Xiaohui Han

The intracellular delivery of biofunctional enzymes or therapeutic proteins through systemic administration is of great importance in therapeutic intervention of various diseases. However, current strategies face substantial challenges owing to various biological barriers, including susceptibility to protein degradation and denaturation, poor cellular uptake, and low transduction efficiency into the cytosol. Here, we developed a biomimetic nanoparticle platform for systemic and intracellular delivery of proteins. Through a biocompatible strategy, guest proteins are caged in the matrix of metal-organic frameworks (MOFs) with high efficiency (up to ∼94%) and high loading content up to ∼50 times those achieved by surface conjunction, and the nanoparticles were further decorated with the extracellular vesicle (EV) membrane with an efficiency as high as ∼97%. In vitro and in vivo study manifests that the EV-like nanoparticles can not only protect proteins against protease digestion and evade the immune system clearance but also selectively target homotypic tumor sites and promote tumor cell uptake and autonomous release of the guest protein after internalization. Assisted by biomimetic nanoparticles, intracellular delivery of the bioactive therapeutic protein gelonin significantly inhibits the tumor growth in vivo and increased 14-fold the therapeutic efficacy. Together, our work not only proposes a new concept to construct a biomimetic nanoplatform but also provides a new solution for systemic and intracellular delivery of protein.

- and bile duct ligation-induced liver fibrosis in mice. Lnc-LFAR1 promotes the binding of Smad2/3 to TGFβR1 and its phosphorylation in the cytoplasm. Lnc-LFAR1 binds directly to Smad2/3 and promotes transcription of TGFβ, Smad2, Smad3, Notch2 and Notch3 which, in turn, results in TGFβ and Notch pathway activation. We show that the TGFβ1/Smad2/3/lnc-LFAR1 pathway provides a positive feedback loop to increase Smad2/3 response and a novel link connecting TGFβ with Notch pathway. Our work identifies a liver-enriched lncRNA that regulates liver fibrogenesis and suggests it as a potential target for fibrosis treatment.Activated hepatic stellate cells are the principal contributors to liver fibrosis by secreting a variety of pro-fibrogenic cytokines . Here Zhang et al. demonstrate that a liver-enriched lncRNA, lnc-LFAR1, promotes liver fibrosis and HSC activation by activating TGFβ and Notch signaling.

The aberrant accumulation of β-amyloid peptide (Aβ) in the brain is a key feature of Alzheimer's disease (AD), and enhanced cleavage of β-amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) has a major causative role in AD. Despite their prominence in AD pathogenesis, the regulation of BACE1 and APP is incompletely understood. In this study, we report that the circular RNA circular RNA sponge for miR-7 (ciRS-7) has an important role in regulating BACE1 and APP protein levels. Previous studies have shown that ciRS-7, which is highly expressed in the human brain, is down-regulated in the brain of people with AD but the relevance of this finding was not clear. We have found that ciRS-7 is not involved in the regulation of APP and BACE1 gene expression, but instead reduces the protein levels of APP and BACE1 by promoting their degradation via the proteasome and lysosome. Consequently, overexpression of ciRS-7 reduces the generation of Aβ, indicating a potential neuroprotective role of ciRS-7. Our data also suggest that ciRS-7 modulates APP and BACE1 levels in a nuclear factor-κB (NF-κB)-dependent manner: ciRS-7 expression inhibits translation of NF-κB and induces its cytoplasmic localization, thus derepressing expression of UCHL1, which promotes APP and BACE1 degradation. Additionally, we demonstrated that APP reduces the level of ciRS-7, revealing a mutual regulation of ciRS-7 and APP. Taken together, our data provide a molecular mechanism implicating reduced ciRS-7 expression in AD, suggesting that ciRS-7 may represent a useful target in the development of therapeutic strategies for AD.