Majority of disease-modifying therapeutic targets are restricted to the intracellular space and are therefore not druggable using existing biologic modalities. The ability to efficiently deliver macromolecules inside target cells or tissues would greatly expand the current landscape of therapeutic targets for future generations of biologic drugs, but remains challenging. Here we report the use of extracellular vesicles, known as arrestin domain containing protein 1 [ARRDC1]-mediated microvesicles (ARMMs), for packaging and intracellular delivery of a myriad of macromolecules, including the tumor suppressor p53 protein, RNAs, and the genome-editing CRISPR-Cas9/guide RNA complex. We demonstrate selective recruitment of these macromolecules into ARMMs. When delivered intracellularly via ARMMs, these macromolecules are biologically active in recipient cells. P53 delivered via ARMMs induces DNA damage-dependent apoptosis in multiple tissues in mice. Together, our results provide proof-of-principle demonstration that ARMMs represent a highly versatile platform for packaging and intracellular delivery of therapeutic macromolecules.

Asthma is a chronic inflammatory respiratory disease that affects over 300 million people worldwide. Glucocorticoids are a mainstay therapy for asthma because they exert anti-inflammatory effects in multiple lung tissues, including the airway smooth muscle (ASM). However, the mechanism by which glucocorticoids suppress inflammation in ASM remains poorly understood. Using RNA-Seq, a high-throughput sequencing method, we characterized transcriptomic changes in four primary human ASM cell lines that were treated with dexamethasone—a potent synthetic glucocorticoid (1 µM for 18 hours). Based on a Benjamini-Hochberg corrected p-value <0.05, we identified 316 differentially expressed genes, including both well known (DUSP1, KLF15, PER1, TSC22D3) and less investigated (C7, CCDC69, CRISPLD2) glucocorticoid-responsive genes. CRISPLD2, which encodes a secreted protein previously implicated in lung development and endotoxin regulation, was found to have SNPs that were moderately associated with inhaled corticosteroid resistance and bronchodilator response among asthma patients in two previously conducted genome-wide association studies. Quantitative RT-PCR and Western blotting showed that dexamethasone treatment significantly increased CRISPLD2 mRNA and protein expression in ASM cells. CRISPLD2 expression was also induced by the inflammatory cytokine IL1β, and small interfering RNA-mediated knockdown of CRISPLD2 further increased IL1β-induced expression of IL6 and IL8. Our findings offer a comprehensive view of the effect of a glucocorticoid on the ASM transcriptome and identify CRISPLD2 as an asthma pharmacogenetics candidate gene that regulates anti-inflammatory effects of glucocorticoids in the ASM.

Nevertheless, the research on SIBs was barely conducted after the successful commercialization of LIBs in 1990s, and this situation continued until the end of the 20th century. An obstacle toward the development of SIBs is the lack of suitable anode materials with acceptable performance. The early work conducted by Dahn et al. [5] suggested that hard carbon (HC) has a reversible capacity of 300 mAh g −1 for sodium, approaching the lithium storage capacity in graphite. Extensive attention has been focused on the development of SIBs recently, with a variety of materials being considered as potential anodes for SIBs, which includes alloys, [6-8] organic materials, [9-11] and carbonaceous materials. [12-14] Because of high sodium-ion storage capacity, appropriate working potential, excellent cycling stability, and natural abundance, HC represents the most promising anode for SIBs. Nowadays, increasing interests have been concentrated on revealing sodium intercalation process in HC, [15-19] but the steady state of sodium stored in HC still remains unexplored, which leads us to investigate the steady state of sodium ions in HC from thermodynamic and kinetic aspects. Heretofore, the steady state of sodium in HC has been incidentally proposed, but remains a controversial issue. Specifically, Stevens and Dahn [20] originally revealed the metallic nature of sodium absorbed in nanopores at the voltage plateau as the adsorption potential approaching the deposition potential of sodium metal. Meanwhile, the formation of metallic sodium was also confirmed with operando 23 Na solid-state nuclear magnetic resonance (NMR) and in situ Raman at the plateau region. [21,22] Moreover, Ji and co-workers [23] suggested that sodium adsorbed onto the pore surface is atomic even close to the cutoff potential (0.05-0 V). On the other hand, Liu et al. [19] demonstrated that neither metallic nor quasi-metallic sodium is presented in the whole discharge region over 0 V, based on the results of ex situ 23 Na NMR and electron paramagnetic resonance (EPR). Recently, Guo et al. [13] claimed that sodium stored in the HC is in the ionic state above 0.1 V, whereas metallic sodium clusters form in the nanopores at the plateau voltage, with the methods of EPR, XRD, and Raman. Apparently, scattered efforts have been devoted to uncover the state of sodium stored in hard carbon recently, nevertheless, systematic investigations are Hard carbon (HC) is the most promising anode material for sodium-ion batteries (SIBs), nevertheless, the understanding of sodium storage mechanism in HC is very limited. As an important aspect of storage mechanism, the steady state of sodium stored in HC has not been revealed clearly to date. Herein, the formation mechanism of quasi-metallic sodium and the quasi-ionic bond between sodium and carbon within the electrochemical reaction on the basis of theoretical calculations are disclosed. The presence of quasi-metallic sodium is further confirmed with the assistance of a specific reaction between the sodiated HC electrode and eth...

A molybdenum disulfide/palladium nanodisk heterostructure was determined to be highly active toward the HER through DFT predictions and experimental verification.

Aggressive chemistry involving Li metal anode (LMA) and high-voltage LiNi0.8Mn0.1Co0.1O2 (NCM811) cathode is deemed as a pragmatic approach to pursue the desperate 400 Wh kg−1. Yet, their implementation is plagued by low Coulombic efficiency and inferior cycling stability. Herein, we propose an optimally fluorinated linear carboxylic ester (ethyl 3,3,3-trifluoropropanoate, FEP) paired with weakly solvating fluoroethylene carbonate and dissociated lithium salts (LiBF4 and LiDFOB) to prepare a weakly solvating and dissociated electrolyte. An anion-enrichment interface prompts more anions’ decomposition in the inner Helmholtz plane and higher reduction potential of anions. Consequently, the anion-derived interface chemistry contributes to the compact and columnar-structure Li deposits with a high CE of 98.7% and stable cycling of 4.6 V NCM811 and LiCoO2 cathode. Accordingly, industrial anode-free pouch cells under harsh testing conditions deliver a high energy of 442.5 Wh kg−1 with 80% capacity retention after 100 cycles.