrificial layers to exfoliate thin films from substrates via wet‐etching. However, these materials face great challenges in terms of either complicated crystalline structures or corrosive solutions. Here, a new sacrificial material, SrCoO2.5, is presented, which can be coherently grown with wide‐range strains and crystalline orientations and is also soluble in eco‐friendly solutions such as acetic acid, vinegar, and even carbonated drinks. With SrCoO2.5 as the sacrificial layer, high‐quality freestanding ferromagnetic SrRuO3 membranes are achieved from wide‐range epitaxial strains and different crystalline orientations. By investigating the evolution of the magnetic properties of these samples, it is discovered that epitaxial strain causes a distinct modification of the magnetic anisotropy of (001)pc‐oriented SrRuO3 samples, while its influence on the (110)pc and (111)pc samples is insignificant. This study not only demonstrates the freestanding SrRuO3 as a promising material for flexible spintronic devices, but also offers a great opportunity to engineer a wide range of strained and oriented complex oxides for novel freestanding electronics using this newly developed sacrificial material. [ABSTRACT FROM AUTHOR]

Bacterial infection and excessive inflammation following abdominal injury can cause life‐threatening complications that lead to multiple organ failure and death. Removing bacteria and proinflammatory factors—which are predominantly negatively charged—from the wound site with a cationic, antibiotic‐containing hydrogel wound dressing is therefore a promising treatment approach for severe abdominal trauma. Here an injectable, self‐healing hydrogel composed of the gel‐forming glycosaminoglycan oxidized chondroitin sulfate (OCS), cationic polyethylenimine (PEI), and the antibiotic tobramycin (Tob) via a Schiff's base reaction is developed. Compared with hydrogels lacking either PEI or Tob, only the Tob/PEI/OCS hydrogels exhibit a large binding capacity for negatively‐charged proinflammatory factors including cell‐free DNA, lipopolysaccharides, TNF‐α, and high mobility group box 1 protein, and a large reduction in bacterial populations in vitro. In a murine model of severe abdominal trauma, the Tob/PEI/OCS hydrogel exhibits good biodegradability and biosafety, reduced local and systemic inflammation and infection, and prevents multiple organ failure, resulting in 100% survival. This hydrogel dressing is thus a promising biomaterial for preventing complications and improving outcomes following severe abdominal trauma. [ABSTRACT FROM AUTHOR]

Integrating dissimilar materials at the nanoscale is crucial for modern electronics and optoelectronics. The structural DNA nanotechnology provides a universal platform for precision assembly of materials; nevertheless, heterogeneous integration of dissimilar materials with DNA nanostructures has yet to be explored. We report a DNA origami‐encoded strategy for integrating silica‐metal heterostructures. Theoretical and experimental studies reveal distinctive mechanisms for the binding and aggregation of silica and metal clusters on protruding double‐stranded DNA (dsDNA) strands that are prescribed on the DNA origami template. In particular, the binding energy differences of silica/metal clusters and DNA molecules underlies the accessibilities of dissimilar material areas on DNA origami. By programming the densities and lengths of protruding dsDNA strands on DNA origami, silica and metal materials can be independently deposited at their predefined areas with a high vertical precision of 2 nm. We demonstrate the integration of silica‐gold and silica‐silver heterostructures with high site addressability. This DNA nanotechnology‐based strategy is thus applicable for integrating various types of dissimilar materials, which opens up new routes to bottom‐up electronics. [ABSTRACT FROM AUTHOR]

