Nanoparticles Coated with Brain Microvascular Endothelial Cell Membranes can Target and Cross the Blood-Brain Barrier to Deliver Drugs to Brain Tumors.

The blood-brain barrier (BBB) contains tightly connected brain microvascular endothelial cells (BMECs) that hinder drug delivery to the brain, which makes brain tumors difficult to treat. Previous studies have shown that nanoparticles coated with tumor cell membranes selectively target their homologous tumors. Therefore, this study investigated whether bEnd.3-line BMEC membrane-coated nanoparticles with poly(lactide-co-glycolide)-poly(ethylene glycol)-based doxorubicin-loaded cores (BM-PDs) can be used to target BMECs and cross the BBB. In vitro, the BM-PDs effectively target BMECs and cross a BBB model. The BM-PDs enter the BMECs via macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and membrane fusion, which result in excellent cellular uptake. The BM-PDs also show excellent cellular uptake in brain tumor cells. In vivo, the BM-PDs target BMECs, cross the BBB, accumulate in brain tumors, and efficiently kill tumor cells. Therefore, the proposed strategy has great therapeutic potential owing to its ability to cross the BBB to reach brain tumors.

Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy.

BACKGROUND: The efficacy of current immunotherapeutic strategies for patients with glioblastoma multiforme (GBM) remains unsatisfactory. The purpose of this study was to investigate the correlation between tumor necrosis factor alpha-induced protein 2 (TNFAIP2) and immunogenic cell death (ICD) in GBM, and to examine the effect of TNFAIP2 knockdown and anti-PD-1 combination treatment in a mouse glioma model. METHODS: The CGGA and TCGA databases were used to explore the possible function of TNFAIP2 in GBM. Multiplex immunohistochemistry (mIHC) staining was performed to detect the immune infiltration of tissues. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, and enzyme linked immunosorbent assay (ELISA) were utilized to detect the release of damage-associated molecular patterns (DAMPs) and the activation of the immune response. A mouse glioma model was applied to examine the induction of immune response. RESULTS: In vitro and in vivo studies demonstrated that TNFAIP2 knockdown increased the surface exposure of calreticulin (CALR), heat shock protein 70 kDa (HSP70), and heat shock protein 90 kDa (HSP90) in GBM cell lines, thereby inducing immunogenic cell death (ICD). Importantly, the study found that TNFAIP2 knockdown in combination with anti-PD-1 therapy significantly improved the overall survival of glioma in a mouse model. CONCLUSIONS: TNFAIP2 knockdown induces ICD by downregulating TNFAIP2 in GBM. In addition, TNFAIP2 knockdown sensitized glioma to anti-PD-1 therapy. Hence, targeting TNFAIP2 alone or in combination with anti-PD-1 therapy may be a potential strategy for GBM treatment through ICD.

Inflammatory responsive neutrophil-like membrane-based drug delivery system for post-surgical glioblastoma therapy.

Surgical resection of glioblastoma (GBM) causes brain inflammation that activates and recruits neutrophils (NEs) to residual GBM tissues. NE-based drug delivery using inflammatory chemotaxis is promising for the post-surgical treatment of residual GBM, but its clinical application is limited by the short life span of NEs and lack of in vitro propagation methods. HL60 cells are a type of infinitely multiplying tumor cells that can be induced to differentiate into NE-like cells. We developed a novel NE-like membrane system (NM-PD) by coating NE-like membranes on the surface of poly (lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG)-based doxorubicin (DOX)-loaded core (PLGA-PEG-DOX, PD) for post-surgical residual GBM treatment. Cell adhesion proteins were detected on NE-like membranes and endowed NM-PDs with inflammatory chemotaxis similar to mature NEs. The resulting NM-PD shows excellent inflamed in vitro blood-brain barrier (BBB) permeability and anti-proliferative effects on GBM cells. In our intracranial GBM resection model, NM-PD exhibited superior inflammatory chemotaxis and targeted residual GBM cells, thus remarkably improving antitumor capability and prolonging the survival time of the mice. These data suggest that NM-PD, which has sufficient sources and is easy to prepare, can efficiently suppress post-surgical residual GBM and holds potential for clinical transformation in GBM post-surgical adjuvant therapy.

Engineered Salmonella inhibits GPX4 expression and induces ferroptosis to suppress glioma growth in vitro and in vivo.

