The physico-chemical landscape of extracellular vesicles
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Packaged release and targeted delivery of cytokines by migrasomes in circulation
In dynamic systems like the circulatory system, establishing localized cytokine gradients is challenging. Upon lipopolysaccharide (LPS) stimulation, we observed that monocytes release numerous migrasomes enriched with inflammatory cytokines, such as TNF-α and IL-6. These cytokines are transported into migrasomes via secretory carriers, leading to their immediate exocytosis or eventual release from detached migrasomes. We successfully isolated TNF-α and IL-6-enriched, monocyte-derived migrasomes from the blood of LPS-treated mice. Total secretion analysis revealed a substantial amount of TNF-α and IL-6 released in a migrasome-packaged form. Thus, detached, monocyte-derived migrasomes represent a type of extracellular vesicle highly enriched with cytokines. Physiologically, these cytokine-laden migrasomes rapidly accumulate at local sites of inflammation, effectively creating a concentrated source of cytokines. Our research uncovers novel mechanisms for cytokine release and delivery, providing new insights into immune response modulation.
Measurement of phospholipid lateral diffusion at high pressure by in situ magic-angle spinning NMR spectroscopy
The development of experimental methodologies that enable investigations of biochemistry at high pressure promises to yield significant advances in our understanding of life on Earth and its origins. Here, we introduce a method for studying lipid membranes at thermodynamic conditions relevant for life at deep sea hydrothermal vents. Using in situ high pressure magic-angle spinning solid state nuclear magnetic resonance spectroscopy (NMR), we measure changes in the fluidity of model microbial membranes at pressures up to 28 MPa. We find that the fluid-phase lateral diffusion of phospholipids at high pressure is significantly affected by the stoichiometric ratio of lipids in the membrane. Our results were facilitated by an accessible pressurization strategy that we have developed to enable routine preparation of solid state NMR rotors to pressures of 30 MPa or greater.
Small extracellular vesicles as biomarkers of response in recurrent/metastatic HNSCC patients treated with immunotherapy
Biomarkers that effectively predict response to anti-PD-1 mAb therapy in cancer patients are an unmet need. We evaluated the utility of small extracellular vesicles (sEV) as biomarkers of response to immunotherapy in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients.
Optofluidic paper-based analytical device for discriminative detection of organic substances via digital color coding
Developing a portable yet affordable method for the discrimination of chemical substances with good sensitivity and selectivity is essential for on-site visual detection of unknown substances. Herein, we propose an optofluidic paper-based analytical device (PAD) that consists of a macromolecule-driven flow (MDF) gate and photonic crystal (PhC) coding units, enabling portable and scalable detection and discrimination of various organic chemical, mimicking the olfactory system. The MDF gate is designed for precise flow control of liquid analytes, which depends on intermolecular interactions between the polymer at the MDF gate and the liquid analytes. Subsequently, the PhC coding unit allows for visualizing the result obtained from the MDF gate and generating differential optical patterns. We fabricate an optofluidic PAD by integrating two coding units into a three-dimensional (3D) microfluidic paper within a 3D-printed cartridge. The optofluidic PADs clearly distinguish 11 organic chemicals with digital readout of pattern recognition from colorimetric signals. We believe that our optofluidic coding strategy mimicking the olfactory system opens up a wide range of potential applications in colorimetric monitoring of chemicals observed in environment.
A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes
Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.
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