Increased expression of immune check point genes, such as PD‐L1, is one of the main reasons for immunosuppression, especially for colon cancer. Development of novel therapeutic strategies is of great importance to improve the prognosis. In this study, outer membrane vesicles (OMV) derived from Gram‐negative bacteria are engineered to immune checkpoint blockade nanosystem for efficient elicitation of anti‐tumor immunity. Briefly, the OMVs are engineered with Lyp1‐Traptavidin (S52G, R53D mutant of streptavidin) fusion protein displayed on the surface. The Lyp‐1 endows the OMV with the capacity to target tumor tissues, while the Traptavidin ensures easy decoration of biotinylated anti‐PD‐L1 and biotinylated M6P (mannose 6‐phosphate). The simultaneously anchored anti‐PD‐L1 and M6P (ligand for cation‐independent mannose 6‐phosphate receptor) on the engineered OMVs coordinately direct the membrane PD‐L1 to lysosome for degradation, and thus unleash the anti‐tumor immunity. With syngeneic tumor model, the engineered OMVs are confirmed to boost immunity, inhibit cancer growth, and thus prolong survival. Together, A proposed OMV‐based modular nanosystem that enables assembly of biotinylated anti‐PD‐L1 and M6P on the surface for tumor‐targeted immune checkpoint blockade.

中文翻译：

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溶酶体靶向细菌外膜囊泡用于肿瘤特异性降解 PD-L1


免疫检查点基因（例如 PD-L1）表达增加是免疫抑制的主要原因之一，尤其是结肠癌。开发新的治疗策略对于改善预后具有重要意义。在这项研究中，源自革兰氏阴性菌的外膜囊泡（OMV）被设计成免疫检查点封锁纳米系统，以有效激发抗肿瘤免疫。简而言之，OMV 是用表面展示的 Lyp1-Traptavidin（链霉亲和素的 S52G、R53D 突变体）融合蛋白进行工程改造的。 Lyp-1 赋予 OMV 靶向肿瘤组织的能力，而 Traptavidin 确保生物素化抗 PD-L1 和生物素化 M6P（甘露糖 6-磷酸）的轻松修饰。工程化 OMV 上同时锚定的抗 PD-L1 和 M6P（阳离子非依赖性甘露糖 6-磷酸受体的配体）协调地将膜 PD-L1 引导至溶酶体进行降解，从而释放抗肿瘤免疫。通过同基因肿瘤模型，工程化 OMV 被证实可以增强免疫力、抑制癌症生长，从而延长生存期。总之，提出了一种基于 OMV 的模块化纳米系统，能够在表面组装生物素化的抗 PD-L1 和 M6P，用于肿瘤靶向免疫检查点阻断。