Chemodynamic therapy (CDT) is seriously limited by the inadequacy of exogenous catalytic ions and endogenous H 2 O 2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO 2 ) and β-lapachone as donors of H 2 O 2 and GSH-sensitive Fe-based coordination polymer as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the GSH-rich cytoplasm. Furthermore, the released CaO 2 and β-lapachone could significantly self-generated sufficient H 2 O 2 , which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca 2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H 2 O 2 , but also efficiently activates ferroptosis and initiates Ca 2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H 2 O 2 .

Wound care is a major clinical and social concern. However, effective wound repair remains challenging where conventional dressings yield detrimental healing outcomes. An emerging technique, named mechanically active dressing (MAD), uses self-contractile hydrogels to mechanically contract the wound bed. MAD has shown improved healing rates with limited side effects. These promising developments in wound care call for a timely review on the development of such technology. Herein, we shed light on the mechanism underlying mechanically modulated wound healing, carry out a systematic discussion on the status quo of designing hydrogels for MAD fabrication, and conclude with perspectives on design, use and clinical translation for realizing the future goal of personalized wound care.

Gastric cancer is a prevalent malignant tumor worldwide, posing challenges due to its poor prognosis and limited treatment options. Cancer stem cells (CSCs) were demonstrated as a subset of cancer cells responsible for tumor initiation and progression, and their inherent resistance to conventional chemotherapy and radiotherapy critically contributes to tumor recurrence and metastasis. Promoting the eradication of cancer stem cells is crucial for enhancing the efficacy of cancer treatments. This study introduces a novel therapeutic strategy utilizing polyhedral magnetic nanoparticles (PMNPs) functionalized with CD44 antibodies and cell-penetrating peptides (CPPs) to improve uptake by gastric cancer stem cells (MCSCs). PMNPs, synthesized via thermal decomposition, exhibited a diameter of 90 nm ± 9 nm and a saturation magnetization of 79.9 emu/g. Functionalization enhanced their uptake capabilities. Under a rotating magnetic field (RMF) of 15 Hz, PMNPs disrupted cellular structure, leading to apoptosis and ferroptosis in MCSCs. The in vitro studies showed significant reduction in MCSCs viability, while in vivo studies demonstrated tumor growth suppression with minimal side effects and high biocompatibility. This work presents a novel strategy for designing magnetic nanoparticles to mechanically destroy cancer stem cells, offering a more efficient and safety treatment option for gastric cancer.

Gastric cancer stem cells (GCSCs) originate from both gastric adult stem cells and bone marrow cells and are conspicuously present within the histological milieu of gastric cancer tissue. GCSCs play pivotal and multifaceted roles in the initiation, progression, and recurrence of gastric cancer. Hence, the characterization of GCSCs not only facilitates precise target identification for prospective therapeutic interventions in gastric cancer but also has significant implications for targeted therapy and the prognosis of gastric cancer. The prevailing techniques for GCSC purification involve their isolation using surface-specific cell markers, such as those identified by flow cytometry and immunomagnetic bead sorting techniques. In addition, in vitro culture and side-population cell sorting are integral methods in this context. This review discusses the surface biomarkers, isolation techniques, and identification methods of GCSCs, as well as their role in the treatment of gastric cancer.

Abstract Chemodynamic therapy (CDT) is seriously limited by the insufficient amounts of both exogenous catalytic ions and endogenous H2O2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO2) and β-lapachone as donors of H2O2 and GSH-sensitive Fe-based covalent organic framework (COFs) as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the high dose of GSH within the cytoplasm. Furthermore, the released CaO2 and β-lapachone could significantly self-generated sufficient H2O2, which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H2O2, but also efficiently activates ferroptosis and inducing Ca2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb system for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H2O2.Keywords: Cascade amplification, tumor starvation, chemodynamic therapy, re-education macrophages, Fe-MOF nanosystem.

