Nanoparticle Orientation to Control RNA Loading and Ligand Display on Extracellular Vesicles for Cancer Regression

Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle. In contrast, placing the cholesterol at the arrowhead results in partial loading of RNA nanoparticles into the extracellular vesicles. Taking advantage of the RNA ligand for specific targeting and extracellular vesicles for efficient membrane fusion, the resulting ligand-displaying extracellular vesicles were capable of specific delivery of siRNA to cells, and efficiently blocked tumour growth in three cancer models. Extracellular vesicles displaying an aptamer that binds to prostate-specific membrane antigen, and loaded with survivin siRNA, inhibited prostate cancer xenograft. The same extracellular vesicle instead displaying epidermal growth-factor receptor aptamer inhibited orthotopic breast cancer models. Likewise, survivin siRNA-loaded and folate-displaying extracellular vesicles inhibited patient-derived colorectal cancer xenograft

Endophytes vs tree pathogens and pests: can they be used as biological control agents to improve tree health?

Like all other plants, trees are vulnerable to attack by a multitude of pests and pathogens. Current control measures for many of these diseases are limited and relatively ineffective. Several methods, including the use of conventional synthetic agro-chemicals, are employed to reduce the impact of pests and diseases. However, because of mounting concerns about adverse effects on the environment and a variety of economic reasons, this limited management of tree diseases by chemical methods is losing ground. The use of biological control, as a more environmentally friendly alternative, is becoming increasingly popular in plant protection. This can include the deployment of soil inoculants and foliar sprays, but the increased knowledge of microbial ecology in the phytosphere, in particular phylloplane microbes and endophytes, has stimulated new thinking for biocontrol approaches. Endophytes are microbes that live within plant tissues. As such, they hold potential as biocontrol agents against plant diseases because they are able to colonize the same ecological niche favoured by many invading pathogens. However, the development and exploitation of endophytes as biocontrol agents will have to overcome numerous challenges. The optimization and improvement of strategies employed in endophyte research can contribute towards discovering effective and competent biocontrol agents. The impact of environment and plant genotype on selecting potentially beneficial and exploitable endophytes for biocontrol is poorly understood. How endophytes synergise or antagonise one another is also an important factor. This review focusses on recent research addressing the biocontrol of plant diseases and pests using endophytic fungi and bacteria, alongside the challenges and limitations encountered and how these can be overcome. We frame this review in the context of tree pests and diseases, since trees are arguably the most difficult plant species to study, work on and manage, yet they represent one of the most important organisms on Earth

Endophytes vs tree pathogens and pests: can they be used as biological control agents to improve tree health?

Like all other plants, trees are vulnerable to attack by a multitude of pests and pathogens. Current control measures for many of these diseases are limited and relatively ineffective. Several methods, including the use of conventional synthetic agro-chemicals, are employed to reduce the impact of pests and diseases. However, because of mounting concerns about adverse effects on the environment and a variety of economic reasons, this limited management of tree diseases by chemical methods is losing ground. The use of biological control, as a more environmentally friendly alternative, is becoming increasingly popular in plant protection. This can include the deployment of soil inoculants and foliar sprays, but the increased knowledge of microbial ecology in the phytosphere, in particular phylloplane microbes and endophytes, has stimulated new thinking for biocontrol approaches. Endophytes are microbes that live within plant tissues. As such, they hold potential as biocontrol agents against plant diseases because they are able to colonize the same ecological niche favoured by many invading pathogens. However, the development and exploitation of endophytes as biocontrol agents will have to overcome numerous challenges. The optimization and improvement of strategies employed in endophyte research can contribute towards discovering effective and competent biocontrol agents. The impact of environment and plant genotype on selecting potentially beneficial and exploitable endophytes for biocontrol is poorly understood. How endophytes synergise or antagonise one another is also an important factor. This review focusses on recent research addressing the biocontrol of plant diseases and pests using endophytic fungi and bacteria, alongside the challenges and limitations encountered and how these can be overcome. We frame this review in the context of tree pests and diseases, since trees are arguably the most difficult plant species to study, work on and manage, yet they represent one of the most important organisms on Earth

RNA delivery by extracellular vesicles in mammalian cells and its applications.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications

On the structure and stability of BaAl4-type ordered derivatives in the Sr-Au-Sn system for the 600 ° C section

The well-known BaAl4-type structure consists of three ordered ternary derivatives, i.e., BaNiSn3-(I4mm), ThCr2Si2-(I4/mmm), and CaBe2Ge2-type (P4/nmm). Few systems, such as Ba-Au-Sn, have been confirmed to manifest all three types as a function of valence electron count. In this work, the SrAuxSn4-xsolid solution at the 600 ° C section was studied thoroughly using both single crystal and powder X-ray diffraction. The crystal structures and phase width for the CaBe2Ge2-type SrAuxSn4-xsolid solution were established to be α = 4.6528(2)-4.6233(3) Å and c = 11.3753(4)-11.2945(10) Å for x ≈ 1.65(1)-2.19(1). In the structure of SrAu2Sn2, no Au/Sn mixing was found, but for x < 2 compositions, Au/Sn mixings were only located at the Wyckoff 2α (3/4 1/4 0) site and for x > 2 compositions, at the 2b (3/4 1/4 1/2) site. Differential scanning calorimetry (DSC) analyses indicated that no phase transition occurred for the CaBe2Ge2-type SrAuxSn4-xphase up to 950 ° C. Attempts to synthesize the ThCr2Si2-and BaNiSn3-type SrAuxSn4-xphases under the same reaction conditions were unsuccessful, and the BaNiSn3-type phase could not be attained even at a pressure of 3 GPa. The instability of a BaNiSn3-type "SrAuSn3" was investigated by both DSC measurements and first principles electronic structure calculations

On the structure and stability of BaAl4-type ordered derivatives in the Sr-Au-Sn system for the 600 ° C section

The well-known BaAl4-type structure consists of three ordered ternary derivatives, i.e., BaNiSn3-(I4mm), ThCr2Si2-(I4/mmm), and CaBe2Ge2-type (P4/nmm). Few systems, such as Ba-Au-Sn, have been confirmed to manifest all three types as a function of valence electron count. In this work, the SrAuxSn4-xsolid solution at the 600 ° C section was studied thoroughly using both single crystal and powder X-ray diffraction. The crystal structures and phase width for the CaBe2Ge2-type SrAuxSn4-xsolid solution were established to be α = 4.6528(2)-4.6233(3) Å and c = 11.3753(4)-11.2945(10) Å for x ≈ 1.65(1)-2.19(1). In the structure of SrAu2Sn2, no Au/Sn mixing was found, but for x < 2 compositions, Au/Sn mixings were only located at the Wyckoff 2α (3/4 1/4 0) site and for x > 2 compositions, at the 2b (3/4 1/4 1/2) site. Differential scanning calorimetry (DSC) analyses indicated that no phase transition occurred for the CaBe2Ge2-type SrAuxSn4-xphase up to 950 ° C. Attempts to synthesize the ThCr2Si2-and BaNiSn3-type SrAuxSn4-xphases under the same reaction conditions were unsuccessful, and the BaNiSn3-type phase could not be attained even at a pressure of 3 GPa. The instability of a BaNiSn3-type "SrAuSn3" was investigated by both DSC measurements and first principles electronic structure calculations