Integrating dissimilar materials at the nanoscale is crucial for modern electronics and optoelectronics. The structural DNA nanotechnology provides a universal platform for precision assembly of materials; nevertheless, heterogeneous integration of dissimilar materials with DNA nanostructures has yet to be explored. We report a DNA origami‐encoded strategy for integrating silica‐metal heterostructures. Theoretical and experimental studies reveal distinctive mechanisms for the binding and aggregation of silica and metal clusters on protruding double‐stranded DNA (dsDNA) strands that are prescribed on the DNA origami template. In particular, the binding energy differences of silica/metal clusters and DNA molecules underlies the accessibilities of dissimilar material areas on DNA origami. By programming the densities and lengths of protruding dsDNA strands on DNA origami, silica and metal materials can be independently deposited at their predefined areas with a high vertical precision of 2 nm. We demonstrate the integration of silica‐gold and silica‐silver heterostructures with high site addressability. This DNA nanotechnology‐based strategy is thus applicable for integrating various types of dissimilar materials, which opens up new routes to bottom‐up electronics. [ABSTRACT FROM AUTHOR]

Liver disease, particularly viral hepatitis and hepatocellular carcinoma (HCC), is a global healthcare burden and leads to more than 2 million deaths per year worldwide. Despite some success in diagnosis and vaccine development, there are still unmet needs to improve diagnostics and therapeutics for viral hepatitis and HCC. The emerging clustered regularly interspaced short palindromic repeat/associated proteins (CRISPR/Cas) technology may open up a unique avenue to tackle these two diseases at the genetic level in a precise manner. Especially, liver is a more accessible organ over others from the delivery point of view, and many advanced strategies applied for nanotheranostics can be adapted in CRISPR‐mediated diagnostics or liver gene editing. In this review, the focus is on these two aspects of viral hepatitis and HCC applications. An overview on CRISPR editor development and current progress in clinical trials is first given, followed by highlighting the recent advances integrating the merits of gene editing and nanotheranostics. The promising systems that are used in other applications but may hold potentials in liver gene editing are also discussed. This review concludes with the perspectives on rationally designing the next‐generation CRISPR approaches and improving the editing performance. [ABSTRACT FROM AUTHOR]

Biomimetic strategies are useful for designing potent vaccines. Decorating a nanoparticulate adjuvant with cell membrane fragments as the antigen‐presenting source exemplifies, such as a promising strategy. For translation, a standardizable, consistent, and scalable approach for coating nanoadjuvant with the cell membrane is important. Here a turbulent mixing and self‐assembly method called flash nanocomplexation (FNC) for producing cell membrane‐coated nanovaccines in a scalable manner is demonstrated. The broad applicability of this FNC technique compared with bulk‐sonication by using ten different core materials and multiple cell membrane types is shown. FNC‐produced biomimetic nanoparticles have promising colloidal stability and narrow particle polydispersity, indicating an equal or more homogeneous coating compared to the bulk‐sonication method. The potency of a nanovaccine comprised of B16‐F10 cancer cell membrane decorating mesoporous silica nanoparticles loaded with the adjuvant CpG is then demonstrated. The FNC‐fabricated nanovaccines when combined with anti‐CTLA‐4 show potency in lymph node targeting, DC antigen presentation, and T cell immune activation, leading to prophylactic and therapeutic efficacy in a melanoma mouse model. This study advances the design of a biomimetic nanovaccine enabled by a robust and versatile nanomanufacturing technique. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation between acetylcholine receptor antibodies (AChR‐Ab) concentration levels and individualized clinical symptoms in patients with AChR myasthenia gravis (AChR‐MG) in China. Methods: ELISA was used to determine the concentration of AChR‐Ab in patients with MG. The Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, Quantitative Myasthenia Gravis (QMG) score, and MG‐specific activities of daily living (MG‐ADL) scoring systems were used to evaluate the clinical status of patients. Spearman correlation analysis was used to determine the correlation between the AChR‐Ab concentration and clinical score. The changes in the antibody concentration and clinical score are shown in MGFA‐antibody concentration–treatment plots. Results: Autoantibody detection tests were performed in 67 patients, and their clinical scores were recorded. Forty‐nine patients received immunosuppressive therapy, 17 patients received pyridostigmine only, and 1 patient under thymectomy without any medication. The AChR‐Ab concentration correlated with the MGFA Classification in 5 (29.4%) patients in the pyridostigmine‐only group and 15 (30.6%) patients in the immunosuppressive drug group. The changes in the MGFA Classification preceded the changes in the AChR‐Ab concentration in 4 (23.5%) patients treated with pyridostigmine and 10 (20.4%) patients on immunosuppressive drugs. In patients on oral non‐steroidal immunosuppressants, the AChR‐Ab concentration changed by more than 50%, whereas the MGFA Classification did not increase. The AChR‐Ab concentration decreased in 17/32 (53.1%) patients after thymectomy, and then increased, whereas the AChR‐Ab concentration increased in 15/32 (46.9%) patients and the MGFA Classification decreased in 27/32 (81.8%) patients after thymectomy. The AChR‐Ab concentration presented a slight correlation with the corresponding MGFA, QMG, and MG‐ADL in patients with thymoma. Discussion: In the Chinese AChR‐MG population, the Changes in the AChR‐Ab concentration in individuals with AChR‐MG did not consistently correlate with the severity of clinical symptoms. [ABSTRACT FROM AUTHOR]

