Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8⁺ T lymphocytes and inhibit CD4⁺ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.

中文翻译：

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iRGD修饰的化学免疫治疗性纳米颗粒可增强针对胶质母细胞瘤的免疫治疗

胶质母细胞瘤是成人中最常见的原发性脑部肿瘤，由于药物在肿瘤区域的积聚有限，因此仍然无法治愈。本文中，开发了iRGD修饰的纳米颗粒DOX @ MSN‐SS‐iRGD＆1MT，用于将化学治疗剂（阿霉素，DOX）和免疫检查点抑制剂（1-甲基色氨酸，1MT）同时递送到原位神经胶质瘤中。纳米粒子由负载有DOX的中孔二氧化硅纳米粒子组成，并与1MT连接的Asp-Glu-Val-Asp（DEVD）结合，最后通过iRGD进行了改性。这些纳米颗粒具有穿透血脑屏障进入肿瘤区域的能力，并以最小的副作用显着提高了药物在原位脑肿瘤中的蓄积。纳米粒子还激活细胞毒性CD8 ⁺体外与脾细胞共培养的GL261细胞和体内GL261-luc原位肿瘤中的T淋巴细胞和抑制性CD4 ⁺ T细胞。此外，在脑肿瘤区域，抗肿瘤细胞因子IFNα/β，IFN-γ，TNF，IL-17，STING和GrzB的表达上调，而肿瘤蛋白p-STAT3和IL-10的表达下调。这项研究证明了在脑肿瘤区域积聚的化学免疫治疗性纳米颗粒的优势及其有效抑制肿瘤增殖的优势，这为促进针对胶质母细胞瘤的抗肿瘤免疫性提供了一个传递平台。