抗脑瘤免疫中，居住的微胶质细胞是关键因素，而恶性病理性胶质瘤中，微胶质细胞的功能受损。目前很少研究免疫疗法来恢复微胶质细胞对胶质瘤的功能。在此研究中，我们将齐墩果酸（OA）（也被称为微胶质“修复剂”）和D PPA-1肽（免疫检查点阻断剂）整合到一个纳米免疫协同剂（D PAM@OA）中以共同发挥作用。OA自组装的核心覆盖着巨噬细胞膜，以实现高效的血脑屏障穿透和微胶质细胞靶向，D PPA-1肽通过酸敏感键连接到细胞膜上，以在肿瘤微环境中特异性释放。随着双药物在各自作用部位的增加积累，D PAM@OA通过抑制微胶质细胞中STAT-3通路的异常活化，有效促进效应T细胞的招募和激活，并通过阻止恶性病理性胶质瘤中免疫检查点蛋白的升高，帮助激活的效应T细胞消灭肿瘤细胞。最终，作为辅助疗法，这种明智设计的纳米免疫协同剂能够阻碍恶性病理性胶质瘤的进展和复发，无论是否使用替莫唑胺。我们的研究证明了基于微胶质细胞的免疫疗法纳米制剂的可行性，该研究结果可为脑肿瘤的治疗提供新方向。本文受版权保护。保留所有权利。

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy has been explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) were integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core was coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide was attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promoted the recruitment and activation of effector T cells by inhibiting aberrant activation of STAT-3 pathway in microglia, and assisted activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hindered malignant glioma progression and recurrence with or without temozolomide. Our work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.