Implantable Microneedle-Mediated Eradication of Postoperative Tumor Foci Mitigates Glioblastoma Relapse.

Glioblastoma multiforme (GBM) remains incurable despite multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin (2-3 cm) of the initial resected lesion due to the unreachable residual cancerous cells. Here, a completely biodegradable microneedle for surgical cavity delivery glioblastoma-associated macrophages (GAMs)-activating immune nano-stimulator that mitigates glioblastoma relapse is reported. The residual tumor lesion-directed biocompatible microneedle releases the nano-stimulator and toll-like receptor 9 agonist in a controlled manner until the microneedles completely degrade over 1 week, efferently induce in situ phonotypic shifting of GAMs from anti- to pro-inflammatory and the tumor recurrence is obviously inhibited. The implantable microneedles offer a significant improvement over conventional transdermal ones, as they are 100% degradable, ensuring safe application within surgical cavities. It is also revealed that the T cells are recruited to the tumor niche as the GAMs initiate anti-tumor response and eradicate residual GBM cells. Taken together, this work provides a potential strategy for immunomodulating the postoperative tumor niche to mitigate tumor relapse in GBM patients, which may have broad applications in other malignancies with surgical intervention.

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

Blood-Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive and lethal form of human brain tumors. Dismantling the suppressed immune microenvironment is an effective therapeutic strategy against GBM; however, GBM does not respond to exogenous immunotherapeutic agents due to low immunogenicity. Manipulating the mitochondrial electron transport chain (ETC) elevates the immunogenicity of GBM, rendering previously immune-evasive tumors highly susceptible to immune surveillance, thereby enhancing tumor immune responsiveness and subsequently activating both innate and adaptive immunity. Here, we report a nanomedicine-based immunotherapeutic approach that targets the mitochondria in GBM cells by utilizing a Trojan-inspired nanovector (ABBPN) that can cross the blood-brain barrier. We propose that the synthetic photosensitizer IrPS can alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. Our synthesized ABBPN coloaded with IrPS and si-OGG1 (ISA) disrupts mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses. The results of our study indicate that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

Versatile metal-phenolic network nanoparticles for multitargeted combination therapy and magnetic resonance tracing in glioblastoma.

Glioblastoma multiforme (GBM) is a common malignancy of the central nervous system, but conventional treatments yield unsatisfactory results. Although innovative therapeutic approaches have been developed, they prolong survival by only approximately 5 months. The heterogeneity of GBM renders growth inhibition with a single drug difficult, and exploring combination approaches with multiple targets for the comprehensive treatment of GBM is expected to overcome this limitation. In this study, we designed a biocompatible cRGD/Pt + DOX@GFNPs (RPDGs) nanoformulation to disrupt redox homeostasis in GBM cells and promote the simultaneous occurrence of efficient apoptosis and ferroptosis. Taking advantage of the highly stable Fenton reaction catalytic activity of gallic acid (GA)/Fe2+ nanoparticles in physiological environments, the ability of Pt (IV) to deplete glutathione (GSH) and increase reactive oxygen species (ROS) levels, and the efficient photothermal conversion efficiency of GA/Fe2+ nanoparticles, our synthesized multifunctional and multitargeted RPDGs significantly increased intracellular ROS levels and thus induced ferroptosis. Furthermore, the RPDGs displayed superior photothermal responsiveness and magnetic resonance imaging (MRI) capabilities. These results indicate that RPDGs can not only directly inhibit the growth of tumors but also effectively improve the efficient translocation of conventional chemotherapeutic drugs across the blood-brain barrier, thereby providing a new approach for the comprehensive treatment of GBM.

Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines.

Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P < 0.001). Protein levels of COPZ1 were significantly increased in GBM compared to non-neoplastic brain tissue samples in immunohistochemistry and western blot analysis. SiRNA knockdown of COPZ1 suppressed proliferation of U87MG, U251 and P3#GBM in vitro. Stable expression of a COPZ1 shRNA construct in U87MG inhibited tumor growth in vivo by ~60% relative to controls at day 21 after implantation (P < 0.001). Kaplan-Meier analysis of the survival data demonstrated that the overall survival of tumor bearing animals increased from 20.8 days (control) to 27.8 days (knockdown, P < 0.05). COPZ1 knockdown also led to the increase in nuclear receptor coactivator 4 (NCOA4), resulting in the degradation of ferritin, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. These data demonstrate that COPZ1 is a critical mediator in iron metabolism. The COPZ1/NCOA4/FTH1 axis is therefore a novel therapeutic target for the treatment of human GBM.

Glioblastoma Therapy Using Codelivery of Cisplatin and Glutathione Peroxidase Targeting siRNA from Iron Oxide Nanoparticles.

Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor in adults. Currently, interventions are lacking, the median overall survival of patients with GBM is less than 15 months, and the postoperative recurrence rate is greater than 60%. We proposed an innovative local chemotherapy involving the construction of gene therapy-based iron oxide nanoparticles (IONPs) as a treatment for patients with glioblastoma after surgery that targeted ferroptosis and apoptosis to address these problems. The porous structure of IONPs with attached carboxyl groups was modified for the codelivery of small interfering RNA (siRNA) targeting glutathione peroxidase 4 (si-GPX4) and cisplatin (Pt) with high drug loading efficiencies. The synthesized folate (FA)/Pt-si-GPX4@IONPs exerted substantial effects on glioblastoma in U87MG and P3#GBM cells, but limited effects on normal human astrocytes (NHAs). During intracellular degradation, IONPs significantly increased iron (Fe2+ and Fe3+) levels, while Pt destroyed nuclear DNA and mitochondrial DNA, leading to apoptosis. Furthermore, IONPs increased H2O2 levels by activating reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). The Fenton reaction between Fe2+, Fe3+, and intracellular H2O2 generated potent reactive oxygen species (ROS) to initiate ferroptosis, while the co-released si-GPX4 inhibited GPX4 expression and synergistically improved the therapeutic efficacy through a mechanism related to ferroptosis. As a result, superior therapeutic effects with low systemic toxicity were achieved both in vitro and in vivo, indicating that our nanoformulations might represent safe and efficient ferroptosis and apoptosis inducers for use in combinatorial glioblastoma therapy.

Knockdown of circHomer1 ameliorates METH-induced neuronal injury through inhibiting Bbc3 expression.

Current studies have illustrated that circular RNAs (circRNAs) are a vital part of non-coding RNA (ncRNAs) species and highly abundant and dynamically expressed in brain. However, the exact mechanisms by which circRNAs modulate methamphetamine (METH)-induced neuronal damage still remain largely unexplored. Consistent with our previous study, the expression of circHomer1 was significantly up-regulated after METH treatment in HT-22 cells. We confirmed its loop structure by detection of its back-splice junction with qRT-PCR product via sequence. Moreover, circHomer1 was resistant against RNase R digestion compared with its linear mRNA Homer1. Inhibition of circHomer1 expression indeed alleviated METH-induced neurotoxicity, with lower apoptosis rate via flow cytometry and cleaved Caspase3 protein level. Furthermore, we speculated that Bbc3 functioned as a target of circHomer1 based on computational algorithm, and knockdown of circHomer1 actually reduced Bbc3 expression at the mRNA and protein level. Besides, suppression of Bbc3 decreased the reactive oxygen species (ROS) level and radio of PI-positive cells. Furthermore, we analyzed the correlation in pairs among circHomer1, Bbc3 and behaviors in well-developed METH-addicted models using Pearson's correlation coefficient, which implied an important role of circHomer1 and Bbc3 in addictive behaviors. In all, we for the first time identified a novel circRNA, circHomer1 and our results suggested that circHomer1 regulated METH-induced lethal process by suppressing the Bbc3 expression.