Lyophilizable Stem Cell-Hybrid Liposome with Long-Term Stability and High Targeting Capacity.

The hybridization of liposome with stem cell membranes is an emerging technology to prepare the nanovehicle with the capacity of disease-responsive targeting. However, the long-term storage of this hybrid liposome has received limited attention in the literature, which is essential for its potential applicability in the clinic. Therefore, the preservation of long-term activity of stem cell-hybrid liposome using freeze-drying is investigated in the present study. Mesenchymal stem cell-hybrid liposome is synthesized and its feasibility for freeze-drying under different conditions is examined. Results reveal that pre-freezing the hybrid liposome at -20 °C in Tris buffer solution (pH 7.4) containing 10% trehalose can well preserve the liposomal structure for at least three months. Notably, major membrane proteins on the hybrid liposome are protected in this formulation and CXCR4-associated targeting capacity is maintained both in vitro and in vivo. Consequently, the hybrid liposome stored for three months demonstrates a comparable tumor inhibition as the fresh-prepared one. The present study provides the first insights into the long-term storage of stem cell hybrid liposome using lyophilization, which may make an important step forward in enhancing the long-term stability of these promising biomimetic nanovehicle and ease the logistics and the freeze-storage in the potential clinical applications.

A large-scale production of mesenchymal stem cells and their exosomes for an efficient treatment against lung inflammation.

Mesenchymal stem cells (MSCs) and their produced exosomes have demonstrated inherent capabilities of inflammation-guided targeting and inflammatory modulation, inspiring their potential applications as biologic agents for inflammatory treatments. However, the clinical applications of stem cell therapies are currently restricted by several challenges, and one of them is the mass production of stem cells to satisfy the therapeutic demands in the clinical bench. Herein, a production of human amnion-derived MSCs (hMSCs) at a scale of over 1 × 109 cells per batch was reported using a three-dimensional (3D) culture technology based on microcarriers coupled with a spinner bioreactor system. The present study revealed that this large-scale production technology improved the inflammation-guided migration and the inflammatory suppression of hMSCs, without altering their major properties as stem cells. Moreover, these large-scale produced hMSCs showed an efficient treatment against the lipopolysaccharide (LPS)-induced lung inflammation in mice models. Notably, exosomes collected from these large-scale produced hMSCs were observed to inherit the efficient inflammatory suppression capability of hMSCs. The present study showed that 3D culture technology using microcarriers coupled with a spinner bioreactor system can be a promising strategy for the large-scale expansion of hMSCs with improved anti-inflammation capability, as well as their secreted exosomes.

Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.

The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.

Apoptotic Vesicles of MSCs: The Natural Therapeutic Agents and Bio-Vehicles for Targeting Drug Delivery.

Mesenchymal stem cell (MSC)-based therapies are increasingly recognized as promising cellular therapeutics and show the ability to treat various diseases. However, the underlying mechanism is not fully elucidated. Some recent studies have shown an unexpected result whereby MSCs undergo rapid apoptosis following administration but still exert therapeutic effects in some disease treatments. Such a therapeutic mechanism is believed to associate with the released apoptotic vesicles from apoptotic MSCs (MSC-ApoVs). This finding inspires a novel therapeutic strategy for using MSC-ApoVs for disease treatment. The present review aims to summarize the biogenesis, physiological functions, therapeutic potentials, and related mechanisms of apoptotic vesicles in MSC-based therapy. In addition, the potential applications of MSC-ApoVs as natural therapeutic agents and natural drug delivery vehicles are proposed and highlighted. The present review is hoped to provide a general understanding of MSC-ApoVs in disease treatment and inspire potential applications in targeted drug delivery.

High Targeting Specificity toward Pulmonary Inflammation Using Mesenchymal Stem Cell-Hybrid Nanovehicle for an Efficient Inflammation Intervention.

