The lysosome-targeting chimera (LYTAC) approach has shown promise for the targeted degradation of secreted and membrane proteins via lysosomes. However, there have been challenges in design, development, and targeting. Here, we have designed a genetically engineered transferrin receptor (TfR)-mediated lysosome-targeting chimera (TfR-LYTAC) that is efficiently internalized via TfR-mediate endocytosis and targets PD-L1 for lysosomal degradation in cultured cells but not due to short half-life and poor tumor targeting. A delivery platform was developed by fusing TfR-LYTAC to the surface of bacterial outer membrane vesicles (OMVs). The engineered OMV-LYTAC combines PD-1/PD-L1 pathway inhibition with LYTAC and immune activation by bacterial OMVs. OMV-LYTAC significantly reduced tumor growth . We have provided a modular and simple genetic strategy for lysosomal degradation as well as a delivery platform for tumor targeting. The study paves the way for the targeting and degradation of extracellular proteins using the TfR-LYTAC system.

中文翻译：

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使用与转铁蛋白受体介导的溶酶体靶向嵌合体融合的工程细菌外膜囊泡进行抗肿瘤免疫治疗

溶酶体靶向嵌合体 (LYTAC) 方法有望通过溶酶体靶向降解分泌蛋白和膜蛋白。然而，在设计、开发和目标定位方面存在挑战。在这里，我们设计了一种基因工程转铁蛋白受体 (TfR) 介导的溶酶体靶向嵌合体 (TfR-LYTAC)，它通过 TfR 介导的内吞作用有效内化，并靶向 PD-L1 以在培养细胞中进行溶酶体降解，但不是由于短半-寿命和肿瘤靶向性差。通过将 TfR-LYTAC 融合到细菌外膜囊泡 (OMV) 表面，开发了一个递送平台。工程化的 OMV-LYTAC 将 PD-1/PD-L1 通路抑制与 LYTAC 结合起来，并通过细菌 OMV 进行免疫激活。OMV-LYTAC 显着减少肿瘤生长。我们提供了用于溶酶体降解的模块化且简单的遗传策略以及用于肿瘤靶向的递送平台。该研究为使用 TfR-LYTAC 系统靶向和降解细胞外蛋白质铺平了道路。