Although adoptive transfer of therapeutic cells to cancer patients is demonstrated with great success and fortunately approved for the treatment of leukemia and B‐cell lymphoma, potential issues, including the unclear mechanism, complicated procedures, unfavorable therapeutic efficacy for solid tumors, and side effects, still hinder its extensive applications. The explosion of nanotechnology recently has led to advanced development of novel strategies to address these challenges, facilitating the design of nano‐therapeutics to improve adoptive cell therapy (ACT) for cancer treatment. In this review, the emerging nano‐enabled approaches, that design multiscale artificial antigen‐presenting cells for cell proliferation and stimulation in vitro, promote the transducing efficiency of tumor‐targeting domains, engineer therapeutic cells for in vivo imaging, tumor infiltration, and in vivo functional sustainability, as well as generate tumoricidal T cells in vivo, are summarized. Meanwhile, the current challenges and future perspectives of the nanostrategy‐based ACT for cancer treatment are also discussed in the end. [ABSTRACT FROM AUTHOR]

Light is a particularly appealing tool for on‐demand drug delivery due to its noninvasive nature, ease of application, and exquisite temporal and spatial control. Great progress is achieved in the development of novel light‐driven drug delivery strategies with both breadth and depth. Light‐controlled drug delivery platforms can be generally categorized into three groups: photochemical, photothermal, and photoisomerization‐mediated therapies. Various advanced materials, such as metal nanoparticles, metal sulfides and oxides, metal–organic frameworks, carbon nanomaterials, upconversion nanoparticles, semiconductor nanoparticles, stimuli‐responsive micelles, polymer‐ and liposome‐based nanoparticles are applied for light‐stimulated drug delivery. In view of the increasing interest in on‐demand targeted drug delivery, the development of light‐responsive systems with a focus on recent advances, key limitations, and future directions is reviewed. [ABSTRACT FROM AUTHOR]

Aim: Myeloid differentiation factor 88 (MyD88) plays a key role in tumor proliferation and metastasis. Targeting MyD88 is a potent strategy in tumor therapy. TJ‐M2010‐5 is a small molecule derivative of aminothiazole and could inhibit dimer formation of MyD88. To explore the potential of TJ‐M2010‐5 in tumor therapy, we determined its antitumor effect and correlate mechanisms of TJ‐M2010‐5 in hepatocellular carcinoma (HCC). Methods: The antitumor effect of intratumoral injection of TJ‐M2010‐5 to H22 tumor‐bearing BALB/c mice was observed. Tumor growth was monitored. The expression of MyD88 and Ki‐67 were detected by immunofluorescence. In vitro, the impacts of TJ‐M2010‐5 on proliferation, cell cycle, necrosis, and apoptosis of H22 cells were evaluated. The direct and indirect effects of TJ‐M2010‐5 on macrophages were evaluated using flow cytometry. Results: TJ‐M2010‐5 induced both G0/G1 and G1/S phase arrests in HCC cells. Mechanically, downstream activation of MyD88 was suppressed by TJ‐M2010‐5 through the extracellular regulated protein kinase‐1/2/p90 ribosomal S6 kinase/glycogen synthase kinase‐3β signaling pathway. In turn, cyclin‐dependent kinase (CDK)6/cyclin D1 and CDK2/cyclin E complexes were downregulated. More importantly, TJ‐M2010‐5 significantly inhibited tumor growth in mice. Additionally, the portion of antitumor M1 macrophages (F4/80+CD11c+) in the tumor microenvironment were increased after TJ‐M2010‐5 treatment. Together, these data indicate that TJ‐M2010‐5 is a promising therapeutic drug for HCC. Conclusions: These results indicate that MyD88 is a feasible target for antitumor treatment and TJ‐M2010‐5 is a qualified candidate for HCC therapy. [ABSTRACT FROM AUTHOR]

