Blood-Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma.
Yulin ZhangKaiyan XiYuying ZhangZezheng FangYi ZhangKaijie ZhaoFan FengJianyu ShenMingrui WangRunlu ZhangBo ChengHuimin GengXingang LiBin HuangKang-Nan WangShilei NiPublished in: ACS nano (2024)
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.
Keyphrases
- oxidative stress
- blood brain barrier
- immune response
- mitochondrial dna
- induced apoptosis
- cell cycle arrest
- signaling pathway
- stem cells
- dna repair
- endothelial cells
- copy number
- photodynamic therapy
- gene expression
- drug delivery
- public health
- cell death
- room temperature
- cancer therapy
- toll like receptor
- dendritic cells
- solar cells
- dna damage
- nitric oxide
- risk assessment
- hydrogen peroxide
- optical coherence tomography
- ionic liquid
- optic nerve