PURPOSE: Glioma is a life-threatening malignancy where conventional therapies are ineffective. Bacterial cancer therapy has shown potential for glioma treatment, in particular, the facultative anaerobe Salmonella has been extensively studied. Meanwhile, ferroptosis is a newly characterized form of cell death. Nevertheless, the role of ferroptosis in Salmonella-induced tumour cell death remains unclear. Therefore, we aim to elucidate whether Salmonella YB1 exerts therapeutic effects via inducing ferroptosis in glioma. METHODS: Following Salmonella YB1 infection, mRNA sequencing was applied to detect ferroptosis-related gene expression and the levels of reactive oxygen species, malondialdehyde, and glutathione were quantified. Transmission electron microscopy (TEM) was then used to observe the changes in the mitochondrial morphology of glioma cells. The role of ferroptosis in the anti-tumor effect of YB1 was assessed in vivo in mouse tumor xenograft models. RESULTS: Whole-transcriptome analysis revealed that Salmonella YB1 infection alters ferroptosis-related gene expression in the U87 glioma cell line. Moreover, we found that Salmonella-induced ferroptosis is correlated with reduced levels of glutathione and glutathione peroxidase-4 (GPX4) and increased levels of reactive oxygen species and malondialdehyde in vitro. Meanwhile, TEM revealed that mitochondria are shrunken and mitochondrial membrane density increases in infected glioma cells. Experiments in vivo further showed that tumor growth in the Salmonella-treated group was significantly slower compared to the control and Fer-1 groups. However, Salmonella-induced tumor suppression can be reversed in vivo by Fer-1 treatment. CONCLUSION: Salmonella YB1 inhibits GPX4 expression and induces ferroptosis to suppress glioma growth. Hence, ferroptosis regulation might represent a promising strategy to improve the efficacy of bacterial cancer therapy.

Preoperative administration of a biomimetic platelet nanodrug enhances postoperative drug delivery by bypassing thrombus.

The postoperative thrombus attached to the damaged blood vessels severely obstructs drugs from crossing the damaged blood-brain barrier (BBB) and targeting residual glioma cells around surgical margins, leading to glioblastoma (GBM) recurrence. A thrombus-bypassing, BBB-crossing, and surgical margin-targeted nanodrug is needed to address this phenomenon. Encouraged by the intrinsic damaged vascular endothelium chemotaxis of platelets, a platelet membrane-coated nanodrug (PM-HDOX) delivering doxorubicin (DOX) for postoperative GBM treatment is proposed and systematically investigated. Because surgery damages the vascular endothelium on the BBB around the surgical margin, the platelet membrane coating endows PM-HDOX with its inherent capacity to cross the broken BBB and target the surgical margin. Moreover, preoperative administration combined with fast-targeted PM-HDOX can realize the potential of bypassing thrombus. In GBM resection models, PM-HDOX with preoperative administration demonstrated significantly enhanced BBB-crossing and surgical margin-targeted efficacy. In particular, the PM-HDOX intensities around the surgical margins of the preoperative administration group were more than twice that of the postoperative administration group due to bypassing the thrombus formed in the broken BBB. In the antitumor experiment, the preoperative administration of PM-HDOX significantly inhibited the growth of postoperative residual tumors and prolonged the median survival time of mice. In conclusion, preoperative administration of a biomimetic platelet nanodrug can be an efficient and promising drug delivery strategy for residual GBM after surgery.

A prognostic pyroptosis-related LncRNA classifier associated with the immune landscape and therapy efficacy in glioma.

Background: Glioma has the highest fatality rate among intracranial tumours. Besides, the heterogeneity of gliomas leads to different therapeutic effects even with the same treatment. Developing a new signature for glioma to achieve the concept of "personalised medicine" remains a significant challenge. Method: The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were searched to acquire information on glioma patients. Initially, correlation and univariate Cox regression analyses were performed to screen for prognostic pyroptosis-related long noncoding RNAs (PRLs). Secondly, 11 PRLs were selected to construct the classifier using certain algorithms. The efficacy of the classifier was then detected by the "timeROC" package for both the training and validation datasets. CIBERSORT and ESTIMATE packages were applied for comparing the differences (variations) in the immune landscape between the high- and low-risk groups. Finally, the therapeutic efficacy of the chemotherapy, radiotherapy, and immunotherapy were assessed using the "oncoPredict" package, survival analysis, and the tumour immune dysfunction and exclusion (TIDE) score, respectively. Results: A classifier comprising 11 PRLs was constructed. The PRL classifier exhibits a more robust prediction capacity for the survival outcomes in patients with gliomas than the clinical characteristics irrespective of the dataset (training or validation dataset). Moreover, it was found that the tumour landscape between the low- and high-risk groups was significantly different. A high-risk score was linked to a more immunosuppressive tumour microenvironment. According to the outcome prediction and analysis of the chemotherapy, patients with different scores showed different responses to various chemotherapeutic drugs and immunotherapy. Meanwhile, the patient with glioma of WHO grade Ⅳ or aged >50 years in the high risk group had better survival following radiotherapy. Conclusion: We constructed a PRL classifier to roughly predict the outcome of patients with gliomas. Furthermore, the PRL classifier was linked to the immune landscape of glioma and may guide clinical treatments.