Pulmonary inflammation is one of the most reported tissue inflammations in clinic. Successful suppression of inflammation is vital to prevent further inevitably fatal lung degeneration. Glucocorticoid hormone, such as methylprednisolone (MP), is the most applied strategy to control the inflammatory progression yet faces the challenge of systemic side effects caused by the requirement of large-dosage and frequent administration. Highly efficient delivery of MP specifically targeted to inflammatory lung sites may overcome this challenge. Therefore, the present study develops an inflammation-targeted biomimetic nanovehicle, which hybridizes the cell membrane of mesenchymal stem cell with liposome, named as MSCsome. This hybrid nanovehicle shows the ability of high targeting specificity toward inflamed lung cells, due to both the good lung endothelium penetration and the high uptake by inflamed lung cells. Consequently, a single-dose administration of this MP-loaded hybrid nanovehicle achieves a prominent treatment of lipopolysaccharide-induced lung inflammation, and negligible treatment-induced side effects are observed. The present study provides a powerful inflammation-targeted nanovehicle using biomimetic strategy to solve the current challenges of targeted inflammation intervention.

In Situ Tumor Vaccine for Lymph Nodes Delivery and Cancer Therapy Based on Small Size Nanoadjuvant.

Tumor vaccine is a promising cancer treatment modality, however, the convenient antigens loading in vivo and efficient delivery of vaccines to lymph nodes (LNs) still remain a formidable challenge. Herein, an in situ nanovaccine strategy targeting LNs to induce powerful antitumor immune responses by converting the primary tumor into whole-cell antigens and then delivering these antigens and nanoadjuvants simultaneously to LNs is proposed. The in situ nanovaccine is based on a hydrogel system, which loaded with doxorubicin (DOX) and nanoadjuvant CpG-P-ss-M. The gel system exhibits ROS-responsive release of DOX and CpG-P-ss-M, generating abundant in situ storage of whole-cell tumor antigens. CpG-P-ss-M adsorbs tumor antigens through the positive surface charge and achieves charge reversal, forming small-sized and negatively charged tumor vaccines in situ, which are then primed to LNs. Eventually, the tumor vaccine promotes antigens uptake by dendritic cells (DCs), maturation of DCs, and proliferation of T cells. Moreover, the vaccine combined with anti-CTLA4 antibody and losartan inhibits tumor growth by 50%, significantly increasing the percentage of splenic cytotoxic T cells (CTLs), and generating tumor-specific immune responses. Overall, the treatment effectively inhibits primary tumor growth and induces tumor-specific immune response. This study provides a scalable strategy for in situ tumor vaccination.

Does teacher's data literacy and digital teaching competence influence empowering students in the classroom? Evidence from China.

With the digital transformation of education, data and digital technologies are regarded as the driving forces for teaching innovation. Teachers' data literacy and digital teaching competence are becoming increasingly important for empowering students' digital capacity, ethically technology usage, and collaboration or communication skills in the classroom. Therefore, whether teachers' data literacy and digital teaching competence can empower students in the classroom needs to be explored. This study aims to reveal the relationship between teacher's information communication technology (ICT) attitude, ICT skills, data literacy, digital teaching competence and empowering students. The data were collected from an online self-assessment scale which included a total of 629 K-9 teachers who participated in this study. Using SPSS and AMOS, a model was built by using Structural Equation Models to explain and predict the relationships. The results indicated that: (a) ICT attitude had no significant impact on digital teaching competence, and ICT skills significantly predicted digital teaching competence, but neither ICT attitude nor skills had a significant direct impact on empowering students; (b) data literacy significantly predicted digital teaching competence and had a significant direct impact on empowering students; (c) digital teaching competence, as dominant mediator in ICT attitude, ICT skills and data literacy, strongly predicted empowering students. The findings provided valuable evidence for teachers, policymakers, administrators, teacher educators, and teachers to better reimagine the teachers' digital teaching competence. In the future, the teachers' digital teaching competence should become the top priority in teacher ICT training, which was the most direct influencing factor for empowering students.

Mesenchymal stem cells: A living carrier for active tumor-targeted delivery.

The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.

Self-propelled nanomotor reconstructs tumor microenvironment through synergistic hypoxia alleviation and glycolysis inhibition for promoted anti-metastasis.

