Dynamic RGD ligands derived from highly mobile cyclodextrins regulate spreading and proliferation of endothelial cells to promote vasculogenesis.

A thiolated RGD was incorporated into the threaded allyl-ß-cyclodextrins (Allyl-ß-CDs) of the polyrotaxane (PR) through a thiol-ene click reaction, resulting in the formation of dynamic RGD ligands on the PR surface (dRGD-PR). When maintaining consistent RGD density and other physical properties, endothelial cells (ECs) cultured on dRGD-PR exhibited significantly increased cell proliferation and a larger cell spreading area compared to those on the non-dynamic RGD (nRGD-PCL). Furthermore, ECs on dRGD-PR demonstrated elevated expression levels of FAK, p-FAK, and p-AKT, along with a larger population of cells in the G2/M stage during cell cycle analysis, in contrast to cells on nRGD-PCL. These findings suggest that the movement of the RGD ligands may exert additional beneficial effects in promoting EC spreading and proliferation, beyond their essential adhesion and proliferation-promoting capabilities, possibly mediated by the RGD-integrin-FAK-AKT pathway. Moreover, in vitro vasculogenesis tests were conducted using two methods, revealing that ECs cultured on dRGD-PR exhibited much better vasculogenesis than nRGD-PCL in vitro. In vivo testing further demonstrated an increased presence of CD31-positive tissues on dRGD-PR. In conclusion, the enhanced EC spreading and proliferation resulting from the dynamic RGD ligands may contribute to improved in vitro vasculogenesis and in vivo vascularization.

Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity.

Breast cancer, a pervasive malignancy affecting women, demands a diverse treatment approach including chemotherapy, radiotherapy, and surgical interventions. However, the effectiveness of doxorubicin (DOX), a cornerstone in breast cancer therapy, is limited when used as a monotherapy, and concerns about cardiotoxicity persist. Ginsenoside Rg3, a classic compound of traditional Chinese medicine found in Panax ginseng C. A. Mey., possesses diverse pharmacological properties, including cardiovascular protection, immune modulation, and anticancer effects. Ginsenoside Rg3 is considered a promising candidate for enhancing cancer treatment when combined with chemotherapy agents. Nevertheless, the intrinsic challenges of Rg3, such as its poor water solubility and low oral bioavailability, necessitate innovative solutions. Herein, we developed Rg3-PLGA@TMVs by encapsulating Rg3 within PLGA nanoparticles (Rg3-PLGA) and coating them with membranes derived from tumor cell-derived microvesicles (TMVs). Rg3-PLGA@TMVs displayed an array of favorable advantages, including controlled release, prolonged storage stability, high drug loading efficiency and a remarkable ability to activate dendritic cells in vitro. This activation is evident through the augmentation of CD86+CD80+ dendritic cells, along with a reduction in phagocytic activity and acid phosphatase levels. When combined with DOX, the synergistic effect of Rg3-PLGA@TMVs significantly inhibits 4T1 tumor growth and fosters the development of antitumor immunity in tumor-bearing mice. Most notably, this delivery system effectively mitigates the toxic side effects of DOX, particularly those affecting the heart. Overall, Rg3-PLGA@TMVs provide a novel strategy to enhance the efficacy of DOX while simultaneously mitigating its associated toxicities and demonstrate promising potential for the combined chemo-immunotherapy of breast cancer.

Tumor-derived microvesicles for cancer therapy.

Extracellular vesicles (EVs) are vesicles with lipid bilayer structures shed from the plasma membrane of cells. Microvesicles (MVs) are a subset of EVs containing proteins, lipids, nucleic acids, and other metabolites. MVs can be produced under specific cell stimulation conditions and isolated by modern separation technology. Due to their tumor homing and large volume, tumor cell-derived microvesicles (TMVs) have attracted interest recently and become excellent delivery carriers for therapeutic vaccines, imaging agents or antitumor drugs. However, preparing sufficient and high-purity TMVs and conducting clinical transformation has become a challenge in this field. In this review, the recent research achievements in the generation, isolation, characterization, modification, and application of TMVs in cancer therapy are reviewed, and the challenges facing therapeutic applications are also highlighted.

Ratiometric antifouling electrochemical biosensors based on designed Y-shaped peptide and MXene loaded with Au@ZIF-67 and methylene blue.

Based on the designed inverted Y-shaped peptide and MXene nanocomposite (MXene-Au@ZIF-67), a ratiometric anti-pollution electrochemical biosensor was designed and applied to the detection of biomarkers in serum. Au@ZIF-67 inserted into the interior of MXene can not only prevent the accumulation of MXene but also provide a large amounts of binding sites for capturing biomolecules. A designed multifunctional Y-shaped peptide containing anchoring, antifouling, and recognition sequences was anchored onto MXene-Au@ZIF-67 through Au-S bonds. Electrochemical signal molecules, ferrocenecarboxylic acid (Fc) and methylene blue (MB), were modified to another end of multifunctional peptide and interior of MXene-Au@ZIF-67, respectively, to produce a ratiometric electrochemical signal. We selected prostate specific antigen (PSA) as the model compound. PSA specifically recognizes and cleaves the recognition segment in the Y-shaped peptide, and the signal of Fc is reduced, while the signal of MB remains unchanged. The ratiometric strategy endows the present biosensor high accuracy and sensitivity with a detection limit of 0.85 pg/mL. In addition, the sensing surface has good antifouling ability due to the antifouling sequence of the two branching parts of the Y-shaped peptide. More importantly, by replacing the recognition segment of peptides also other targets are accessible, indicating the potential application of the universal detection strategy to the detection of various biomarkers in clinical diagnosis.

Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression.

Succinate is an important intermediate product of mitochondrial energy metabolism. Recent studies revealed that beyond its known traditional metabolic functions, succinate plays important roles in signal transduction, immunity, inflammation, and posttranslational modification. Recent studies showed that patients and mouse models with cardiovascular disease have high levels of serum succinate and succinate accumulation. Atherosclerosis (As) is the pathological basis of cardiovascular and peripheral vascular diseases, such as coronary heart disease, cerebral infarction, and peripheral vascular disease, and is a major factor affecting human health. This article reviews the progression of succinate in As diseases and its underlying mechanisms.

Krebs Cycle Rewired: Driver of Atherosclerosis Progression?

The tricarboxylic acid (TCA) cycle is the center of energy metabolism in eukaryotic cells and is dynamically adjusted according to the energy needs of cells. Macrophages are activated by inflammatory stimuli, and then two breakpoints in TCA cycle lead to the accumulation of intermediates. Atherosclerosis is a chronic inflammatory process. Here, the "non-metabolic" signaling functions of TCA cycle intermediates in the macrophage under inflammatory stimulation and the role of intermediates in the progression of atherosclerosis are discussed.

Efficacy and Mechanism of Active Fractions in Fruit of Amomum villosum Lour. for Gastric Cancer.

Amomi Fructus is the dried ripe fruit of Amomum villosum Lour. (A. villosum). It is a well-known traditional Chinese medicine widely used to treat gastrointestinal diseases, while the efficacy or mechanism of main components in Amomi Fructus on cancer treatment remains unknown. In this study, volatile oil of A. villosum (VOAV), total flavonoids of A. villosum (FNAV) and the other residue of A. villosum (RFAV) were distilled, extracted and separated as different active fractions of A. villosum. The cell toxicity test results indicated that VOAV and FNAV can effectively inhibit the cell growth of MFC cells. Flow cytometry test results confirmed that MFC cells were caused apoptosis after being treated with VOAV, FNAV or RFAV. VOAV, FNAV or RFAV induced MFC cells apoptosis through reactive oxygen species (ROS)-mediated mitochondrial pathway, evident by the increase of endogenous ROS and mitochondrial membrane potential collapse. In addition, FNAV exhibited robust inhibitory effects on MFC tumor growth, and could improve the health status of mice compared to that of mice in 5-FU treated group. To sum up, all the above results suggest that FNAV may be a good candidate for the development of new drugs for the treatment of gastric cancer.

Recent Advances in Cell Membrane-Derived Biomimetic Nanotechnology for Cancer Immunotherapy.

Immunotherapy will significantly impact the standard of care in cancer treatment. Recent advances in nanotechnology can improve the efficacy of cancer immunotherapy. However, concerns regarding efficiency of cancer nanomedicine, complex tumor microenvironment, patient heterogeneity, and systemic immunotoxicity drive interest in more novel approaches to be developed. For this purpose, biomimetic nanoparticles are developed to make innovative changes in the delivery and biodistribution of immunotherapeutics. Biomimetic nanoparticles have several advantages that can advance the clinical efficacy of cancer immunotherapy. Thus there is a greater push toward the utilization of biomimetic nanotechnology for developing effective cancer immunotherapeutics that demonstrate increased specificity and potency. The recent works and state-of-the-art strategies for anti-tumor immunotherapeutics are highlighted here, and particular emphasis has been given to the applications of cell-derived biomimetic nanotechnology for cancer immunotherapy.

Low shear stress-induced endothelial mesenchymal transformation via the down-regulation of TET2.

Atherosclerotic cardiovascular disease is the major cause of death worldwide. Low shear stress plays key roles on the initiation and progression of atherosclerosis (As). However, its underlying mechanism remains unclear. In this study, the effect of low shear stress on endothelial mesenchymal transformation (EndMT) and its underlying mechanism were explored. Results showed that in cultured human umbilical vein endothelial cells, low shear stress down-regulated the expression of TET2 and promoted EndMT. Loss of TET2 promoted EndMT with the Wnt/ß-catenin signaling pathway. The enhancement in EndMT induced by low shear stress was attenuated by TET2 overexpression. In apoE-/- mice subjected to carotid artery local ligation, the EndMT and atherosclerotic lesions induced by low shear stress was attenuated by TET2 overexpression. Taken together, low shear stress promoted EndMT through the down-regulation of TET2, indicating that intervention with EndMT or the up-regulation of TET2 might be an alternative strategy for preventing As.

Low shear stress induced vascular endothelial cell pyroptosis by TET2/SDHB/ROS pathway.

