CircASPH Enhances Exosomal STING to Facilitate M2 Macrophage Polarization in Colorectal Cancer.

Exosomes are considered a mediator of communication within the tumor microenvironment (TME), which modulates cancer progression through transmitting cargos between cancer cells and other cancer-related cells in TME. Circular RNAs (circRNAs) have emerged to be regulators in colorectal cancer (CRC) progression, but most of them have not been discussed in CRC. This study aims to investigate the role of circRNA aspartate beta-hydroxylase (circASPH) in CRC progression and its correlation with exosome-mediated TME. At first, we determined that circASPH was upregulated in CRC samples and cell lines. Functionally, the circASPH deficiency suppressed the malignant processes of CRC cells and also inhibited in vivo tumor growth via enhancing antitumor immunity. Mechanically, circASPH facilitated macrophage M2 polarization by upregulating exosomal stimulator of interferon genes (STING). CircASPH interacted with insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) to stabilize IGF2BP2 protein, therefore enhancing the stability of m6A-modified STING mRNA. In turn, coculture of STING-overexpressed macrophages recovered the suppression of silenced circASPH on the malignancy of CRC cells both in vitro and in vivo. Our study demonstrated that circASPH enhances exosomal STING to facilitate M2 macrophage polarization, which further accelerates CRC progression. The findings support circASPH as a promising therapeutic target for CRC treatment.

CircASPH is markedly overexpressed in CRC cell lines and promotes CRC progression. CircASPH deficiency inhibits in vivo tumor growth via enhancing antitumor immunity. CircASPH upregulates STING to enhance M2 macrophage polarization.

The Effect of Frailty on the Efficacy and Safety of Intensive Blood Pressure Control: A Post Hoc Analysis of the SPRINT Trial.

BACKGROUND: Frailty is associated with an increased risk of all-cause death and cardiovascular events. However, it is uncertain whether frailty modifies the efficacy and safety of intensive blood pressure control. METHODS: Data from SPRINT (Systolic Blood Pressure Intervention Trial) were used to construct a frailty index. Subgroup differences in intensive blood pressure control treatment effects and safety outcomes were measured on a relative and an absolute scale in patients with and without frailty (defined as a frailty index >0.21) using Cox proportional hazard models and generalized linear models, respectively. The primary outcome was a composite of myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, heart failure, and cardiovascular death. RESULTS: A total of 9306 patients (mean age, 67.9±9.4 years), 2560 (26.7%) of whom had frailty, were included in our study. Over a median follow-up of 3.22 years, 561 primary outcomes were observed. Patients with frailty had a significantly higher risk of primary outcome in both the intensive and standard blood pressure control arms (adjusted hazard ratio, 2.10 [95% CI, 1.59-2.77] and 1.85 [95% CI, 1.46-2.35], respectively). Intensive treatment effects on primary and secondary outcomes were not significantly different on a relative scale (except for cardiovascular death [hazard ratio in patients with and without frailty, 0.91 (95% CI, 0.52-1.60) versus 0.30 (95% CI, 0.16-0.59), respectively; Pinteraction=0.01]) or absolute scale. There was no significant interaction between frailty and risks for serious adverse events with intensive treatment. CONCLUSIONS: Frailty status was a marker of high cardiovascular risk. Patients with frailty benefit similarly to other patients from intensive blood pressure control without an increased risk of serious adverse events.

Robust and smart polypeptide-based nanomedicines for targeted tumor therapy.

Nanomedicines based on synthetic polypeptides are among the most versatile and advanced platforms for tumor therapy. Notably, several polypeptide-based nanodrugs are currently under human clinical assessments. The previous (pre)clinical studies clearly show that dynamic stability (i.e. stable in circulation while destabilized in tumor) of nanomedicines plays a vital role in their anti-tumor performance. Various strategies have recently been developed to design dynamically stabilized polypeptide-based nanomedicines by e.g. crosslinking the nanovehicles with acid, reactive oxygen species (ROS), glutathione (GSH), or photo-sensitive linkers, inter-crosslinking between vehicles and drugs, introducing π-π stacking or lipid-lipid interactions in the nanovehicles, chemically conjugating drugs to vehicles, and forming unimolecular micelles. Interestingly, these robust and smart nanodrugs have demonstrated improved tumor targetability, anti-tumor efficacy, as well as safety profiles in different tumor models. In this review, representative strategies to robust and smart polypeptide-based nanomedicines for targeted treatment of varying malignancies are highlighted. The exciting development of dynamic nanomedicines will foresee further increasing clinical translation in the future.

Small, Traceable, Endosome-Disrupting, and Bioresponsive Click Nanogels Fabricated via Microfluidics for CD44-Targeted Cytoplasmic Delivery of Therapeutic Proteins.

Nanogels (NG) are among the most ideal cytoplasmic protein delivery vehicles; however, their performance is suboptimal, partly owing to relatively big size, poor cell uptake, and endosomal entrapment. Here, we developed small, traceable, endosome-disrupting, and bioresponsive hyaluronic acid NG (HA-NG) for CD44-targeted intracellular delivery of therapeutic proteins. With microfluidics and catalyst-free photo-click cross-linking, HA-NG with hydrodynamic diameters of ca. 80 and 150 nm, strong green fluorescence and efficient loading of various proteins including saporin (Sap), cytochrome C, herceptin, immunoglobulin G (IgG), and bovine serum albumin could be fabricated. Interestingly, 80 nm-sized HA-NG revealed clearly better cellular uptake than its 150 nm counterparts in both CD44-negative U87 cancer cells and CD44-positive 4T1 and MDA-MB-231 cells. Moreover, small NG exhibited accelerated endosomal escape, which was further boosted by introducing GALA, a pH-sensitive fusogenic peptide. Accordingly, Sap-loaded small and GALA-functionalized HA-NG showed the highest cytotoxicity in CD44-positive MDA-MB-231, 4T1, A549, and SMMC-7721 cancer cells. The biodistribution studies demonstrated that 80 nm-sized HA-NG displayed significantly greater tumor uptake as well as penetration in MDA-MB-231 human breast tumor xenografts than its 150 nm counterparts, whereas the introduction of GALA had no detrimental effect on tumor accumulation. Small, endosome-disrupting, and bioresponsive HA-NG with easy and controlled fabrication hold a great potential for targeted protein therapy.