Zhang Yulin, Xi Kaiyan, Zhang Yuying, Fang Zezheng, Zhang Yi, Zhao Kaijie, Feng Fan, Shen Jianyu, Wang Mingrui, Zhang Runlu, Cheng Bo, Geng Huimin, Li Xingang, Huang Bin, Wang Kang-Nan, Ni Shilei
Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan 250012, Shandong, China.
Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan 250117, Shandong, China.
ACS Nano. 2024 Apr 2;18(13):9511-9524. doi: 10.1021/acsnano.3c12434. Epub 2024 Mar 18.
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.
多形性胶质母细胞瘤（GBM）是人类脑肿瘤中最具侵袭性和致命性的类型。打破被抑制的免疫微环境是对抗GBM的一种有效治疗策略；然而，由于免疫原性低，GBM对外源性免疫治疗药物无反应。操纵线粒体电子传递链（ETC）可提高GBM的免疫原性，使先前具有免疫逃逸能力的肿瘤极易受到免疫监视，从而增强肿瘤免疫反应性，并随后激活先天性和适应性免疫。在此，我们报告一种基于纳米药物的免疫治疗方法，该方法利用一种受特洛伊木马启发的纳米载体（ABBPN）靶向GBM细胞中的线粒体，该纳米载体能够穿过血脑屏障。我们提出，合成光敏剂IrPS可通过将si-OGG1递送至GBM细胞来改变线粒体电子流，并同时干扰线粒体抗氧化机制。我们合成的同时负载IrPS和si-OGG1的ABBPN（ISA）破坏线粒体电子流，抑制ATP生成并诱导线粒体DNA氧化，从而招募免疫细胞并内源性激活颅内抗肿瘤免疫反应。我们的研究结果表明，靶向线粒体ETC的策略有可能治疗免疫原性有限的肿瘤。