Sandwich-Structured Implants to Obstruct Multipath Energy Supply and Trigger Self-Enhanced Hypoxia-Initiated Chemotherapy Against Postsurgical Tumor Recurrence and Metastasis (Adv. Sci. 22/2023) The postsurgical adjuvant treatment with combretastatin A4 phosphate and tirapazamineloaded implants efficiently inhibits tumor recurrence and metastasis, showing great potential for clinical applications. B Postsurgical Tumor Therapy with In Situ Implantation b In article number 2300899, Yanteng Xu, Zhaohui Tang, Yu Tao, Mingqiang Li, and co-workers report an implantable sandwich-structured dual-drug depot to achieve self-enhanced postsurgical tumor treatment through starvation therapy and hypoxia-induced chemotherapy that are triggered in sequence. [Extracted from the article]

Keywords: CRISPR/Cas9; gene editing; hepatitis B virus (HBV); liver-specific promoters; magnetic nanosystems EN CRISPR/Cas9 gene editing hepatitis B virus (HBV) liver-specific promoters magnetic nanosystems 1 1 1 02/13/23 20230209 NES 230209 B Spatiotemporal Liver Genome Editing b In article number 2210860, Mingqiang Li, Yu Tao, Yeh-Hsing Lao, and co-workers report spatiotemporally-controlled gene editing to inactivate hepatitis B infection based on magnetic nanoparticles and liver-specific promoter-driven CRISPR/Cas9 plasmid. CRISPR/Cas9, gene editing, hepatitis B virus (HBV), liver-specific promoters, magnetic nanosystems Magnetic-Activated Nanosystem with Liver-Specific CRISPR Nonviral Vector to Achieve Spatiotemporal Liver Genome Editing as Hepatitis B Therapeutics (Adv. Funct. [Extracted from the article]

Berberine, an bioactive isoquinolin alkaloid from traditional Chinese herbs, is considered to be a promising agent based on its remarkable activity against hepatocellular carcinoma. However, the clinical application of this nature compound had been hampered owing to its properties such as poor aqueous solubility, low gastrointestinal absorption, and reduced bioavailability. Therefore, we developed Janus magnetic mesoporous silica nanoparticles (Fe3O4- mSiO2 NPs) consisting of a Fe3O4 head for magnetic targeting and a mesoporous SiO2 body for berberine delivery. A pH-sensitive group was introduced on the surface of mesoporous silica for berberine loading to develop a tumor microenvironment-responsive nanocarrier, which exhibited uniform morphology, good superparamagnetic properties, high drug-loading amounts, superior endocytic ability, and low cytotoxicity. Berberine-loaded Fe3O4- mSiO2 NPs exerted extraordinarily high specificity for hepatocellular carcinoma cells, which was due to the pH-responsive berberine release, as well as higher endocytosis capacity in hepatocellular carcinoma cells rather than normal liver cells. More importantly, an external magnetic field could significantly improve antitumor activity of Ber-loaded Fe3O4- mSiO2 NPs through enhancing berberine internalization. Taken together, our results suggest that Janus nanocarriers driven by the magnetic field may provide an effective and safe way to facilitate clinical use of berberine against hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