Solid tumors always exhibit local hypoxia, resulting in the high metastasis and inertness to chemotherapy. Reconstruction of hypoxic tumor microenvironment (TME) is considered a potential therapy compared to directly killing tumor cells. However, the insufficient oxygen delivery to deep tumor and the confronting "Warburg effect" compromise the efficacy of hypoxia alleviation. Herein, we construct a cascade enzyme-powered nanomotor (NM-si), which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy. Catalase (Cat) and glucose oxidase (GOx) are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor (NM), with hexokinase-2 (HK-2) siRNA further condensed (NM-si). The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H2O2 gradient towards deep tumor, with hypoxia successfully alleviated in the meantime. The autonomous movement also facilitates NM-si with lysosome escaping for efficient HK-2 knockdown to inhibit glycolysis. In vivo results demonstrated a promising anti-metastasis effect of commercially available albumin-bound paclitaxel (PTX@HSA) after pre-treated with NM-si for TME reconstruction. This cascade enzyme-powered nanomotor provides a potential prospect in reversing the hypoxic TME and metabolic pathway for reinforced anti-metastasis of chemotherapy.

Iron oxide nanoparticles augment the intercellular mitochondrial transfer-mediated therapy.

The transfer of mitochondria between cells has recently been revealed as a spontaneous way to protect the injured cells. However, the utilization of this natural transfer process for disease treatment is so far limited by its unsatisfactory transfer efficiency and selectivity. Here, we demonstrate that iron oxide nanoparticles (IONPs) can augment the intercellular mitochondrial transfer from human mesenchymal stem cells (hMSCs) selectively to diseased cells, owing to the enhanced formation of connexin 43­containing gap junctional channels triggered by ionized IONPs. In a mouse model of pulmonary fibrosis, the IONP-engineered hMSCs achieve a remarkable mitigation of fibrotic progression because of the promoted intercellular mitochondrial transfer, with no serious safety issues identified. The present study reports a potential method of using IONPs to enable hMSCs for efficient and safe transfer of mitochondria to diseased cells to restore mitochondrial bioenergetics.

Iron Oxide Nanoparticles Promote Cx43-Overexpression of Mesenchymal Stem Cells for Efficient Suicide Gene Therapy during Glioma Treatment.

Background: Mesenchymal stem cells (MSCs) have been applied as a promising vehicle for tumour-targeted delivery of suicide genes in the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy against malignant gliomas. The efficiency of this strategy is largely dependent on the bystander effect, which relies on high suicide gene expression levels and efficient transportation of activated GCV towards glioma cells. However, up to now, the methods to enhance the bystander effect of this strategy in an efficient and safe way are still lacking and new approaches to improve this therapeutic strategy are required. Methods: In this study, MSCs were gene transfected using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs) to highly express HSV-tk. Both the suicide and bystander effects of HSV-tk expressed MSCs (MSCs-tk) were quantitatively evaluated. Connexin 43 (Cx43) expression by MSCs and glioma cells was measured under different treatments. Intercellular communication between MSCs and C6 glioma cells was examined using a dye transfer assay. Glioma tropism and the bio-distribution of MSCs-tk were observed. Anti-tumour activity was investigated in the orthotopic glioma of rats after intravenous administration of MSCs-tk followed by intraperitoneal injection of GCV. Results: Gene transfection using MFIONs achieved sufficient expression of HSV-tk and triggered Cx43 overexpression in MSCs. These Cx43 overexpressing MSCs promoted gap junction intercellular communication (GJIC) between MSCs and glioma cells, resulting in significantly inhibited growth of glioma through an improved bystander effect. Outstanding tumour targeting and significantly prolonged survival with decreased tumour size were observed after the treatment using MFION-transfected MSCs in glioma model rats. Conclusion: Our results show that iron oxide nanoparticles have the potential to improve the suicide gene expression levels of transfected MSCs, while promoting the GJIC formation between MSCs and tumour cells, which enhances the sensitivity of glioma cells to HSV-tk/GCV suicide gene therapy.

Self-Propelled Micro/Nanomotors for Tumor Targeting Delivery and Therapy.

Cancer is still one of the most serious diseases with threats to health and life. Although some advances have been made in targeting delivery of antitumor drugs over the past number of years, there are still many problems needing to be solved, such as poor efficacy and high systemic toxicity. Micro/nanomotors capable of self-propulsion in fluid provide promising platforms for improving the efficiency of tumor delivery. Herein, the recent progress in micro/nanomotors for tumor targeting delivery and therapy is reviewed, with special focus on the contributions of micro/nanomotors to the different stages of tumor targeting delivery as well as the combination therapy by micro/nanomotors. The present limitations and future directions are also put forward for further development.

