Abstract

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 new avenues for developing linker-free, modular, and bioinspired targeted protein degradation platforms.