Background: Long non-coding RNAs (lncRNAs) play critical roles in gastric cancer (GC) initiation progression. However, the biological function of the lncRNA telomerase RNA component (TERC) remains unknown in human GC. The present study sought to determine the biological function and underlying molecular mechanism of the lncRNA TERC in GC progression. Methods: The expression levels of the lncRNA TERC in GC tissues and cell lines were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of the lncRNA TERC on the proliferation, migration, and invasion of GC cells were determined using Cell Counting Kit-8 (CCK-8) and Transwell assays. Dual luciferase reporter and argonaute 2 (AGO2)-RNA immunoprecipitation (RIP) assays were used to detect the binding between the lncRNA TERC and microRNA-423-5p (miR-423-5p). Western blotting was performed to measure the expression levels of sex determining region Y-box 12 (SOX12), N-cadherin, E-cadherin, matrix metallopeptidase 9 (MMP9), and proliferating cell nuclear antigen (PCNA). Results: The results demonstrated that the lncRNA TERC expression levels were upregulated in GC cells and tissues, while miR-423-5p expression levels were downregulated. The upregulation of the lncRNA TERC was associated with a shorter overall survival in patients with GC. The knockdown of the lncRNA TERC significantly reduced the proliferation, migration, and invasion of human GC cell lines HGC-27 and SNU-1 cells. Further, the lncRNA TERC knockdown in the HGC-27 and SNU-1 cells significantly downregulated the expression levels of SOX12, N-cadherin, MMP9, and PCNA, and upregulated the expression levels of miR-423-5p and E-cadherin. MiR-423-5p was also identified as a target of the lncRNA TERC and was found to directly bind to the lncRNA TERC. Additionally, miR-423-5p was found to directly target SOX12 to inhibit the proliferation, migration, and invasion of the HGC-27 and SNU-1 cells. Conclusions: In conclusion, the findings of this study suggested that the lncRNA TERC may regulate the miR-423-5p/SOX12 signaling axis by directly sponging miR-423-5p and inhibiting SOX12 expression, thereby leading to the progression of GC. These findings may reveal novel targets for future GC therapy.

Introduction: With the widespread development of organ donation after cardiac death (DCD), the quality of organs has attracted more and more attention. The preservation time of DCD organs is significantly longer than that of living related donation, and the organic ischemia-reperfusion injury (IRI) is more significant. IRI is one of the main factors of chronic rejection in DCD-related kidney transplantation. The chronic rejection is an important cause of long-term failure of renal transplantation and the treatment is very difficult. During DCD kidney transplantation, an emergency response was initiated and inflammatory factors were highly expressed in vivo, especially the increase of IFN-γ. Umbilical cord mesenchymal stem cells (UC-MSCs) can rapidly inhibit the inflammatory response and secrete high concentrations of prostaglandin PGE2, which can mediate the hypermethylation of MDSCs to regulate the differentiation of M2 macrophages and their subpopulations. By injecting pre-sensitized UC-MSCs with IFN-γ, the method can inhibit or delay chronic rejection and induce specific immune tolerance while protecting IRI of transplanted kidney. Methods: MDSC primary cells were prepared from fresh umbilical cord tissue, and the cells were passaged to the third passage (P3). The cell concentration was adjusted to 1×105cells/mL. UC-MSCs were pretreated with 100 ng/mL IFN-γ for 48 hours, and then transfused into DCD kidney transplanted C57BL/6 recipient mice, and three control groups were set up for observation. The peripheral blood, transplanted kidney and local tissues of the above-mentioned rats were isolated, and the expression abundance of PGE2 was detected by RT-PCR at the 3rd,7th,14th and 28th days after operation. The proportion, distribution, methylation and phenotypic changes of M2 macrophage cells and MDSC were also identified by single-cell sequencing technology. Pathological specimens were used to analyze T lymphocyte, neutrophil, and macrophage infiltration. Biochemical samples were used to detect the expression of inflammatory factors, oxidative stress (SOD, MPO, MDA), and the expression of apoptosis-related proteins (caspase-3, caspase-9, Bcl-2, Bax) in kidney cells were detected by western-blotting. Results: The rat model of DCD kidney transplantation was successfully established. The hypermethylation status of MDSCs in the IFN-γ-UC-MSCs kidney transplantation group was higher than that in the PBS and UC-MSCs groups(P<0.05). The abundance of PGE2 expression in the transplanted kidney and local tissue in the IFN-γ-UC-MSCs group was higher than that in the other two groups. The ratio of M2/M1 macrophages was significantly higher than that in the other two groups (P<0.05).M2 macrophages were mainly distributed in the microenvironment around the transplanted kidney, and the phenotypes were dominated by M2b and M2c subtypes. From the 3rd day to the 7th day of transplantation, the expression levels of IL-12, IL-2 and IFN-γ cytokines in the serum of each group were increased. The increased levels of the IFN-γ-UC-MSCs group and the UC-MSCs group was significantly lower than the PBS group (P<0.05). On the 14th day of transplantation, the serum level of IL-10 in the IFN-γ-UC-MSCs group was significantly higher than other two groups (P<0.05). On the 28th day, CD4+CD25+ Tregs and CD4+CD25+Foxp3+ Tregs the spleen accounted for the highest proportion of CD4+ T cells, which was significantly different from other groups (P<0.05). Foxp3 mRNA expression in IFN-γ-UC-MSCs group was significantly higher than that in UC-MSCs and PBS groups (P<0.05). The ratio of M2/M1 macrophages in IFN-γ -UC-Mscs group was significantly higher than that in other groups (P<0.05). The HE staining of the transplanted kidney showed that the inflammatory response of the transplant was significantly lower than that of the PBS and UC-MSCs groups. Conclusions: By injecting UC-MSCs pre-sensitized with IFN-γ, the DCD kidney transplanted rats can secrete a large amount of PGE2, which mediate the hypermethylation of MDSCs to induce an increase in the M2 macrophages. The increase of M2 macrophages forms a local immunosuppressive microenvironment, inhibit the occurrence of chronic rejection and induce long-term specific immune tolerance.