Vascular endothelial cell (VEC) inflammation induced by low shear stress plays key roles in the initiation and progression of atherosclerosis (As). Pyroptosis is a form of inflammatory programmed cell death that is critical for As. However, the effect of low shear stress on VEC pyroptosis and the underlying mechanisms were not clear. Here we show that low shear stress promoted VEC pyroptosis and reduced the expression of Ten-Eleven Translocation 2 (TET2) methylcytosine dioxygenase. Loss of TET2 resulted in the upregulation of the expression and activity of mitochondrial respiratory complex II subunit succinate dehydrogenase B (SDHB) by decreasing the recruitment of histone deacetylase 2, independent of DNA demethylation modification. The overexpression of SDHB mediated mitochondrial injury and increased the production of reactive oxygen species (ROS). The administration of ROS scavenger NAC alleviated VEC pyroptosis induced by SDHB overexpression and TET2 shRNA. These findings show that low shear stress induced endothelial cell pyroptosis through the TET2/SDHB/ROS pathway and offer new insights into As.

Effective Radiotherapy in Tumor Assisted by Ganoderma lucidum Polysaccharide-Conjugated Bismuth Sulfide Nanoparticles through Radiosensitization and Dendritic Cell Activation.

Radiotherapy is a traditional method for cancer therapy but may become ineffective likely due to the radiation-induced immunosuppression. Instead of simply increasing the radiation dose, reactivation of immunosuppression in the tumor microenvironment is an alternative strategy for successful cancer treatment. In this work, we synthesized bismuth sulfide nanoparticles (BiNP) and conjugated with immunoactive Ganoderma lucidum polysaccharide (GLP). GLP-BiNP were able to increase the sensitivity of radiotherapy, attributing to the efficient X-ray absorption of bismuth element. BiNP alone can mildly activate dendritic cells (DC) in vitro, while GLP-BiNP further enhanced the level of DC maturation, shown as the increase in phenotypic maturation markers, cytokine release, acid phosphatase activity, and T cell proliferation in DC/T cell co-culture. Compared to BiNP, GLP-BiNP altered the tissue distribution with faster accumulation in the tumor. Meanwhile, mature DC greatly increased in both tumor and spleen by GLP-BiNP within 24 h. GLP-BiNP combination with radiation achieved remarkable inhibition of tumor growth through apoptosis. Alternatively, lung metastasis was largely prohibited by GLP-BiNP, shown as a reduced amount of tumor nodules and cancer cell invasion by pathological findings. Mechanistically, GLP-BiNP altered the tumor immunosuppression microenvironment by preferably increasing the number of intratumor CD8+ T cell proliferation, as well as the improved immunobalance shown as the increased serum interferon-γ/interleukin-4 ratio. Specifically, GLP conjugation seemed to protect the kidney from injury occasionally introduced by bare BiNP. As a result, GLP-BiNP play a dual role in tumor treatment through radiosensitization and immunoactivities.

Immunoactive polysaccharide functionalized gold nanocomposites promote dendritic cell stimulation and antitumor effects.

Aim: To investigate the immune responses and antitumor efficacy of immunoactive polysaccharide functionalized gold nanocomposites (APS-AuNP). Materials & methods: Immunoregulation of APS-AuNP on dendritic cells/T cells in vitro was evaluated by flow cytometry and their inhibitions against primary/metastatic tumors were determined on 4T1-bearing mice model. Results & conclusion: APS-AuNP exhibited remarkable capability to induce dendritic cells maturation through phenotypic markers with functional changes, which further promoted T-cell proliferation and enhanced cytotoxicity against 4T1 tumor cells. The inhibitory rate of APS-AuNP against 4T1 primary tumor growth and pulmonary metastasis in mice was higher than paclitaxel-treated group. In addition, APS-AuNP exhibited strong capability to increase the population of CD4+/CD8+ T lymphocytes as well as effector memory cells rather than central memory cells.

Effective cancer immunotherapy by Ganoderma lucidum polysaccharide-gold nanocomposites through dendritic cell activation and memory T cell response.

Polysaccharides purified from natural herbs possess immunoregulatory functions, while the efficacy of natural polysaccharides on cancer treatment remains unreliable, likely due to their low prescribed doses and fast clearances in clinical settings. In this study, gold nanocomposites containing Ganoderma lucidum polysaccharide (GLP-Au) efficiently induced dendritic cell (DC) activation, evident by the increase of CD80/CD86/CD40/MHCII, decrease of phagocytic ability and acid phosphatase activity, and increased cytokine transcription. GLP-Au significantly promoted the proliferation of CD4+ and CD8+ T cells in splenocytes. DC/T cell co-culture study proved that GLP-Au activation on DC directly resulted in T cell proliferation. GLP-Au exhibited strong inhibitory effects on 4T1 tumor growth and pulmonary metastasis when combined with doxorubicin. GLP-Au recovered body weight loss by doxorubicin and increased the percentage of CD4+/CD44+ memory T cells. This work suggests that polysaccharides from natural herbs can be incorporated into nanocomposites with immunoregulatory characteristics for enhanced efficacy on tumor therapy.