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Many diseases, especially cancer, are caused by the abnormal expression of non-coding microRNAs (miRNAs), which regulate gene expression, leading to the development of miRNA-based therapeutics. Synthetic miRNA inhibitors have shown promising efficacy in blocking the activity of aberrant miRNAs that are upregulated in disease-specific pathologies. On the other hand, miRNAs that aid in preventing certain diseases and are reduced in expression in the disease state need different strategies. To tackle this, miRNA mimics, which mimic the activity of endogenous miRNAs, can be delivered for those miRNAs downregulated in different disease states. However, the delivery of miRNA mimics remains a challenge. Here, we report a cationic polylactic-co-glycolic acid (PLGA)-poly-L-histidine delivery system to deliver miRNA mimics. We chose miR-34a mimics as a proof of concept for miRNA delivery. miR-34a-loaded PLGA-poly-L-histidine nanoparticles (NPs) were formulated and biophysically characterized to analyze the structural properties of miRNA mimic-loaded NPs. In vitro efficacy was determined by investigating miR-34a and downstream target levels and performing cell viability and apoptosis assays. We confirmed in vivo efficacy through prolonged survival of miR-34a NP-treated A549-derived xenograft mice treated intratumorally. The results of these studies establish PLGA-poly-L-histidine NPs as an effective delivery system for miRNA mimics for treating diseases characterized by downregulated miRNAs.

Design of polymer grafted plasmonic metal nanoparticles (PGNPs) has received continuous interest due to polymer-driven self-assembly of plasmonic nanoparticles (NPs) as a means to control interparticle plasmon coupling in ensembles. We report the use of supramolecular “V-shaped” block copolymers (VBCPs) as surface ligands of PGNPs to study their hydrophobicity-driven self-assembly. The amphiphilic VBCPs are prepared from two homopolymers, namely dipicolyamine (DPA)-terminated polystyrene (PS) and pyridine (Py)-terminated poly(N,N-dimethylacrylamide) (PDMA) where the two polymers are bridged with Cu2+ ions. Those supramolecular VBCPs formed spherical micelles in the range of 100–300 nm, much larger than those of linear BCPs with similar chemical composition as a result of Cu2+ ions at the hydrophobic/hydrophilic interface. Thioester-containing supramolecular polymers can modify plasmonic AuNPs through ligand exchange even in the presence of Cu2+ ions. Those supramolecular polymers can drive PGNPs to form giant vesicles and two-dimensional (2-D) layered nanosheets. Using in situ light scattering, the supramolecular dynamics is found to allow maximum chain reconformation of polymer ligands where the interparticle distance of PGNPs grafted with VBCPs is smaller compared to that of PGNPs with linear BCPs. The assembled nanostructures with VBCPs also showed similar stimuli-responsive properties where the dissociation of DPA-Cu2+-Py coordination results in the disruption of assembled nanostructures. The supramolecular approaches potentially provide a new toolbox to design PGNP assemblies with tunable nanostructures and interesting dynamic properties enabled by non-covalent interaction.