The nanoscale CRISPR/Cas systems could act as smart enzymatic robots to target the disease-associated cells and nucleic acid signatures and may be potentially added to the armamentarium for efficiently addressing these challenging liver diseases. B CRISPR Nanotheranostics b In article number 2102051, Yeh-Hsing Lao, Qi Zhang, Yu Tao, Mingqiang Li, and co-workers overview the recent advances of CRISPR nanotheranostics in tacking viral hepatitis and hepatocellular carcinoma. [Extracted from the article]

For patients carrying BRCA1 mutations, at least one‐third develop triple negative breast cancer (TNBC). Not only is TNBC difficult to treat due to the lack of molecular target receptors, but BRCA1 mutations (BRCA1m) also result in chemotherapeutic resistance, making disease recurrence more likely. Although BRCA1m are highly heterogeneous and therefore difficult to target, BRCA1 gene's synthetic lethal pair, PARP1, is conserved in BRCA1m cancer cells. Therefore, we hypothesize that targeting PARP1 might be a fruitful direction to sensitize BRCA1m cancer cells to chemotherapy. We used CRISPR/Cas9 technology to generate PARP1 deficiency in two TNBC cell lines, MDA‐MB‐231 (BRCA1 wild‐type) and MDA‐MB‐436 (BRCA1m). We explored whether this PARP1 disruption (PARP1m) could significantly lower the chemotherapeutic dose necessary to achieve therapeutic efficacy in both a 2D and 3D tumor‐on‐a‐chip model. With both BRCA1m and PARP1m, the TNBC cells were more sensitive to three representative chemotherapeutic breast cancer drugs, doxorubicin, gemcitabine and docetaxel, compared with the PARP1 wild‐type counterpart in the 2D culture environment. However, PARP1m did not result in this synergy in the 3D tumor‐on‐a‐chip model, suggesting that drug dosing in the tumor microenvironment may influence the synergy. Taken together, our results highlight a discrepancy in the efficacy of the combination of PARP1 inhibition and chemotherapy for TNBC treatment, which should be clarified to justify further clinical testing. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is clinically promising in destructing primary tumors but ineffective against distant metastases. This study reports the use of immunogenic nanoparticles mediated combination of PDT and magnetic hyperthermia to synergistically augment the anti‐metastatic efficacy of immunotherapy. Janus nanobullets integrating chlorine e6 (Ce6) loaded, disulfide‐bridged mesoporous organosilica bodies with magnetic heads (M‐MONs@Ce6) are tailored for redox/pH‐triggered photosensitizer release accompanying their matrix degradation. Cancer cell membrane cloaking enables favorable tumor‐targeted accumulation and prolonged blood circulation time of M‐MONs@Ce6. The combination of PDT and magnetic hyperthermia has a strong synergy anticancer activity and simultaneously elicits a sequence of immunogenic cell death, resulting in synergistically tumor‐specific immune responses. When combined with anti‐CTLA‐4 antibody, the biomimetic and biodegradable nanoparticle enables the notable eradication of primary and deeply metastatic tumors with low systematic toxicity, thus potentially advancing the development of combined hyperthermia, PDT, and checkpoint blockade immunotherapy to combat cancer metastasis. [ABSTRACT FROM AUTHOR]

Inflammation is ubiquitous in the body, triggering desirable immune response to defend against dangerous signals or instigating undesirable damage to cells and tissues to cause disease. Nanomedicine holds exciting potential in modulating inflammation. In particular, cell membranes derived from cells involved in the inflammatory process may be used to coat nanotherapeutics for effective targeted delivery to inflammatory tissues. Herein, the recent progress of rationally engineering cell membrane‐based nanotherapeutics for inflammation therapy is highlighted, and the challenges and opportunities presented in realizing the full potential of cell‐membrane coating in targeting and manipulating the inflammatory microenvironment are discussed. [ABSTRACT FROM AUTHOR]