An Engineered Nanovesicles-Based Lysosome-Targeting Protein Degradation Platform (NV-TACs) for Cancer Immunotherapy

作者：Youmei Xiao, Xiuman Zhou, Xiaoshuang Niu, Xiaoyun Ye, Danhong Chen, Qingyu Dong, Zhuoying He, Xia Yang, Mengfan Wang, Wenxuan Zeng, Ye Su, Feiyu Luo, Juan Liu, Yanfeng Gao · 发表于：Journal of the American Chemical Society · 年份：2026 · DOI：10.1021/jacs.5c17801 · 被引用次数：2 · 研究领域：Protein Degradation and Inhibitors、Nanoplatforms for cancer theranostics、Click Chemistry and Applications

Lysosome-Targeting Chimeras (LYTAC) technology offers a revolutionary approach for specifically degrading extracellular and membrane proteins. However, current LYTAC platforms face multiple technical challenges, including ligand screening, linker optimization, and the need to balance the characteristics between the protein of interest (POI) and lysosome-targeting receptor (LTR). To overcome these challenges, we engineered NV-TACs (Nanovesicle-based TArgeting Chimeras)─a linker-free LYTAC platform that integrates native nanovesicles displaying the endogenous ligands of POI and LTRs as bioinspired membrane protein degradation modules. As a proof-of-concept, PD-1 (as the binder of PD-L1) and transferrin (as the binder of transferrin receptor, TFRC) were engineered into biocompatible fibroblast-derived nanovesicles. This platform demonstrates significant scalability, allowing flexible module integration and functional assembly. NV-TACs efficiently degrade PD-L1 on tumor and immune cells through the TFRC-mediated specific lysosomal endocytosis pathway, and it has been expanded to the degradation of other membrane proteins. Notably, by incorporation of a therapeutic payload (ML210), NV-TACs simultaneously exhibited targeted protein degradation and ML210-mediated ferroptosis through payload delivery capacity. Both in anti-PD-1-responsive and -resistant tumor models, NV-TACs demonstrated significant therapeutic efficacy without obvious systemic toxicity. The platform of NV-TACs paves...