Immunomodulatory mechanism of a purified polysaccharide isolated from Isaria cicadae Miquel on RAW264.7 cells via activating TLR4-MAPK-NF-κB signaling pathway.

The immunomodulatory effect of a novel purified polysaccharide (JCH-1) isolated from Isaria cicadae Miquel had been confirmed to promote secretion of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) in our previous study. However, the immunomodulatory mechanism was still unclear. The purpose of this study was to investigate the immunomodulatory mechanism of JCH-1. Experimental data showed that JCH-1 could increase protein expression of toll-like receptor 4 (TLR4), promote the phosphorylation of mitogen-activated protein kinase (MAPK), as well as nuclear factor-kappa B (NF-κB) p65. Importantly, TLR4 inhibitor inhibited JCH-1-induced activation of MAPK-NF-κB signaling pathway, thus suppressed JCH-1-induced secretion of NO, TNF-α and IL-6. Collectively, these results indicated that JCH-1 actives RAW264.7 cells through TLR4-MAPK-NF-κB signaling pathway.

Degradation of 2,4-dichlorophenol by CuO-activated peroxydisulfate: Importance of surface-bound radicals and reaction kinetics.

Peroxydisulfate (PDS, S2O82-) is a promising oxidant for water treatment and contaminated groundwater remediation. It requires activation to generate sulfate radical (SO4-) and hydroxyl radical (OH) for indirect oxidation of organic pollutants. Recently, efforts were devoted to developing PDS activation systems for direct oxidation of organic pollutants without producing radicals. However, the mechanism was still ambiguous and the kinetics was either not quantified or empirical in nature. In this research, we examined the activation of PDS by CuO for the degradation of 2,4-dichlorophenol (2,4-DCP). Dual-compound control experiments, radical scavenging tests and electron paramagnetic resonance (EPR) studies showed that surface-bound OH generated from the adsorbed PDS was the main reactive species responsible for the degradation of 2,4-DCP. A kinetic model considering the important reaction steps, including the adsorption of PDS onto CuO, activation of adsorbed PDS to form surface-bound SO4- and then surface-bound OH, and degradation of 2,4-DCP by surface-bound OH, was developed to better elucidate the reaction kinetics. The results suggested that the overall reaction kinetics of 2,4-DCP degradation was regulated by the adsorption of PDS onto CuO and the electron transfer between surface Cu and adsorbed PDS to form surface-bound SO4-. The developed kinetic model could serve as a framework to characterize other persulfate oxidation systems relying on surface-bound radicals.

The prevalence of and factors associated with willingness to utilize HTC service among college students in China.

BACKGROUND: College students in China are emerging as one of the most vulnerable groups to contract HIV, because they are in a sexually active age group and also because of their open attitude toward sex and high risk sexual behaviors. This study aimed to explore the prevalence of willingness among college students to utilize HIV testing and counseling (HTC) service and the factors that may affect willingness, including predisposing, enabling and need factors, based on the Andersen's behavioral model. METHODS: A cross-sectional study was conducted from October 6, 2016 to December 31, 2016 in Hubei University of Science and Technology in China. After signing informed consent, college students completed a self-designed online questionnaire distributed via  https://www.wjx.cn/ voluntarily, anonymously and confidentially. Pearson's chi-square test and Logistic regression models were chosen to analyze the factors associated with willingness to utilize HTC service. RESULTS: Out of 3314 college students in the sample, 2583 (77.9%) expressed their willingness to utilize HTC service. After adjustment, those with low levels of discrimination towards people living with HIV (PLHIV) (OR = 1.41, 95%CI:1.17-1.68), being more knowledgeable about free HTC service centers (OR = 1.44, 95%CI:1.17-1.77), having recognized the necessity to provide HTC service in the local university (OR = 2.20, 95%CI:1.73-2.80), and having a higher HIV risk perception (OR = 1.64, 95%CI:1.37-1.95) were more willing to utilize HTC service, compared with their respective counterparts. CONCLUSIONS: In order to improve their willingness to utilize HTC service and finally to achieve the goal of zero-AIDS, a comprehensive intervention measure should be taken to publicize HTC service, eliminate stigma and discrimination against PLHIV, recruit and train peer volunteers to serve in the local university, and increase self-perceived risk of HIV infection.