The mucus layer and cell membrane are two major barriers against pulmonary siRNA delivery. Commonly used polycationic gene vectors can hardly penetrate the mucus layer due to the adsorption of mucin glycoproteins that trap and destabilize the polyplexes. Herein, guanidinated and fluorinated bifunctional helical polypeptides were developed to synchronizingly overcome these two barriers. The guanidine domain and α-helix facilitated trans-membrane siRNA delivery into macrophages, whereas fluorination of the polypeptides dramatically enhanced the mucus permeation capability by ∼240 folds, because incorporated fluorocarbon segments prevented adsorption of mucin glycoproteins onto polyplexes surfaces. Thus, when delivering TNF-α siRNA intratracheally, the top-performing polypeptide P7F7 provoked highly efficient gene knockdown by ∼96% at 200 μg/kg siRNA and exerted pronounced anti-inflammatory effect against acute lung injury. This study thus provides an effective strategy for transmucosal gene delivery, and it also renders promising utilities for the noninvasive, localized treatment of inflammatory pulmonary diseases.
The scaffold layer plays an important role in transporting electrons and preventing carrier recombination in mesoporous perovskite solar cells (PSCs), so the engineering of the interface between the scaffold layer and the light absorption layer has attracted widespread concern. In this work, vertically grown TiO2 nanorods (NRs) as scaffold layers are fabricated and further treated with TiCl4 aqueous solution. It can be found that a thin brookite TiO2 nanoparticle (NP) layer is formed by the chemical bath deposition (CBD) method on the surface of every rutile NR with a low annealing temperature (150 °C), which is beneficial for the infiltration and growth of perovskite. The PSC based on the TiO2 NR/brookite NP structure shows the best power conversion of 15.2%, which is 56.37% higher than that of the PSC based on bare NRs (9.72%). This complex structure presents an improved pore filling fraction and better carrier transport capability with less trap-assisted carrier recombination. In addition, low-annealing-temperature-formed brookite NPs possess a more suitable edge potential for electrons to transport from the perovskite layer to the electron collection layer when compared with high-annealing-temperature-formed anatase NPs. The brookite phase TiO2 fabricated at a low temperature presents great potential for flexible PSCs.
We systematically explore the shape-dependent catalytic activities of Au nanocrystals toward glucose oxidation in alkaline electrolytes, which is strongly dependent on the shape of the Au nanocrystals. The {100}-bounded cubic Au nanocrystals are significantly more active than the {110}-bounded rhombic dodecahedral and {111}-bounded octahedral Au nanocrystals.
Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associatedtumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.
Abstract Dysregulated inflammation and failure in resolution account for the incidence and deterioration of rheumatoid arthritis (RA). IL‐4 and miR‐21 possess complementary functions in inhibiting inflammation and fostering resolution. Thus, inflammation‐instructed nanocomplexes (NCs) are herein developed to mediate hierarchical co‐delivery of miR‐21 and IL‐4 to orchestrate the osteoimmune microenvironment against RA. The NCs comprise a cationic inner core assembled from the membrane‐penetrating, helical polypeptide (PG) and miR‐21, an outer layer based on the acid‐responsive, charge reversal polymer (PLL‐CA), and surface‐adsorbed IL‐4. The negatively charged NCs enable prolonged blood circulation after systemic administration, and thus passively accumulate in the inflamed joint. In the slightly acidic microenvironment of inflamed synovium, PLL‐CA transforms from negative to positive, which sheds off to liberate IL‐4 extracellularly and facilitate the intracellular delivery of the PG/miR‐21 core into macrophages. Thus, the anti‐inflammatory miR‐21 cooperates with the proresolving IL‐4 to attenuate inflammation via NF‐κB inhibition, promote macrophage polarization to M2a/M2c phenotypes, propel resolution, and promote tissue repair against Zymosan A‐induced arthritis. This study provides an effective strategy toward the programmed delivery of drug/gene cargoes at different extracellular/intracellular locations, and the combined mechanism of anti‐inflammation and proresolution renders insights into the treatment of inflammatory diseases.
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