We study electromagnetic ion cyclotron (EMIC) waves based on observations from the ionosphere, magnetosphere, and ground during a geomagnetic storm recovery phase on 28 August 2018. In this case, multiple ducting EMIC waves in the ionosphere show higher frequencies in the post‐midnight than those in the pre‐midnight. Ionospheric EMIC wave frequency differences in magnetic local time (MLT) are consistent with MLT frequency differences in the equatorial magnetosphere, which are mainly caused by different background magnetic field at different L‐shells. Moreover, we report the first observation of frequency range selections in ionospheric ducting EMIC waves and find that frequency selections depend on the magnetic field intensity in the main part of the ionospheric waveguide, with higher frequency corresponding to larger magnetic field. This study reveals the important role of background magnetic field in regulating ducting EMIC wave frequencies in the ionosphere. Plain Language Summary: Electromagnetic ion cyclotron (EMIC) waves are in the frequency range of 0.2–5 Hz, and they may occur in three different bands, which are named as H+, He+, and O+ bands from high to low frequencies. In this paper, He+ band EMIC waves in the nightside during a geomagnetic storm are observed by satellites in the ionosphere, and their frequencies are different, that is, frequencies are higher in the post‐midnight than those in the pre‐midnight. Ionospheric EMIC wave frequency differences in local time have been noticed before but have not yet been explained. We discover that ionospheric EMIC wave frequency differences in local time agree well with frequency differences in the magnetosphere. Besides frequency discrepancies in local time, in the post‐midnight, ionospheric EMIC waves tend to select higher or lower frequency range relative to frequencies in the magnetosphere. We find that these frequency selections mainly depend on the magnetic field intensity in the ionosphere. The frequency selections in ionospheric EMIC waves have not been identified before, and it is important to understand variations of EMIC waves in the ionosphere. Key Points: Ionospheric EMIC wave frequency differences in magnetic local time (MLT) are consistent with MLT frequency differences in the equatorial magnetosphereHigher/lower wave frequencies in the equatorial magnetosphere are at lower/higher L‐shells with larger/smaller background magnetic fieldFrequency selections of ducting EMIC waves depend on local magnetic field, and frequency is higher when the magnetic field is larger [ABSTRACT FROM AUTHOR]

Nanotechnology has long been used to improve the tumor targeting of chemotherapeutics. The structure of these nanocarriers greatly affects their efficacy and toxicity. Herein, structurally stable nanodiscoidal phospholipid bicelles, which are capable of encapsulating anticancer drugs, paclitaxel (PTX) and parthenolide (PTL), are designed. This nanodiscoidal bicelle structure is shown previously to exhibit longer blood circulation, deeper tumor penetration, and increased tumor cell uptake compared with spherical particles of similar compositions. Structural characterization and loading capacity of the PTX‐ and PTL‐ loaded nanodiscs are conducted along with an investigation into the cytotoxicity of the bicelles based on the drug‐to‐lipid ratios of both drugs loaded separately and in combination. A significant synergistic effect between both loaded drugs is also observed in A549 lung cancer and drug‐resistant MDA‐MB‐231 cell lines. An in vivo study using mice bearing subcutaneous A549 tumors shows a long circulation time of the intravenously injected DiR‐loaded bicelles and significant antitumor efficacy of the PTX‐ and PTL‐loaded bicelles. This efficacious self‐assembled nanoparticle system displays great potential as a nanoplatform to codeliver multiple therapeutics or diagnostics for improving cancer therapy.

Polycistronic microRNA (miRNA) clusters are a common feature of vertebrate genomes. The coordinated expression of miRNAs belonging to different seed families from a single transcriptional unit suggests functional cooperation, but this hypothesis has not been experimentally tested. Here we report the characterization of an allelic series of genetically engineered mice harboring selective targeted deletions of individual components of the miR-17 ∼ 92 cluster. Our results demonstrate the coexistence of functional cooperation and specialization among members of this cluster, identify a previously undescribed function for the miR-17 seed family in controlling axial patterning in vertebrates and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. By integrating phenotypic analysis and gene expression profiling, we provide a genome-wide view of how the components of a polycistronic miRNA cluster affect gene expression in vivo. The reagents and data sets reported here will accelerate exploration of the complex biological functions of this important miRNA cluster.

Polycistronic microRNA (miRNA) clusters are a common feature of vertebrate genomes. The coordinated expression of miRNAs belonging to different seed families from a single transcriptional unit suggests functional cooperation, but this hypothesis has not been experimentally tested. Here we report the characterization of an allelic series of genetically engineered mice harboring selective targeted deletions of individual components of the miR-17 ∼ 92 cluster. Our results demonstrate the coexistence of functional cooperation and specialization among members of this cluster, identify a previously undescribed function for the miR-17 seed family in controlling axial patterning in vertebrates and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. By integrating phenotypic analysis and gene expression profiling, we provide a genome-wide view of how the components of a polycistronic miRNA cluster affect gene expression in vivo. The reagents and data sets reported here will accelerate exploration of the complex biological functions of this important miRNA cluster.