RNA-based logic for selective protein expression in senescent cells.

Cellular senescence is a cellular state characterized by irreversible growth arrest, resistance to apoptosis and secretion of inflammatory molecules, which is causally linked to the pathogenesis of many age-related diseases. Besides, there is accumulating evidence that selective removal of senescent cells can benefit therapies for cancer and fibrosis by modulating the inflammatory microenvironment. While the field of so-called senolytics has spawned promising small molecules and peptides for the selective removal of senescent cells, there is still no effective means to detect senescent cells in vivo, a prerequisite for understanding the role of senescence in pathophysiology and to assess the effectiveness of treatments aimed at removing senescent cells.

Unraveling mRNA delivery bottlenecks of ineffective delivery vectors by co-transfection with effective carriers.

The messenger RNA (mRNA) SARS-CoV-2 vaccines have demonstrated the therapeutic potential of this novel drug modality. Protein expression is the consequence of a multistep delivery process that relies on proper packaging into nanoparticle carriers to protect the mRNA against degradation enabling effective cellular uptake and endosomal release, and liberating the mRNA in the cytosol. Bottlenecks along this route remain challenging to pinpoint.

Potent and selective eradication of tumor cells by an EpCAM-targeted Ras-degrading enzyme.

Despite decades of efforts, an urgent need remains to develop tumor cell-selective rat sarcoma (Ras)-targeting therapies that can treat patients with Ras-driven tumors. Here we report modular engineered proteins that degrade Ras selectively in tumor cells that overexpress the tumor cell marker epithelial cell adhesion molecule (EpCAM) by fusing the Ras degrader Ras-Rap1-specific endopeptidase with the translocation domain of the exotoxin A (ETA) or diphtheria toxin (DT). Redirection to EpCAM is achieved by a designed ankyrin repeat protein.

Functional Proteomic Profiling of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because of their receptor status, conventional chemotherapy remains the main therapeutic option for TNBC patients. We employed a reverse phase protein array approach (RPPA), complemented by immunohistochemistry, to quantitatively profile the activation state of 84 actionable key signaling intermediates and phosphoproteins in a set of 44 TNBC samples.

Modulation of Orai1 by cationic peptides triggers their direct cytosolic uptake.

At concentrations exceeding 10 μM, arginine-rich cell-penetrating peptides (CPPs) trigger a rapid cytoplasmic import that involves activation of acid sphingomyelinase (ASMase). ASMase activation occurs through a variety of stress signals and has also been related to the reorganization of membrane microdomains during entry of pathogens. However, in none of these cases has the initial trigger for ASMase activation been established on a molecular level.