Glioma is recognized as the most infiltrative and lethal form of central nervous system tumors and is known for its limited response to standard therapeutic interventions, high recurrence rate, and unfavorable prognosis. Recent progress in gene and immunotherapy presents a renewed sense of optimism in the treatment of glioblastoma. However, the barriers to overcome include the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB), as well as the suppressive immune microenvironment. Overcoming these barriers remains a significant challenge. Here, we developed a lipid nanoparticle platform incorporating a dual-functional peptide (cholesterol-DP7-ACP-T7-modified DOTAP or DAT-LNP) capable of targeting glioma across the BBB and BBTB for brain tumor immunotherapy. This system was designed to achieve two key functions. First, the system could effectively penetrate the BBB during accumulation within brain tissue following intravenous administration. Second, this system enhances the maturation of dendritic cells, the polarization of M1 macrophages, and the activation of cytotoxic CD8 T cells. This multifaceted approach effectively mitigates the immunosuppressive tumor microenvironment of glioma and promotes robust antitumor immune responses. Overall, the intravenous administration of the delivery system designed in this study demonstrates significant therapeutic potential for glioma and holds promising applications in the field of cancer immunotherapy.

中文翻译：

---

一种针对神经胶质瘤的血脑屏障和血脑肿瘤屏障穿透 siRNA 递送系统，用于脑肿瘤免疫治疗


神经胶质瘤被认为是最具浸润性和致命性的中枢神经系统肿瘤，因其对标准治疗干预的反应有限、复发率高和预后不良而闻名。基因和免疫疗法的最新进展让人们对胶质母细胞瘤的治疗产生了新的乐观情绪。然而，需要克服的障碍包括血脑屏障（BBB）和血脑肿瘤屏障（BBTB），以及抑制性免疫微环境。克服这些障碍仍然是一项重大挑战。在这里，我们开发了一种脂质纳米颗粒平台，其中包含双功能肽（胆固醇-DP7-ACP-T7-修饰的DOTAP或DAT-LNP），能够跨BBB和BBTB靶向神经胶质瘤，用于脑肿瘤免疫治疗。该系统旨在实现两个关键功能。首先，该系统在静脉注射后在脑组织内积聚期间可以有效地穿透血脑屏障。其次，该系统增强了树突状细胞的成熟、M1巨噬细胞的极化以及细胞毒性CD8 T细胞的激活。这种多方面的方法有效地减轻了神经胶质瘤的免疫抑制肿瘤微环境，并促进了强大的抗肿瘤免疫反应。总体而言，本研究设计的输送系统的静脉注射显示出对神经胶质瘤的显着治疗潜力，并在癌症免疫治疗领域具有广阔的应用前景。