Introduction: Ischemia reperfusion injury (IRI) of donation After Cardiac death (DCD) transplanted kidney is the key factor of acute renal injury, acute and chronic rejection of renal transplantation and transplanted kidney disease.The latest researches show that mesenchymal stem cells (MSCs) have the function of protecting damaged tissues and organs and strong immune regulation. Induced pluripotent stem (iPS) cells have higher proliferative capacity and exosome secretion potential than MSCs. In addition to the functions of stem cells, exosomes have the unique ability to cross the blood-brain barrier and deliver remotely, which means that exosomes have better advantages in clinical disease treatment compared with the therapeutic potential of stem cells. Therefore, the main purpose of this study is to clarify the role of IPS derived exosomes in protecting the IRI of DCD transplanted kidney and regulating its local immune microenvironment. Methods: The iPS cells were passaged to the third passage and massively expanded. After 48 hours of culture, 100 mL of cell culture supernatant was collected and exosomes were extracted from the supernatant by the kit method, and the morphology and surface membrane marker proteins of the exosomes were identified. The SD rats were established with DCD renal transplantation model and 10, 50, and 100 μg of exosomes were infused into that SD rats respectively, and a PBS control group was set at the same time. On the 3rd, 5th, 7th, 14th and 28th days after transplantation, the content of cytokines in the serum of the recipient rats, the proportion of lymphocyte subsets CD4+CD25+Foxp3+Tregs in the spleen and the relative expression of Foxp3 mRNA were detected. The proliferation of renal tubular cells was detected by PCNA immunofluorescence. The pathological changes of renal tissue were determined by HE staining, and the apoptosis of renal tubular epithelial cells was detected by Tunel staining. The infiltration of inflammatory cells was detected by immunohistochemistry. The expression changes of regulatory T cells in renal tissue and macrophage phenotypic characteristics were analyzed by flow cytometry. Results: The experimental amount of exosomes was successfully obtained, and the morphology was observed by transmission electron microscope. The exosomes were round or oval membranous vesicles with uniform size, and the edges were clearly visible. The TSG101, CD63, and CD9 proteins were highly expressed on the exosome membrane surface by western-blot. A DCD rat kidney transplantation model was successfully established. The expression levels of IL-12, IL-2, IFN-γ, and TNF-α in the serum of each group were increased to varying degrees from the 3rd day after operation. On the 3rd and 7th days, the levels of IL-12, IL-2, IFN-γ, and TNF-α in the 100 μg exosome infusion group were significantly lower than those in the 10 μg, 50 μg and PBS groups (P<0.05), and the expression level of IL-10 in the 100 μg exosome infusion group was significantly higher than 10μg, 50μg and PBS groups (P<0.05). On the 28th day, the expression level of IL-10 in the 100 μg exosome infusion group was significantly higher than other groups (P<0.01). Compared with other groups, the CD4+CD25+Tregs and CD4+CD25+Foxp3+Tregs accounted for the highest proportion of CD4+T cells in the spleen of the 100μg infusion group (P<0.05). On the 28th day, the expression level of Foxp3 mRNA in the 100 μg infusion group was significantly higher than that in the 50 μg group (P<0.05). The stainings of PCNA, HE and Tunel showed that SD rats infused with 100μg exosomes could significantly reduce the pathological damage, inflammatory response and apoptosis of renal tubular epithelial cells in the transplanted kidney, promote the proliferation of renal tubular epithelial cells, and have a protective effect on IRI kidney. On the 28th day, the expression of CD4+CD25+Foxp3+Tregs cells in the transplanted kidney tissue was significantly increased, which further promoted the differentiation of macrophages into the immunomodulatory M2 subset. Conclusions: The infusion of iPS-derived high-dose exosomes is involved in the protection of the DCD kidney transplant during IRI process, and alleviates the acute and chronic injury of the DCD kidney transplant, and promotes the formation of the local immunosuppressive microenvironment in the DCD kidney transplantation. The National Natural Science Foundation of China (No.81900686).