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

in ACS nano by Yulin Zhang, Kaiyan Xi, Yuying Zhang, Zezheng Fang, Yi Zhang, Kaijie Zhao, Fan Feng, Jianyu Shen, Mingrui Wang, Runlu Zhang, Bo Cheng, Huimin Geng, Xingang Li, Bin Huang, Kang-Nan Wang, Shilei Ni

TLDR

  • The study is about a new way to treat a type of brain tumor called Glioblastoma multiforme (GBM). GBM is very aggressive and hard to treat. The study found that by using a special kind of medicine called a nanomedicine, they could make the tumor more vulnerable to the immune system, which is the body's defense against infection and disease. The study used a special kind of medicine called IrPS to make the tumor more vulnerable to the immune system. The study found that the medicine was effective and could help treat GBM.

Abstract

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.

Overview

  • The study focuses on Glioblastoma multiforme (GBM), the most aggressive and lethal form of human brain tumors. The hypothesis being tested is that manipulating the mitochondrial electron transport chain (ETC) can elevate 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. The methodology used for the experiment includes the use of a Trojan-inspired nanovector (ABBPN) that can cross the blood-brain barrier and the synthetic photosensitizer IrPS to alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. The primary objective of the study is to disrupt mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the use of the Trojan-inspired nanovector (ABBPN) coloaded with the synthetic photosensitizer IrPS and si-OGG1 (ISA) versus control groups. The results indicate that the ISA treatment 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 study found that the ISA treatment significantly increased the recruitment of immune cells and the activation of intracranial antitumor immune responses compared to control groups. The key findings of the study suggest that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that manipulating the mitochondrial ETC can elevate 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. The study identifies limitations, such as the need for further preclinical studies to evaluate the safety and efficacy of the ISA treatment in animal models and the need for clinical trials to evaluate the safety and efficacy of the ISA treatment in human patients. Future research directions could include the development of new nanomedicine-based immunotherapeutic approaches that target the mitochondrial ETC and the evaluation of the safety and efficacy of these approaches in clinical trials.
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