转铁蛋白受体
溶酶体
转铁蛋白
免疫疗法
小泡
细胞生物学
化学
生物
膜
免疫系统
免疫学
生物化学
酶
作者
Ling-Yan Su,Yang Tian,Qin Zheng,Yu Cao,Mengyu Yao,Shuangping Wang,Wen Xi,Chuyu Xi,Andrea Clocchiatti,Guangjun Nie,Hejiang Zhou
标识
DOI:10.1016/j.chembiol.2024.01.002
摘要
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 in vivo 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 in vivo. We have provided a modular and simple genetic strategy for lysosomal degradation as well as a delivery platform for in vivo tumor targeting. The study paves the way for the targeting and degradation of extracellular proteins using the TfR-LYTAC system.
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