Extracellular vesicle surface display enhances the therapeutic efficacy and safety profile of cancer immunotherapy.

Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released by cells, can be efficiently engineered via inverse electron demand Diels-Alder (iEDDA)-mediated conjugation to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands on the EV surface conferred substantial enhancements in signaling efficacy, particularly for tumor necrosis factor receptor superfamily (TNFRSF) agonists, where the EV surface display served as an alternative FcγR-independent approach to induce ligand multimerization and efficient receptor crosslinking. EVs displaying a complementary combination of immunotherapeutic ligands were able to shift the tumor immune milieu toward an anti-tumorigenic phenotype and significantly suppress tumor burden and increase survival in multiple models of metastatic cancer to a greater extent than an equivalent dose of free ligands. In summary, we present an EV-based delivery platform for cancer immunotherapeutic ligands that facilitates superior anti-tumor responses at significantly lower doses with fewer side effects than is possible with conventional delivery approaches.

Endocytosis of red blood cell extracellular vesicles by macrophages leads to cytoplasmic heme release and prevents foam cell formation in atherosclerosis.

Extracellular vesicles (EVs) can be produced from red blood cells (RBCs) on a large scale and used to deliver therapeutic payloads efficiently. However, not much is known about the native biological properties of RBCEVs. Here, we demonstrate that RBCEVs are primarily taken up by macrophages and monocytes. This uptake is an active process, mediated mainly by endocytosis. Incubation of CD14+ monocytes with RBCEVs induces their differentiation into macrophages with an Mheme-like phenotype, characterized by upregulation of heme oxygenase-1 (HO-1) and the ATP-binding cassette transporter ABCG1. Moreover, macrophages that take up RBCEVs exhibit a reduction in surface CD86 and decreased secretion of TNF-α under inflammatory stimulation. The upregulation of HO-1 is attributed to heme derived from haemoglobin in RBCEVs. Heme is released from internalized RBCEVs in late endosomes and lysosomes via the heme transporter, HRG1. Consequently, RBCEVs exhibit the ability to attenuate foam cell formation from oxidized low-density lipoproteins (oxLDL)-treated macrophages in vitro and reduce atherosclerotic lesions in ApoE knockout mice on a high-fat diet. In summary, our study reveals the uptake mechanism of RBCEVs and their delivery of heme to macrophages, suggesting the potential application of RBCEVs in the treatment of atherosclerosis.

Case Report: Exposure to Respirable Crystalline Silica and Respiratory Health Among Australian Mine Workers.

Occupational exposure to respirable crystalline silica (RCS) is common in a range of industries, including mining, and has been associated with adverse health effects such as silicosis, lung cancer, and non-malignant respiratory diseases. This study used a large population database of 6,563 mine workers from Western Australia who were examined for personal exposure to RCS between 2001 and 2012. A standardized respiratory questionnaire was also administered to collect information related to their respiratory health. Logistic regression analyses were performed to ascertain the association between RCS concentrations and the prevalence of respiratory symptoms among mine workers. The estimated exposure levels of RCS (geometric mean 0.008mg/m3, GSD 4.151) declined over the study period (p < 0.001) and were below the exposure standard of 0.05 mg/m3. Miners exposed to RCS had a significantly higher prevalence of phlegm (p = 0.017) and any respiratory symptom (p = 0.013), even at concentrations within the exposure limit. Miners are susceptible to adverse respiratory health effects at low levels of RCS exposure. More stringent prevention strategies are therefore recommended to protect mine workers from RCS exposures.

Dietary inflammatory index is associated with increased risk for prostate cancer among Vietnamese men.

OBJECTIVE: Inflammatory potential of diet, as measured by the dietary inflammatory index (DII), has consistently been associated with an increased risk for prostate cancer (PCa). However, data has largely been reported in populations with more proinflammatory dietary patterns, whereas there is high diversity in dietary pattern worldwide. The aim of this study was to assess the association between DII scores and the risk for PCa in Vietnam. METHODS: A case-control study of 652 participants (244 incident PCa patients, 64-75 y of age, and 408 controls, frequency matched for age) was conducted in Ho Chi Minh City, Vietnam, from 2013 to 2015. Habitual diet was ascertained using a validated food frequency questionnaire (FFQ), whereas other factors, including demographic and lifestyle characteristics, were assessed via face-to-face interviews. The daily intake of pro- and anti-inflammatory nutrients for each participant was calculated from the FFQ and used to estimate individuals' energy-adjusted DII (E-DII) scores. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. RESULTS: Comparing the middle and highest versus lowest tertile of DII scores, there was an increased risk for overall PCa. The OR and associated 95% CI was 2.63 (1.61-4.37) and 3.35 (2.06-5.53), respectively (Ptrend < 0.01). Similar results were found for low-moderate and high-grade PCa. The respective ORs (95% CI) were 3.34 (1.66-7.13) and 5.29 (2.69-11.18), Ptrend < 0.001, and 2.51 (1.40-4.63) and 2.57 (1.43-4.73), Ptrend 0.006. CONCLUSION: A proinflammatory diet was associated with increased risk for PCa among Vietnamese men.