As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma.

作为胶质母细胞瘤护理标准的关键组成部分，放疗可诱导多种免疫耐药机制，例如 CD47 和 PD-L1 的上调。在这里，利用这些放疗引发的过程，我们生成了一种桥接脂质纳米颗粒 （B-LNP），该颗粒通过抗 CD47/PD-L1 双重连接将肿瘤相关髓细胞 （TAMC） 与胶质母细胞瘤细胞结合。我们表明接合器 B-LNPs 阻断 CD47 和 PD-L1 并促进 TAMC 吞噬活性。为了增强肿瘤吞噬后随后的 T 细胞募集和抗肿瘤反应，B-LNP 用 diABZI 封装，diABZI 是一种用于刺激干扰素基因的非核苷酸激动剂。用负载 diABZI 的 B-LNPs 进行体内处理诱导 TAMC 中的转录组学和代谢转换，将这些免疫抑制细胞转化为抗肿瘤效应器，从而诱导脑肿瘤中的 T 细胞浸润和激活。在临床前小鼠模型中，B-LNP/diABZI 给药与放疗协同作用，促进脑肿瘤消退并诱导针对神经胶质瘤的免疫记忆。总之，我们的研究描述了一种基于纳米技术的方法，该方法劫持了辐射触发的免疫检查点分子，以增强针对胶质母细胞瘤的强大和持久的抗肿瘤免疫力。